Trial Outcomes & Findings for A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of Alisertib in Participants With Advanced Solid Tumors or Relapsed/Refractory Lymphoma (NCT NCT02259010)

NCT ID: NCT02259010

Last Updated: 2019-09-20

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

24 participants

Primary outcome timeframe

Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose in Cycle 1 for alisertib without itraconazole arm; Day 10 pre-dose and at multiple time points (up to 96 hours) post-dose in Cycle 1 for alisertib with itraconazole arm

Results posted on

2019-09-20

Participant Flow

Participants took part in the study at 4 investigative sites in the United States from 22 October 2014 to 21 October 2016. Data cutoff for the primary analysis was 27 March 2015.

Participants with a diagnosis of advanced solid tumors or lymphomas were enrolled to receive alisertib 30 mg tablets, orally along with itraconazole 200 mg, oral solution in part A followed by alisertib 50 mg, tablets in part B.

Participant milestones

Participant milestones
Measure	Part A: Alisertib 30 mg+Itraconazole; Part B: Alisertib 50 mg All participants were to complete Part A prior to Part B. Part A: Alisertib 30 mg, tablets, orally, on Days 1 and 10 plus itraconazole, 200 mg, oral solution, once daily on Days 5 to 13. Part A and B were separated by a washout period of at least 10 days (and up to 4 weeks). Part B: Alisertib 50 mg, tablets, orally, twice daily, for 7 days in 21-day cycles until disease progression or unacceptable toxicity (up to 16 cycles).
Overall Study STARTED	24
Overall Study COMPLETED	19
Overall Study NOT COMPLETED	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A: Alisertib 30 mg+Itraconazole; Part B: Alisertib 50 mg All participants were to complete Part A prior to Part B. Part A: Alisertib 30 mg, tablets, orally, on Days 1 and 10 plus itraconazole, 200 mg, oral solution, once daily on Days 5 to 13. Part A and B were separated by a washout period of at least 10 days (and up to 4 weeks). Part B: Alisertib 50 mg, tablets, orally, twice daily, for 7 days in 21-day cycles until disease progression or unacceptable toxicity (up to 16 cycles).
Overall Study Didn't Completed Dosing; PK Assessment	5

Baseline Characteristics

A Study to Evaluate the Effect of Itraconazole on the Pharmacokinetics of Alisertib in Participants With Advanced Solid Tumors or Relapsed/Refractory Lymphoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part A: Alisertib 30 mg+Itraconazole; Part B: Alisertib 50 mg n=24 Participants All participants were to complete Part A prior to Part B. Part A: Alisertib 30 mg, tablets, orally, on Days 1 and 10 plus itraconazole, 200 mg, oral solution, once daily on Days 5 to 13. Part A and B were separated by a washout period of at least 10 days (and up to 4 weeks). Part B: Alisertib 50 mg, tablets, orally, twice daily, for 7 days in 21-day cycles until disease progression or unacceptable toxicity (up to 16 cycles).
Age, Continuous	61.0 years STANDARD_DEVIATION 9.52 • n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	1 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	20 Participants n=5 Participants
Race/Ethnicity, Customized Not Reported	3 Participants n=5 Participants
Race/Ethnicity, Customized White	20 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants
Region of Enrollment United States	24 Participants n=5 Participants
Height	168.3 cm STANDARD_DEVIATION 8.99 • n=5 Participants
Weight	85.55 kg STANDARD_DEVIATION 25.641 • n=5 Participants
Body Surface Area	1.983 m^2 STANDARD_DEVIATION 0.3024 • n=5 Participants

PRIMARY outcome

Timeframe: Day 1 pre-dose and at multiple time points (up to 96 hours) post-dose in Cycle 1 for alisertib without itraconazole arm; Day 10 pre-dose and at multiple time points (up to 96 hours) post-dose in Cycle 1 for alisertib with itraconazole arm

Population: Pharmacokinetic (PK) -Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=19 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=19 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Cmax: Maximum Observed Concentration of Alisertib in Presence and Absence of Itraconazole in Part A	1060.3 nmol/L Standard Deviation 403.90	1002.8 nmol/L Standard Deviation 263.81

PRIMARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=19 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=19 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alisertib in Presence and Absence of Itraconazole in Part A	15541.6 hr*nmol/L Standard Deviation 9119.52	20219.5 hr*nmol/L Standard Deviation 9930.93

PRIMARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters. Here number of participants analyzed are the participants who were evaluable for this outcome measure at specified time points.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=13 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=15 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity of Alisertib in Presence and Absence of Itraconazole in Part A	16804.6 hr*nmol/L Standard Deviation 9232.87	23488.7 hr*nmol/L Standard Deviation 13262.31

SECONDARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters. Here, number of participants analyzed are the total number of participants who were evaluable to this outcome measure at specified endpoint.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=13 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=15 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
CL/F: Oral Clearance of Alisertib in Presence and Absence of Itraconazole in Part A	4.416 L/hr Standard Deviation 2.4007	3.177 L/hr Standard Deviation 1.5765

SECONDARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=19 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=19 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Tmax: Time to Reach Maximum Plasma Concentration of Alisertib in Presence and Absence of Itraconazole in Part A	2.920 hr Full Range 2.3710 • Interval 1.07 to 10.0	2.920 hr Full Range 2.0244 • Interval 1.83 to 7.82

SECONDARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters. Here, number of participants analyzed are the total number of participants who were evaluable to this outcome measure at specified endpoint.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=13 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=15 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Terminal Phase Elimination Half-Life of Alisertib in Presence and Absence of Itraconazole in Part A	22.55 hr Standard Deviation 10.316	25.37 hr Standard Deviation 9.215

SECONDARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters. Here, number of participants analyzed are the total number of participants who were evaluable to this outcome measure at specified endpoint.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=18 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=19 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 in Presence and Absence of Itraconazole in Part A Metabolite 2 (M2)	114.0 nmol/L Standard Deviation 52.71	103.5 nmol/L Standard Deviation 99.28
Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 in Presence and Absence of Itraconazole in Part A Metabolite 1 (M1)	409.4 nmol/L Standard Deviation 479.92	450.0 nmol/L Standard Deviation 664.65

SECONDARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters. Here, number of participants analyzed are the total number of participants who were evaluable to this outcome measure at specified endpoint.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=18 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=19 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib Metabolites M1 and M2 in Presence and Absence of Itraconazole in Part A Metabolite 1 (M1)	3.090 hr Interval 1.0 to 23.1	3.800 hr Interval 1.98 to 10.0
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib Metabolites M1 and M2 in Presence and Absence of Itraconazole in Part A Metabolite 2 (M2)	9.360 hr Interval 2.95 to 47.7	23.600 hr Interval 5.73 to 95.3

SECONDARY outcome

Population: PK-Evaluable Population included participants who completed the protocol-specified dosing at Part A and had sufficient PK assessment to reliably estimate PK parameters. Here, number of participants analyzed are the total number of participants who were evaluable to this outcome measure at specified endpoint.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=18 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole n=19 Participants Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 in Presence and Absence of Itraconazole in Part A Metabolite 1 (M1)	10550.8 hr*nmol/L Standard Deviation 17276.38	15776.1 hr*nmol/L Standard Deviation 29461.34
AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 in Presence and Absence of Itraconazole in Part A Metabolite 2 (M2)	5880.6 hr*nmol/L Standard Deviation 3404.27	5081.6 hr*nmol/L Standard Deviation 3334.41

SECONDARY outcome

Timeframe: First dose of study drug to 30 days after the last dose of study drug (up to 12 months)

Population: Safety Population is defined as all participants who received at least 1 dose of any study drug and were used for all safety analyses. Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.

An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE is any experience that suggests a 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 a congenital anomaly/birth defect or is medically significant. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=24 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) AEs	24 Participants	—
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	12 Participants	—

SECONDARY outcome

Timeframe: First dose of study drug to 30 days after the last dose of study drug (up to 12 months)

Standard safety laboratory tests included Chemistry and Hematology. Abnormal laboratory values that led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or were considered by the investigator to be a clinically significant change from baseline were reported as AEs.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=24 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Number of Participants With Abnormal Laboratory Values Reported as AEs Hypokalemia	3 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Elevated blood creatinine	3 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Increased international normalized ratio	2 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Hypercalcemia	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Hypomagnesemia	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Hypoalbuminemia	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Decreased blood potassium	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Decreased blood sodium	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Elevated blood alkaline phosphatase	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Anemia	5 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Neutropenia	4 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Leukopenia	2 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Thrombocytopenia	2 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Decreased lymphocyte count	2 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Decreased white blood cell count	1 Participants	—
Number of Participants With Abnormal Laboratory Values Reported as AEs Decreased platelet count	1 Participants	—

SECONDARY outcome

Timeframe: First dose of study drug to 30 days after the last dose of study drug (up to 12 months)

Change relative to baseline in participant's weight measured throughout study.

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=24 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Number of Participants With Clinically Significant Change in Weight Reported as AEs	2 Participants	—

SECONDARY outcome

Timeframe: First dose of study drug to 30 days after the last dose of study drug (up to 12 months)

Vital signs will include body temperature (oral), sitting blood pressure (after the participant has rested for at least 5 minutes), and pulse (bpm).

Outcome measures

Outcome measures
Measure	Alisertib Without Itraconazole n=24 Participants Alisertib 30 mg, tablets, orally, on Day 1 in Part A.	Alisertib With Itraconazole Itraconazole, 200 mg, oral solution, once daily on Days 5 to 13 along with alisertib 30 mg, tablets, orally, on Day 10 in Part A .
Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs Palpitations	2 Participants	—
Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs Pyrexia	3 Participants	—
Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs Tachycardia	1 Participants	—

Adverse Events

Part A: Alisertib 30 mg+Itraconazole; Part B: Alisertib 50 mg

Serious events: 12 serious events

Other events: 24 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Part A: Alisertib 30 mg+Itraconazole; Part B: Alisertib 50 mg n=24 participants at risk All participants were to complete Part A prior to Part B. Part A: Alisertib 30 mg, tablets, orally, on Days 1 and 10 plus itraconazole, 200 mg, oral solution, once daily on Days 5 to 13. Part A and B were separated by a washout period of at least 10 days (and up to 4 weeks). Part B: Alisertib 50 mg, tablets, orally, twice daily, for 7 days in 21-day cycles until disease progression or unacceptable toxicity (up to 16 cycles).
Gastrointestinal disorders Abdominal pain	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Constipation	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Intestinal obstruction	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Vomiting	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Gastrointestinal haemorrhage	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Melaena	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Cellulitis	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Herpes zoster disseminated	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Pneumonia	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Sepsis	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Blood and lymphatic system disorders Anaemia	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Gait disturbance	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Disease progression	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Injury, poisoning and procedural complications Hip fracture	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Metabolism and nutrition disorders Dehydration	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Musculoskeletal and connective tissue disorders Arthralgia	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Glioblastoma	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Nervous system disorders Haemorrhage intracranial	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Psychiatric disorders Confusional state	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Respiratory, thoracic and mediastinal disorders Pleural effusion	4.2% 1/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.

Other adverse events

Other adverse events
Measure	Part A: Alisertib 30 mg+Itraconazole; Part B: Alisertib 50 mg n=24 participants at risk All participants were to complete Part A prior to Part B. Part A: Alisertib 30 mg, tablets, orally, on Days 1 and 10 plus itraconazole, 200 mg, oral solution, once daily on Days 5 to 13. Part A and B were separated by a washout period of at least 10 days (and up to 4 weeks). Part B: Alisertib 50 mg, tablets, orally, twice daily, for 7 days in 21-day cycles until disease progression or unacceptable toxicity (up to 16 cycles).
Gastrointestinal disorders Nausea	45.8% 11/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Diarrhoea	41.7% 10/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Vomiting	33.3% 8/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Stomatitis	29.2% 7/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Constipation	25.0% 6/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Abdominal pain	16.7% 4/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Abdominal distension	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Dyspepsia	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Gastrointestinal disorders Haemorrhoids	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Fatigue	37.5% 9/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Oedema peripheral	25.0% 6/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Gait disturbance	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Pyrexia	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
General disorders Chills	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Metabolism and nutrition disorders Decreased appetite	25.0% 6/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Metabolism and nutrition disorders Hypokalaemia	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Metabolism and nutrition disorders Dehydration	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Metabolism and nutrition disorders Hypomagnesaemia	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Nervous system disorders Headache	29.2% 7/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Nervous system disorders Dizziness	20.8% 5/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Nervous system disorders Dysarthria	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Nervous system disorders Hypoaesthesia	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Nervous system disorders Memory impairment	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Alopecia	33.3% 8/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Pruritus	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Decubitus ulcer	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Rash	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Rash maculo-papular	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Musculoskeletal and connective tissue disorders Back pain	20.8% 5/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Musculoskeletal and connective tissue disorders Pain in extremity	20.8% 5/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Musculoskeletal and connective tissue disorders Flank pain	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Respiratory, thoracic and mediastinal disorders Dyspnoea	16.7% 4/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Respiratory, thoracic and mediastinal disorders Upper-airway cough syndrome	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Respiratory, thoracic and mediastinal disorders Cough	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Respiratory, thoracic and mediastinal disorders Nasal congestion	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Blood and lymphatic system disorders Anaemia	25.0% 6/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Blood and lymphatic system disorders Neutropenia	25.0% 6/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Blood and lymphatic system disorders Thrombocytopenia	16.7% 4/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Blood and lymphatic system disorders Leukopenia	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Psychiatric disorders Confusional state	16.7% 4/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Psychiatric disorders Insomnia	16.7% 4/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Psychiatric disorders Agitation	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Psychiatric disorders Anxiety	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Psychiatric disorders Depression	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Upper respiratory tract infection	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Oral candidiasis	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Infections and infestations Urinary tract infection	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Investigations Blood creatinine increased	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Investigations International normalised ratio increased	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Investigations Lymphocyte count decreased	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Investigations Weight decreased	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Injury, poisoning and procedural complications Fall	16.7% 4/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Cardiac disorders Palpitations	12.5% 3/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Eye disorders Vision blurred	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Renal and urinary disorders Micturition urgency	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.
Vascular disorders Hypertension	8.3% 2/24 • First dose of study drug up to 30 days after the last dose of study drug (up to 12 months) Although there were 2 parts to the study, however, data for adverse events was not collected separately for each part.

Additional Information

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