Trial Outcomes & Findings for Gemcitabine and Carboplatin With or Without AZD2171 as First-Line Therapy in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer (NCT NCT00326599)

Last Updated: 2017-03-21

Results Overview

A confirmed tumor response was defined as a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: * Complete Response (CR): disappearance of all target lesions; * Partial Response (PR) 30% decrease in sum of longest diameter of target lesions

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

101 participants

Primary outcome timeframe

Up to 5 years

Results posted on

2017-03-21

Participant Flow

One hundred-and one (101) participants were enrolled between June 15, 2007 and December 5, 2008. Data for this report were frozen on September 13, 2011.

Five participants were excluded from all analyses due to withdrew consent or never received study treatment: 1 lead-in arm I; 2 phase II arm I; and 2 phase II arm II. The starting cediranib dose of 45 mg was not tolerable and was reduced to 30 mg once daily on a continuous schedule for the phase II portion of the study.

Participant milestones

Participant milestones
Measure	Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin) Patients receive oral cediranib 45mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Lead-in Phase: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Overall Study STARTED	6	3	58	29
Overall Study COMPLETED	0	2	5	10
Overall Study NOT COMPLETED	6	1	53	19

Reasons for withdrawal

Reasons for withdrawal
Measure	Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin) Patients receive oral cediranib 45mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Lead-in Phase: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Overall Study Withdrawal by Subject	1	0	5	2
Overall Study Adverse Event	1	0	32	3
Overall Study Disease Progression	3	1	13	11
Overall Study Alternate Treatment	1	0	0	0
Overall Study Death	0	0	1	2
Overall Study Other Unspecified Reason	0	0	2	1

Baseline Characteristics

Gemcitabine and Carboplatin With or Without AZD2171 as First-Line Therapy in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin) n=6 Participants Patients receive oral cediranib 45mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Lead-in Phase: Arm II (Gemcitabine + Carboplatin) n=3 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Total n=96 Participants Total of all reporting groups
Age, Continuous	65.5 years n=5 Participants	74 years n=7 Participants	65 years n=5 Participants	64 years n=4 Participants	64 years n=21 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	3 Participants n=7 Participants	26 Participants n=5 Participants	12 Participants n=4 Participants	45 Participants n=21 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	0 Participants n=7 Participants	32 Participants n=5 Participants	17 Participants n=4 Participants	51 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants	2 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) White	6 Participants n=5 Participants	3 Participants n=7 Participants	55 Participants n=5 Participants	26 Participants n=4 Participants	90 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	1 Participants n=21 Participants
Region of Enrollment United States	6 participants n=5 Participants	3 participants n=7 Participants	58 participants n=5 Participants	29 participants n=4 Participants	96 participants n=21 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0=Asymptomatic and fully active	3 Participants n=5 Participants	1 Participants n=7 Participants	33 Participants n=5 Participants	17 Participants n=4 Participants	54 Participants n=21 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1=Symptomatic and fully ambulatory	3 Participants n=5 Participants	2 Participants n=7 Participants	25 Participants n=5 Participants	12 Participants n=4 Participants	42 Participants n=21 Participants
Before adjuvant treatment Yes	1 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants
Before adjuvant treatment No	5 Participants n=5 Participants	3 Participants n=7 Participants	56 Participants n=5 Participants	28 Participants n=4 Participants	92 Participants n=21 Participants
Cell type Squamous	0 Participants n=5 Participants	1 Participants n=7 Participants	9 Participants n=5 Participants	8 Participants n=4 Participants	18 Participants n=21 Participants
Cell type Adenocarcinoma	4 Participants n=5 Participants	1 Participants n=7 Participants	22 Participants n=5 Participants	16 Participants n=4 Participants	43 Participants n=21 Participants
Cell type All other	2 Participants n=5 Participants	1 Participants n=7 Participants	27 Participants n=5 Participants	5 Participants n=4 Participants	35 Participants n=21 Participants

PRIMARY outcome

Timeframe: Up to 5 years

Population: All phase II participants who met eligibility criteria and have received at least one cycle of treatment.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II Patients Only)	19 percentage of participants Interval 10.0 to 31.0	20 percentage of participants Interval 8.0 to 40.0

SECONDARY outcome

Timeframe: 6 months

Population: All phase II participants who met eligibility criteria and have received at least one cycle of treatment.

Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Progression-free Survival Rate at 6 Months After Randomization (Phase II Patients Only)	48 percentage of participants Interval 35.0 to 62.0	38 percentage of participants Interval 21.0 to 58.0

SECONDARY outcome

Timeframe: Up to 5 years

Population: All phase II participants who met eligibility criteria and have received at least one cycle of treatment.

Progression-free survival was defined as the time from study enrollment to the first date of disease progression or death as a result of any cause, whichever occurs first. Progression-free survival will be censored at the date of the last contact for patients who are still alive and who have not had disease progression.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Progression-free Survival (Phase II Patients Only)	6.3 months Interval 4.7 to 7.9	4.5 months Interval 2.6 to 7.2

SECONDARY outcome

Timeframe: Up to 15 months

Population: All phase II participants who met the eligibility criteria and have ended the study treatment.

Time to treatment failure was defined to be the time from date of registration to the date at which the patient was removed from the treatment due to progression, toxicity, refusal or death from any cause.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Time to Treatment Failure (Phase II Patients Only)	2.48 months Interval 1.94 to 3.25	2.89 months Interval 1.71 to The upper limit of 95%CI was not attainable.

SECONDARY outcome

Timeframe: 1 year

Population: All phase II participants who met eligibility criteria and started the treatment.

Overall survival was defined as the time from study enrollment to the time of death from any cause. A patient is classified as a success if alive at 1 year.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Overall Survival at 1 Year After Randomization (Phase II Patients Only)	48 percentage of participants Interval 34.9 to 60.7	41 percentage of participants Interval 23.7 to 58.3

SECONDARY outcome

Timeframe: Up to 5 years

Population: All phase II participants who met eligibility criteria and started the treatment.

Overall survival was defined as the time from study enrollment to the time of death from any cause. Overall survival will be censored at the date of the last follow-up visit for patients who are still alive or lost to follow-up.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 Participants Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Overall Survival (Phase II Patients Only)	12.0 months Interval 7.5 to 20.6	9.9 months Interval 5.4 to 13.7

SECONDARY outcome

Timeframe: Cycle 1 (up to 3 weeks)

Population: The first 6 participants treated on Arm I (lead-in phase).

DLT was defined as an adverse event occurring in cycle 1 only, at least possibly attributed to the study treatment and meeting the following criteria: 1) Grade 4 absolute neutrophil count (ANC) \>5 days or of any duration with fever \>38.5 degree Celsius; 2) Grade 4 platelet count; 3) Grade 3 or higher non-hematologic toxicities (for nausea, vomiting or diarrhea, grade 3 toxicities will be DLT if they occur despite maximal use of anti-emetic support or anti-diarrhea agents, respectively); 4) Cediranib dose interruption of \>14 days for drug-related toxicities.

Outcome measures

Outcome measures
Measure	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=6 Participants Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Dose Limiting Toxicity (DLT) (Lead-in Phase Arm I Patients Only)	1 participants	—

Adverse Events

Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin)

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Lead-in Phase: Arm II (Gemcitabine + Carboplatin)

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin)

Serious events: 39 serious events

Other events: 58 other events

Deaths: 0 deaths

Phase II: Arm II (Gemcitabine + Carboplatin)

Serious events: 8 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Alex A. Adjei, M.D., Ph.D.

Roswell Park Cancer Institute

Phone: 716-845-4101

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin) n=6 participants at risk Patients receive oral cediranib 45mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Lead-in Phase: Arm II (Gemcitabine + Carboplatin) n=3 participants at risk Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) n=58 participants at risk Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.	Phase II: Arm II (Gemcitabine + Carboplatin) n=29 participants at risk Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/58 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Blood and lymphatic system disorders Hemoglobin decreased	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	6.9% 4/58 • Number of events 4 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Cardiac disorders Atrial fibrillation	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Cardiac disorders Left ventricular failure	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Endocrine disorders Hypothyroidism	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	66.7% 2/3 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/58 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Constipation	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Diarrhea	16.7% 1/6 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 2/58 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Ileus	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/58 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Lower gastrointestinal hemorrhage	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Nausea	16.7% 1/6 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	6.9% 4/58 • Number of events 5 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Oral hemorrhage	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	5.2% 3/58 • Number of events 4 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Gastrointestinal disorders Vomiting	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
General disorders Chest pain	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
General disorders Disease progression	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
General disorders Fatigue	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	33.3% 1/3 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 2/58 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
General disorders Fever	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/58 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations Bilirubin increased	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations Creatinine increased	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations Fibrinogen decreased	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations INR increased	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations Leukocyte count decreased	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	33.3% 1/3 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	19.0% 11/58 • Number of events 12 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations Neutrophil count decreased	16.7% 1/6 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	33.3% 1/3 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	27.6% 16/58 • Number of events 20 • Up to 15 months All participants who met eligibility criteria and started the treatment.	13.8% 4/29 • Number of events 4 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Investigations Platelet count decreased	16.7% 1/6 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	39.7% 23/58 • Number of events 28 • Up to 15 months All participants who met eligibility criteria and started the treatment.	10.3% 3/29 • Number of events 3 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Metabolism and nutrition disorders Anorexia	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Metabolism and nutrition disorders Dehydration	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Musculoskeletal and connective tissue disorders Muscle weakness	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Nervous system disorders Ischemia cerebrovascular	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Psychiatric disorders Confusion	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Renal and urinary disorders Hemorrhage urinary tract	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	6.9% 4/58 • Number of events 4 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Respiratory, thoracic and mediastinal disorders Hemorrhage nasal	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	12.1% 7/58 • Number of events 8 • Up to 15 months All participants who met eligibility criteria and started the treatment.	6.9% 2/29 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/58 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 1/29 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary hemorrhage	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 2/58 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Vascular disorders Hypertension	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	3.4% 2/58 • Number of events 2 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Vascular disorders Hypotension	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	1.7% 1/58 • Number of events 1 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.
Vascular disorders Thrombosis	0.00% 0/6 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/3 • Up to 15 months All participants who met eligibility criteria and started the treatment.	6.9% 4/58 • Number of events 4 • Up to 15 months All participants who met eligibility criteria and started the treatment.	0.00% 0/29 • Up to 15 months All participants who met eligibility criteria and started the treatment.