Trial Outcomes & Findings for Phase 2 Study of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC) (NCT NCT02038647)

NCT ID: NCT02038647

Last Updated: 2018-12-27

Results Overview

PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 178 participants
• Primary outcome timeframe: Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)
• Results posted on: 2018-12-27

Participant Flow

Participants took part in the study at 54 investigative sites in the United States, Canada, European Union (Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland and Spain) from 12 May 2014 to 10 July 2017. Data cutoff for the primary analysis was 3 January 2016.

Participants with a diagnosis of Small Cell Lung Cancer (SCLC) were enrolled in 1 of 2 treatment groups: alisertib + paclitaxel or placebo + paclitaxel arm group.

Participant milestones

Measure	Alisertib + Paclitaxel Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Overall Study STARTED	89	89
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	89	89

Reasons for withdrawal

Measure	Alisertib + Paclitaxel Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Overall Study Progressive Disease	50	59
Overall Study Adverse Event	18	10
Overall Study Symptomatic Deterioration	7	7
Overall Study Withdrawal by Subject	5	2
Overall Study Not Reported	0	1
Overall Study Ongoing at Datacut	9	10

Baseline Characteristics

Height data is available for n=86,87 participants respectively.

Baseline characteristics by cohort

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).	Total n=178 Participants Total of all reporting groups
Region of Enrollment United States	35 participants n=89 Participants	35 participants n=89 Participants	70 participants n=178 Participants
Weight	78.47 kg STANDARD_DEVIATION 20.561 • n=89 Participants	75.26 kg STANDARD_DEVIATION 17.602 • n=89 Participants	76.87 kg STANDARD_DEVIATION 19.153 • n=178 Participants
Height	169.5 cm STANDARD_DEVIATION 10.43 • n=86 Participants • Height data is available for n=86,87 participants respectively.	168.8 cm STANDARD_DEVIATION 9.52 • n=87 Participants • Height data is available for n=86,87 participants respectively.	169.2 cm STANDARD_DEVIATION 9.96 • n=173 Participants • Height data is available for n=86,87 participants respectively.
Age, Continuous	61.8 years STANDARD_DEVIATION 8.55 • n=89 Participants	63.4 years STANDARD_DEVIATION 8.56 • n=89 Participants	62.6 years STANDARD_DEVIATION 8.57 • n=178 Participants
Sex: Female, Male Female	38 Participants n=89 Participants	39 Participants n=89 Participants	77 Participants n=178 Participants
Sex: Female, Male Male	51 Participants n=89 Participants	50 Participants n=89 Participants	101 Participants n=178 Participants
Race/Ethnicity, Customized Hispanic or Latino	2 participants n=89 Participants	3 participants n=89 Participants	5 participants n=178 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	81 participants n=89 Participants	84 participants n=89 Participants	165 participants n=178 Participants
Race/Ethnicity, Customized Unknown or Not Reported	6 participants n=89 Participants	1 participants n=89 Participants	7 participants n=178 Participants
Race/Ethnicity, Customized Missing	0 participants n=89 Participants	1 participants n=89 Participants	1 participants n=178 Participants
Race/Ethnicity, Customized White	83 participants n=89 Participants	83 participants n=89 Participants	166 participants n=178 Participants
Race/Ethnicity, Customized Black or African American	3 participants n=89 Participants	2 participants n=89 Participants	5 participants n=178 Participants
Race/Ethnicity, Customized Not reported	2 participants n=89 Participants	2 participants n=89 Participants	4 participants n=178 Participants
Race/Ethnicity, Customized Asian	1 participants n=89 Participants	0 participants n=89 Participants	1 participants n=178 Participants
Race/Ethnicity, Customized Other	0 participants n=89 Participants	1 participants n=89 Participants	1 participants n=178 Participants
Region of Enrollment Belgium	8 participants n=89 Participants	8 participants n=89 Participants	16 participants n=178 Participants
Region of Enrollment Czech Republic	6 participants n=89 Participants	5 participants n=89 Participants	11 participants n=178 Participants
Region of Enrollment France	7 participants n=89 Participants	5 participants n=89 Participants	12 participants n=178 Participants
Region of Enrollment Germany	2 participants n=89 Participants	1 participants n=89 Participants	3 participants n=178 Participants
Region of Enrollment Hungary	16 participants n=89 Participants	15 participants n=89 Participants	31 participants n=178 Participants
Region of Enrollment Italy	2 participants n=89 Participants	0 participants n=89 Participants	2 participants n=178 Participants
Region of Enrollment Poland	1 participants n=89 Participants	3 participants n=89 Participants	4 participants n=178 Participants
Region of Enrollment Spain	6 participants n=89 Participants	11 participants n=89 Participants	17 participants n=178 Participants
Region of Enrollment Canada	6 participants n=89 Participants	6 participants n=89 Participants	12 participants n=178 Participants
Body Surface Area	1.911 m^2 STANDARD_DEVIATION 0.2829 • n=86 Participants • Body Surface Area data is available for n=86,87 participants respectively.	1.872 m^2 STANDARD_DEVIATION 0.2433 • n=87 Participants • Body Surface Area data is available for n=86,87 participants respectively.	1.891 m^2 STANDARD_DEVIATION 0.2637 • n=173 Participants • Body Surface Area data is available for n=86,87 participants respectively.

PRIMARY outcome

Timeframe: Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)

Population: The intent-to-treat (ITT) population was defined as all participants who were randomized to study treatment. For participants who have not progressed and is last known to be alive, PFS was censored at the last response assessment that is stable disease (SD) or better as determined by Investigator, and analyzed using FDA Guidelines.

PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines	101 days Interval 80.0 to 113.0	66 days Interval 53.0 to 83.0

SECONDARY outcome

Timeframe: From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months)

Population: The safety population was defined as all participants who received at least 1 dose of any study drug.

An Adverse Event (AE) is defined as any untoward medical occurrence in clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. An AE can be any unfavorable and unintended sign (eg, clinically significant abnormal laboratory finding), symptom, or disease temporally associated with use of drug, whether or not it is considered related to drug. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests significant hazard, contraindication, side effect or precaution that:results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is congenital anomaly/birth defect or is medically significant per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

Outcome measures

Measure	Alisertib + Paclitaxel n=87 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	99 percentage of participants	96 percentage of participants
Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	44 percentage of participants	31 percentage of participants

SECONDARY outcome

Timeframe: Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months)

Population: The ITT population was defined as all participants who were randomized to study treatment. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

OS was defined as the time in days from the date of randomization to the date of death due to any cause.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Overall Survival (OS)	186 days Interval 150.0 to 219.0	165 days Interval 128.0 to 183.0

SECONDARY outcome

Timeframe: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment.

ORR is defined as the percentage of participants who achieved CR or partial response (PR) as best response based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Overall Response Rate (ORR)	22 percentage of participants Interval 14.0 to 33.0	18 percentage of participants Interval 11.0 to 28.0

SECONDARY outcome

Timeframe: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment.

CRR is defined as the percentage of participants who achieved CR as best response and based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Complete Response Rate (CRR)	1 percentage of participants Interval 1.0 to 6.0	0 percentage of participants Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment.

DCR was defined as the percentage of participants who achieved CR, PR, or SD (when SD was a minimum of 8 weeks in duration). Duration of SD was defined as the time from the date of randomization to the date of first documentation of disease progression for participants who achieved SD as their best overall response. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Disease Control Rate (DCR)	58 percentage of participants Interval 47.0 to 69.0	46 percentage of participants Interval 35.0 to 57.0

SECONDARY outcome

Timeframe: From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment. Responders were evaluated for this outcome measure. Responders without documentation of PD were censored at their date of last response assessment that was SD or better.

DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders. PR was defined as ≥ 30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Outcome measures

Measure	Alisertib + Paclitaxel n=20 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=16 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Duration of Response (DOR)	96 days Interval 84.0 to 141.0	85 days Interval 58.0 to 177.0

SECONDARY outcome

Timeframe: Baseline up to Cycle 5 (approximately 4.6 months)

Population: The ITT population was defined as all participants who were randomized to study treatment. Here number of participants analyzed are participants evaluated in this outcome measure at the specific timepoint.

European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions use 7-point scale (1=very poor - 7=Excellent). Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the quality of life (QL) of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. The change between (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) score collected at Cycle 5 relative to baseline.

Outcome measures

Measure	Alisertib + Paclitaxel n=20 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=15 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 Change at Cycle 5, QLQ-LC-13 Cough Scale	-10.94 score on a scale Standard Error 3.07	8.07 score on a scale Standard Error 6.04
Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 Change at Cycle 5, QLQ-C30 Dyspnea Scale	-3.48 score on a scale Standard Error 4.25	-1.09 score on a scale Standard Error 2.92
Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 Change at Cycle 5, QLQ-C30 Pain Scale	-4.82 score on a scale Standard Error 4.86	-4.88 score on a scale Standard Error 5.16

SECONDARY outcome

Timeframe: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment. Participants without coughing/dyspnea/pain relief were censored at their last assessment.

Percentage of participants experiencing symptom relief, including coughing relief, dyspnea relief, and pain relief. Coughing relief is defined as a decrease from baseline ≥ 10 in QLQ-LC13 cough scale/item score. Dyspnea relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 dyspnea scale/item score. Pain relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales, 1 global health status scale, 3 symptom scales, 6 single items. Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the QL of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Percentage of Participants Experiencing Symptom Relief Coughing Relief	28 percentage of participants Interval 19.0 to 39.0	24 percentage of participants Interval 15.0 to 34.0
Percentage of Participants Experiencing Symptom Relief Dyspnea Relief	31 percentage of participants Interval 22.0 to 42.0	16 percentage of participants Interval 9.0 to 25.0
Percentage of Participants Experiencing Symptom Relief Pain Relief	39 percentage of participants Interval 29.0 to 50.0	36 percentage of participants Interval 26.0 to 47.0

SECONDARY outcome

Timeframe: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment. Participants without coughing/dyspnea/pain relief were censored at their last assessment.

Time to symptom (coughing/dyspnea/pain) relief was defined as the time from the date of randomization to the date of first detection of coughing/dyspnea/pain relief, respectively.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Time to Symptom Relief Time to Coughing Relief	NA months Interval 7.6 to Median and Upper Limit of Confidence Interval (CI) were not estimable due to low number of participants with events.	NA months Median, Lower and Upper Limit of CI were not estimable due to low number of participants with events.
Time to Symptom Relief Time to Dyspnea Relief	NA months Median, Lower and Upper Limit of CI were not estimable due to low number of participants with events.	NA months Median, Lower and Upper Limit of CI were not estimable due to low number of participants with events.
Time to Symptom Relief Time to Pain Relief	3.0 months Interval 1.9 to Upper Limit of CI was not reached due to low number of participants with events.	3.7 months Interval 1.1 to Upper limit of CI was not reached due to low number of participants with events.

SECONDARY outcome

Timeframe: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Population: The ITT population was defined as all participants who were randomized to study treatment. Participant without coughing/dyspnea/pain progression were censored at their last assessment.

Time to coughing/dyspnea/pain progression was defined as time from the date of randomization to date of first detection of progression. Coughing progression was defined as increase from baseline ≥10 in QLQ-LC13 cough scale/item score. Dyspnea progression was defined as increase from baseline ≥10 in QLQ-C30 dyspnea scale/item score. Pain progression was defined as increase from baseline ≥10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-LC13 is 13-item scale for assessing treatment-specific symptoms in lung cancer. Total Score= 0-100 scale; for 5 functional scales and global quality-of-life scale, higher score=better level of functioning. For symptoms scale, higher score=higher level of symptoms.

Outcome measures

Measure	Alisertib + Paclitaxel n=89 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 Participants Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Time to Symptom Progression Time to Coughing Progression	NA months Median, Lower and Upper Limit of CI were not estimable due to low number of participants with events.	2.8 months Interval 2.2 to 6.3
Time to Symptom Progression Time to Dyspnea Progression	3.7 months Interval 1.9 to Upper Limit of CI was not estimable due to low number of participants with events.	4.6 months Interval 1.9 to 6.3
Time to Symptom Progression Time to Pain Progression	2.9 months Interval 2.1 to Upper Limit of CI was not estimable due to low number of participants with events.	2.8 months Interval 1.9 to Upper Limit of CI was not estimable due to low number of participants with events.

SECONDARY outcome

Timeframe: Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours (hrs) post-dose

Population: Safety population was defined as all participants who received at least 1 dose of any study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Outcome measures

Measure	Alisertib + Paclitaxel n=87 Participants Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Observed Plasma Concentration for Alisertib Cycle 1, Day 1, Pre-Dose	0 nM Standard Deviation 0	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 1, 1 hr Post-Dose	495.37 nM Standard Deviation 663.456	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 1, 2-4 hrs Post-Dose	861.18 nM Standard Deviation 616.951	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 1, 3-6 hrs Post-Dose	1048.88 nM Standard Deviation 716.447	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 1, 10-11 hrs Post-Dose	539.15 nM Standard Deviation 291.170	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 8, 2 hrs Post-Dose	897.41 nM Standard Deviation 816.387	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 15, 6-9 hrs Post-Dose (1st Sample)	1102.93 nM Standard Deviation 612.265	—
Observed Plasma Concentration for Alisertib Cycle 1, Day 15, 6-9 hrs Post-Dose (2nd Sample)	976.92 nM Standard Deviation 572.090	—

SECONDARY outcome

Timeframe: Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours post-dose

Population: Due to change in planned analysis, data was only collected and summarized for alisertib not for paclitaxel.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Day 1 cycle 1 in a 28-day cycle

Population: This is an exploratory endpoint.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Population: This is an exploratory endpoint.

Outcome measures

Outcome data not reported

Adverse Events

Alisertib + Paclitaxel

Serious events: 39 serious events

Other events: 85 other events

Deaths: 12 deaths

Placebo + Paclitaxel

Serious events: 30 serious events

Other events: 80 other events

Deaths: 11 deaths

Serious adverse events

Measure	Alisertib + Paclitaxel n=87 participants at risk Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 participants at risk Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Blood and lymphatic system disorders Febrile neutropenia	10.3% 9/87 • Number of events 12 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Neutropenia	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Anaemia	2.3% 2/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Leukopenia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Pancytopenia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Diarrhoea	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Stomatitis	4.6% 4/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Abdominal pain	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Vomiting	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	2.2% 2/89 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Constipation	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Neutropenic sepsis	2.3% 2/87 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Bacteraemia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Sepsis	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Septic shock	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Pneumonia	3.4% 3/87 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Pneumocystis jirovecii infection	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Pneumocystis jirovecii pneumonia	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Fungal infection	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Oral herpes	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Respiratory tract infection	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Influenza	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to meninges	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to peritoneum	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	2.3% 2/87 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioblastoma	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Respiratory failure	3.4% 3/87 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.1% 1/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.3% 2/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	1.1% 1/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Cardiac disorders Cardiac failure	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Cardiac disorders Acute coronary syndrome	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Cardiac disorders Angina pectoris	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Cardiac disorders Pericardial effusion	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	2.2% 2/89 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders General physical health deterioration	3.4% 3/87 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Fatigue	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Pyrexia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Systemic inflammatory response syndrome	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Dehydration	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	2.2% 2/89 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Diabetic metabolic decompensation	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Hypokalaemia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Epilepsy	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Seizure	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Ataxia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Cognitive disorder	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Neuropathy peripheral	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Back pain	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	2.2% 2/89 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Psychiatric disorders Confusional state	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Psychiatric disorders Mental status changes	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Vascular disorders Aortic thrombosis	1.1% 1/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Vascular disorders Embolism	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Injury, poisoning and procedural complications Fall	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Paraplegia	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Hepatobiliary disorders Bile duct stenosis	1.1% 1/87 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	0.00% 0/89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Erysipelas	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.

Other adverse events

Measure	Alisertib + Paclitaxel n=87 participants at risk Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m\^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Placebo + Paclitaxel n=89 participants at risk Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m\^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Gastrointestinal disorders Constipation	9.2% 8/87 • Number of events 11 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	23.6% 21/89 • Number of events 25 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Abdominal pain	13.8% 12/87 • Number of events 13 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	3.4% 3/89 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Diarrhoea	55.2% 48/87 • Number of events 104 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	20.2% 18/89 • Number of events 32 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Nausea	34.5% 30/87 • Number of events 43 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	33.7% 30/89 • Number of events 38 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Vomiting	32.2% 28/87 • Number of events 45 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	21.3% 19/89 • Number of events 27 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Stomatitis	31.0% 27/87 • Number of events 49 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Abdominal pain upper	8.0% 7/87 • Number of events 9 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 6 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Dyspepsia	9.2% 8/87 • Number of events 9 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	4.5% 4/89 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.7% 5/87 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Gastrointestinal disorders Dysphagia	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	3.4% 3/89 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Fatigue	43.7% 38/87 • Number of events 52 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	31.5% 28/89 • Number of events 35 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Asthenia	16.1% 14/87 • Number of events 32 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	12.4% 11/89 • Number of events 16 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Oedema peripheral	6.9% 6/87 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	11.2% 10/89 • Number of events 14 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Pyrexia	9.2% 8/87 • Number of events 8 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
General disorders Non-cardiac chest pain	4.6% 4/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Anaemia	43.7% 38/87 • Number of events 55 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	20.2% 18/89 • Number of events 23 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Neutropenia	47.1% 41/87 • Number of events 89 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	7.9% 7/89 • Number of events 11 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Leukopenia	13.8% 12/87 • Number of events 18 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 8 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Blood and lymphatic system disorders Thrombocytopenia	8.0% 7/87 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	3.4% 3/89 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Decreased appetite	33.3% 29/87 • Number of events 36 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	21.3% 19/89 • Number of events 26 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Hypokalaemia	11.5% 10/87 • Number of events 12 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Dehydration	8.0% 7/87 • Number of events 8 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	4.5% 4/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Hypomagnesaemia	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 10 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Hypocalcaemia	8.0% 7/87 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Metabolism and nutrition disorders Hyperglycaemia	5.7% 5/87 • Number of events 6 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 1 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	24.1% 21/87 • Number of events 23 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	21.3% 19/89 • Number of events 22 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Cough	19.5% 17/87 • Number of events 19 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	19.1% 17/89 • Number of events 18 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Productive cough	4.6% 4/87 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	10.1% 9/89 • Number of events 12 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Epistaxis	3.4% 3/87 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	7.9% 7/89 • Number of events 10 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Respiratory, thoracic and mediastinal disorders Dysphonia	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	3.4% 3/89 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Dizziness	17.2% 15/87 • Number of events 17 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	10.1% 9/89 • Number of events 14 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Headache	10.3% 9/87 • Number of events 9 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Neuropathy peripheral	9.2% 8/87 • Number of events 10 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	7.9% 7/89 • Number of events 10 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Paraesthesia	4.6% 4/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 9 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Hypoaesthesia	4.6% 4/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 6 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Somnolence	5.7% 5/87 • Number of events 6 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	3.4% 3/89 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Nervous system disorders Dysgeusia	2.3% 2/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Arthralgia	10.3% 9/87 • Number of events 12 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 10 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Muscular weakness	6.9% 6/87 • Number of events 6 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 11 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Back pain	5.7% 5/87 • Number of events 8 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 9 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.6% 4/87 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Pain in extremity	3.4% 3/87 • Number of events 3 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 8 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Investigations Neutrophil count decreased	16.1% 14/87 • Number of events 28 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	4.5% 4/89 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Investigations Weight decreased	14.9% 13/87 • Number of events 18 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Investigations White blood cell count decreased	13.8% 12/87 • Number of events 20 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	1.1% 1/89 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Skin and subcutaneous tissue disorders Alopecia	16.1% 14/87 • Number of events 15 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.00% 0/87 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	6.7% 6/89 • Number of events 10 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Psychiatric disorders Insomnia	8.0% 7/87 • Number of events 7 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	7.9% 7/89 • Number of events 8 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Psychiatric disorders Confusional state	2.3% 2/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Vascular disorders Hypertension	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	12.4% 11/89 • Number of events 13 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Injury, poisoning and procedural complications Fall	5.7% 5/87 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	3.4% 3/89 • Number of events 4 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Infections and infestations Upper respiratory tract infection	2.3% 2/87 • Number of events 2 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.	5.6% 5/89 • Number of events 5 • First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days) At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.

Additional Information

Medical Director

Takeda

Phone: +1-877-825-3327

Email: trialdisclosures@takeda.com

Results disclosure agreements

• Principal investigator is a sponsor employee In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
• Publication restrictions are in place

Restriction type: OTHER