Trial Outcomes & Findings for Paclitaxel, Carboplatin, and Bevacizumab With or Without Cixutumumab in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer (NCT NCT00955305)

Last Updated: 2018-06-06

Results Overview

Progression-free survival was defined as the time from randomization to progression or death without documentation of progression. For cases without progression, follow-up was censored at the date of last disease assessment without progression, unless death occurs within 3 months following the date last known progression-free, in which case the death was counted as a failure. Progression was evaluated using RECIST 1.1 criteria and defined as: 1. At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study and the sum must also demonstrate an absolute increase of at least 5 mm. OR 2. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

175 participants

Primary outcome timeframe

Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years

Results posted on

2018-06-06

Participant Flow

This study opened to accrual on March 9, 2010 and was suspended on February 24, 2011 for safety evaluation. As the safety criterion was met, this study reopened on May 16, 2011 and closed to accrual on June 28, 2013 due to the end of the clinical development program with cixutumumab (IMC-A12) with final accrual of 175 patients.

Participant milestones

Participant milestones
Measure	Arm A (CPB) Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Overall Study STARTED	88	87
Overall Study Treated	83	82
Overall Study Eligible and Treated	78	75
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	88	87

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm A (CPB) Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Overall Study Disease progression	39	41
Overall Study Adverse Event	22	22
Overall Study Death	2	1
Overall Study Withdrawal by Subject	5	4
Overall Study Alternative therapy	4	0
Overall Study Other complicating disease	2	4
Overall Study Physician Decision	1	0
Overall Study Continued presence of residual disease	0	1
Overall Study Functional decline	2	0
Overall Study Maximum response achieved	0	1
Overall Study Lost to Follow-up	0	1
Overall Study No off-treatment reason submitted	1	0
Overall Study Never started protocol treatment	5	5
Overall Study Ineligible	5	7

Baseline Characteristics

Paclitaxel, Carboplatin, and Bevacizumab With or Without Cixutumumab in Treating Patients With Stage IV or Recurrent Non-small Cell Lung Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm A (CPB) n=78 Participants Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) n=75 Participants Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.	Total n=153 Participants Total of all reporting groups
Age, Continuous	64 years n=99 Participants	61 years n=107 Participants	63 years n=206 Participants
Sex: Female, Male Female	40 Participants n=99 Participants	40 Participants n=107 Participants	80 Participants n=206 Participants
Sex: Female, Male Male	38 Participants n=99 Participants	35 Participants n=107 Participants	73 Participants n=206 Participants

PRIMARY outcome

Timeframe: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years

Population: Eligible and treated patients

Outcome measures

Outcome measures
Measure	Arm A (CPB) n=78 Participants Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) n=75 Participants Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Progression-free Survival (PFS)	5.8 months Interval 5.4 to 7.1	7.0 months Interval 5.7 to 7.6

SECONDARY outcome

Timeframe: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry; up to 5 years

Population: Eligible and treated patients

Overall survival is defined as the time from randomization to death or date last known alive.

Outcome measures

Outcome measures
Measure	Arm A (CPB) n=78 Participants Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) n=75 Participants Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Overall Survival (OS)	16.2 months Interval 9.9 to 18.6	16.1 months Interval 12.3 to 19.4

SECONDARY outcome

Timeframe: Assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry; up to 5 years

Population: Eligible and treated patients

Objective response was evaluated using the RECIST 1.1 criteria. Objective response includes complete response (CR) and partial response (PR). Objective response is defined as disappearance of all target lesions or at least a 30% decrease in the sum of the diameters of target lesions. In addition, non-target lesions do not meet the criteria for disease progression and no new lesions were observed.

Outcome measures

Outcome measures
Measure	Arm A (CPB) n=78 Participants Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) n=75 Participants Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Proportion of Patients With Objective Response	0.462 Proportion of participants Interval 0.348 to 0.578	0.587 Proportion of participants Interval 0.467 to 0.699

Adverse Events

Arm A (CPB)

Serious events: 58 serious events

Other events: 80 other events

Deaths: 0 deaths

Arm B (CPB+Cixutumumab)

Serious events: 74 serious events

Other events: 78 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Statistician

ECOG-ACRIN Statistical Office

Phone: 617-632-3012

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Serious adverse events
Measure	Arm A (CPB) n=83 participants at risk Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) n=82 participants at risk Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Anemia	7.2% 6/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	12.2% 10/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	8.5% 7/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Fatigue	6.0% 5/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	20.7% 17/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Fever	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	2.4% 2/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Infusion related reaction	2.4% 2/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Anal fistula	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Colitis	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Colonic perforation	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	0.00% 0/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Dental caries	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	0.00% 0/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Diarrhea	2.4% 2/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	2.4% 2/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Dysphagia	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	0.00% 0/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Mucositis oral	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Nausea	4.8% 4/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	11.0% 9/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Oral pain	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Pancreatitis	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Rectal pain	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Rectal ulcer	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Vomiting	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	7.3% 6/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Catheter related infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Enterocolitis infectious	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	0.00% 0/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Gum infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Joint infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Lung infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	3.7% 3/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Mucosal infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Sepsis	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Tooth infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Urinary tract infection	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Wound infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Injury, poisoning and procedural complications Wound complication	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Alanine aminotransferase increased	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	2.4% 2/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Aspartate aminotransferase increased	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Lipase increased	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	2.4% 2/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Lymphocyte count decreased	10.8% 9/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	11.0% 9/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Neutrophil count decreased	32.5% 27/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	54.9% 45/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Platelet count decreased	9.6% 8/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	25.6% 21/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Serum amylase increased	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Weight gain	1.2% 1/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	0.00% 0/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Weight loss	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations White blood cell decreased	4.8% 4/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	19.5% 16/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.

Other adverse events
Measure	Arm A (CPB) n=83 participants at risk Patients receive carboplatin intravenously (IV) over 30 minutes, paclitaxel IV over 3 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab may continue in the absence of disease progression or unacceptable toxicity.	Arm B (CPB+Cixutumumab) n=82 participants at risk Patients receive carboplatin, paclitaxel, and bevacizumab as in Arm A. Patients also receive cixutumumab (IMC-A12) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with bevacizumab and cixutumumab may continue in the absence of disease progression or unacceptable toxicity.
Blood and lymphatic system disorders Anemia	77.1% 64/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	70.7% 58/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Chills	3.6% 3/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	8.5% 7/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Edema limbs	6.0% 5/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	2.4% 2/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Fatigue	79.5% 66/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	84.1% 69/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Fever	6.0% 5/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	4.9% 4/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
General disorders Infusion related reaction	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	7.3% 6/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Skin and subcutaneous tissue disorders Alopecia	72.3% 60/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	58.5% 48/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Skin and subcutaneous tissue disorders Pruritus	6.0% 5/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	7.3% 6/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Skin and subcutaneous tissue disorders Rash maculo-papular	8.4% 7/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	15.9% 13/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Abdominal pain	7.2% 6/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	1.2% 1/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Constipation	32.5% 27/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	30.5% 25/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Diarrhea	21.7% 18/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	37.8% 31/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Mucositis oral	8.4% 7/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	25.6% 21/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Nausea	45.8% 38/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	59.8% 49/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Oral hemorrhage	3.6% 3/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	6.1% 5/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Oral pain	6.0% 5/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	14.6% 12/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Gastrointestinal disorders Vomiting	21.7% 18/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	29.3% 24/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Infections and infestations Mucosal infection	0.00% 0/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	6.1% 5/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Alanine aminotransferase increased	12.0% 10/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	17.1% 14/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Alkaline phosphatase increased	14.5% 12/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	18.3% 15/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Aspartate aminotransferase increased	13.3% 11/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	22.0% 18/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Creatinine increased	8.4% 7/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	18.3% 15/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Lymphocyte count decreased	33.7% 28/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	31.7% 26/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Neutrophil count decreased	32.5% 27/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	28.0% 23/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Platelet count decreased	48.2% 40/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	63.4% 52/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations Weight loss	22.9% 19/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	42.7% 35/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Investigations White blood cell decreased	25.3% 21/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	31.7% 26/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Anorexia	42.2% 35/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	58.5% 48/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Dehydration	4.8% 4/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	7.3% 6/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hypercalcemia	2.4% 2/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	6.1% 5/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hyperglycemia	18.1% 15/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	54.9% 45/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hypoalbuminemia	13.3% 11/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	12.2% 10/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hypocalcemia	6.0% 5/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	8.5% 7/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hypokalemia	7.2% 6/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	6.1% 5/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hypomagnesemia	10.8% 9/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	8.5% 7/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Metabolism and nutrition disorders Hyponatremia	16.9% 14/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	31.7% 26/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Musculoskeletal and connective tissue disorders Arthralgia	25.3% 21/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	20.7% 17/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	19.3% 16/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	17.1% 14/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Musculoskeletal and connective tissue disorders Myalgia	26.5% 22/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	20.7% 17/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.
Musculoskeletal and connective tissue disorders Pain in extremity	10.8% 9/83 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.	13.4% 11/82 • Assessed every 3 weeks while on treatment and for 30 days after the end of treatment Patients received a maximum of 6 cycles of chemotherapy and remained on bevacizumab (Arm A) or bevacizumab + cixutumumab (Arm B) continuously until evidence of documented progressive disease or unacceptable toxicity.