Trial Outcomes & Findings for A Study of Cetuximab and Bevacizumab in Combination With Paclitaxel and Carboplatin in Stage IIIb/IV NSCLC (NCT NCT00343291)

Last Updated: 2011-06-07

Results Overview

PFS is defined as the time from randomization until the date of progression of disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD ≥20% increase in sum of longest diameter of target lesions. Participants who are alive and without PD will be censored at the date of their last tumor assessment.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

121 participants

Primary outcome timeframe

Randomization to PD or date of death from any cause up to 33.1 months

Results posted on

2011-06-07

Participant Flow

Participant milestones

Participant milestones
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Overall Study STARTED	60	61
Overall Study RECEIVED AT LEAST ONE DOSE OF STUDY DRUG	58	58
Overall Study COMPLETED	3	5
Overall Study NOT COMPLETED	57	56

Reasons for withdrawal

Reasons for withdrawal
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Overall Study Adverse Event	13	13
Overall Study Death	3	2
Overall Study Progressive disease	33	34
Overall Study Withdrawal by Subject	0	2
Overall Study Other	8	5

Baseline Characteristics

A Study of Cetuximab and Bevacizumab in Combination With Paclitaxel and Carboplatin in Stage IIIb/IV NSCLC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=60 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=61 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Total n=121 Participants Total of all reporting groups
Age Continuous	63.4 years STANDARD_DEVIATION 11.52 • n=5 Participants	62.1 years STANDARD_DEVIATION 8.97 • n=7 Participants	62.8 years STANDARD_DEVIATION 10.29 • n=5 Participants
Age, Customized < 65 years	31 participants n=5 Participants	32 participants n=7 Participants	63 participants n=5 Participants
Age, Customized ≥ 65 years	29 participants n=5 Participants	29 participants n=7 Participants	58 participants n=5 Participants
Age, Customized < 70 years	41 participants n=5 Participants	51 participants n=7 Participants	92 participants n=5 Participants
Age, Customized ≥ 70 years	19 participants n=5 Participants	10 participants n=7 Participants	29 participants n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants	27 Participants n=7 Participants	52 Participants n=5 Participants
Sex: Female, Male Male	35 Participants n=5 Participants	34 Participants n=7 Participants	69 Participants n=5 Participants
Race/Ethnicity, Customized White	53 participants n=5 Participants	53 participants n=7 Participants	106 participants n=5 Participants
Race/Ethnicity, Customized Black	2 participants n=5 Participants	4 participants n=7 Participants	6 participants n=5 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Race/Ethnicity, Customized Hispanic	3 participants n=5 Participants	0 participants n=7 Participants	3 participants n=5 Participants
Race/Ethnicity, Customized Other	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Region of Enrollment United States	60 participants n=5 Participants	61 participants n=7 Participants	121 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - Full Active	24 participants n=5 Participants	29 participants n=7 Participants	53 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 - Ambulatory, Restricted Strenuous Activity	28 participants n=5 Participants	27 participants n=7 Participants	55 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Missing/Unknown	8 participants n=5 Participants	5 participants n=7 Participants	13 participants n=5 Participants
Smoking Status Current	17 participants n=5 Participants	11 participants n=7 Participants	28 participants n=5 Participants
Smoking Status Past	37 participants n=5 Participants	44 participants n=7 Participants	81 participants n=5 Participants
Smoking Status Exposed to Second-hand Smoke	2 participants n=5 Participants	1 participants n=7 Participants	3 participants n=5 Participants
Smoking Status Not Exposed to Second-hand Smoke	4 participants n=5 Participants	4 participants n=7 Participants	8 participants n=5 Participants
Smoking Status Missing/Unknown	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization to PD or date of death from any cause up to 33.1 months

Population: Included all enrolled, randomized participants. All participants were analyzed as part of the treatment group to which they were randomized.

Outcome measures

Outcome measures
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=60 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=61 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Progression Free Survival (PFS)	6.05 months Interval 5.65 to 7.03	4.50 months Interval 4.01 to 5.42

SECONDARY outcome

Timeframe: Randomization to the date of death from any cause up to 42.7 months

Population: Included all enrolled, randomized participants. All participants were analyzed as part of the treatment group to which they were randomized.

Overall survival is defined as the time from randomization to death. Participants who are alive will be censored on the last known alive date.

Outcome measures

Outcome measures
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=60 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=61 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Overall Survival	12.06 months Interval 9.4 to 19.25	11.63 months Interval 6.64 to 17.61

SECONDARY outcome

Timeframe: Randomization to measured progressive disease up to 31.8 months

Population: Included all enrolled, randomized participants. All participants were analyzed as part of the treatment group to which they were randomized.

The best objective overall response rate (ORR) is the percentage of randomized participants with a best overall response of complete response (CR) or partial response (PR), as classified by the investigator according to the RECIST guidelines. CR=disappearance of all target lesions; PR≥30% decrease in sum of longest diameter of target lesions. ORR is calculated as a total number of participants with CR or PR divided by the total number of participants treated in that arm, multiplied by 100. Participants with no post-baseline evaluation will be considered as a non-responder.

Outcome measures

Outcome measures
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=60 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=61 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Percentage of Participants Achieving an Objective Overall Response (Overall Response Rate)	51.7 percentage of participants Interval 39.0 to 64.3	44.3 percentage of participants Interval 31.8 to 56.7

SECONDARY outcome

Timeframe: Time of first response to the first date of PD or death due to any cause up to 31.8 months

Population: Included all enrolled, randomized participants with a best overall response of CR or PR (responders). All participants were analyzed as part of the treatment group to which they were randomized.

The duration of response, in participants with best overall response of CR or PR, is measured from the date criteria are met for CR/PR (whichever is first recorded), until the first date that the criteria for PD is met or death. CR, PR, and PD, as classified by the investigator according to the RECIST guidelines. CR=disappearance of all target lesions; PR≥30% decrease in sum of longest diameter of target lesions; PD≥20% increase in sum of longest diameter of target lesions. Participants who are alive and without PD will be censored at the date of their last tumor assessment.

Outcome measures

Outcome measures
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=31 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=27 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Duration of Overall Response	4.86 months Interval 4.3 to 7.16	3.94 months Interval 2.92 to 4.47

SECONDARY outcome

Timeframe: From date of partial response until progression of disease up to 31.8 months

Population: Included all enrolled, randomized participants with a score of ≤26 at baseline. All participants were analyzed as part of the treatment group to which they were randomized.

Functional Assessment of Cancer Therapy for Patients With Lung Cancer (FACT-L) measures domains of health-related quality of life (HR-QL): physical wellbeing (WB), social/family WB, emotional WB, functional WB, and additional lung cancer concerns. Symptom response (improvement) was defined as ≥2 point increase from baseline in the 7-item Lung cancer subscale (LCS) score maintained for 2 consecutive assessments. Scores range from 0-28 with higher scores indicating fewer symptoms. Patients with a score of \>26 were not evaluable for symptom response, since a score of 28 is the maximum possible.

Outcome measures

Outcome measures
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=43 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=44 Participants Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Percentage of Participants With Symptomatic Response (Symptom Response Rate)	41.9 percentage of participants Interval 27.1 to 56.6	38.6 percentage of participants Interval 24.2 to 53.0

Adverse Events

Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6)

Serious events: 38 serious events

Other events: 56 other events

Deaths: 0 deaths

Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3)

Serious events: 28 serious events

Other events: 57 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Chief Medical Officer

Eli Lilly and Company

Phone: 800-545-5979

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Serious adverse events
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=58 participants at risk Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=58 participants at risk Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
Blood and lymphatic system disorders Anaemia	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Bone marrow failure	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Febrile neutropenia	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Neutropenia	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Acute myocardial infarction	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Arrhythmia supraventricular	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Atrial fibrillation	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Cardiac arrest	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Cardiac failure congestive	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Myocardial infarction	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Abdominal pain	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Constipation	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Diarrhoea	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Duodenal ulcer	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Duodenal ulcer haemorrhage	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Dysphagia	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Gastrointestinal haemorrhage	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Intestinal perforation	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Nausea	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Odynophagia	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Rectal haemorrhage	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Vomiting	6.9% 4/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.
General disorders Chest pain	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
General disorders Chills	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
General disorders Death	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
General disorders Disease progression	6.9% 4/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
General disorders Fatigue	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
General disorders Non-cardiac chest pain	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
General disorders Pain	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
General disorders Pyrexia	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Immune system disorders Anaphylactic reaction	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Immune system disorders Hypersensitivity	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Catheter site infection	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Cellulitis	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Clostridium difficile colitis	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Device related infection	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Endocarditis	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.

Other adverse events
Measure	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/6) n=58 participants at risk Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle * Paclitaxel 200mg/m² on day 1 of every 3 week cycle * Carboplatin AUC=6 min\*mg/mL on day 1 of every 3 week cycle Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met	Cetuximab + Bevacizumab + Paclitaxel + Carboplatin (6/3) n=58 participants at risk Cycles 1-6: * Cetuximab 400 mg/m² initial dose on day 1 and then 250 mg/m² given every week * Bevacizumab 15 mg/kg given on day 8 of every 3 week cycle Cycles 1-3: * Paclitaxel 200 mg/m² on day 1 of each 3 week cycle for the first 3 cycles * Carboplatin AUC=6 min\*mg/mL on day 1 of each 3 week cycle for the first 3 cycles Patients who demonstrate a response or stable disease after six cycles of therapy may continue on weekly cetuximab monotherapy until disease progression, unacceptable toxicity, or another withdrawal criterion is met
General disorders Oedema peripheral	12.1% 7/58 • Number of events 10 Adverse events include all grades, regardless of severity or possible causality.	6.9% 4/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.
General disorders Pain	5.2% 3/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.	6.9% 4/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.
General disorders Pyrexia	12.1% 7/58 • Number of events 10 Adverse events include all grades, regardless of severity or possible causality.	6.9% 4/58 • Number of events 5 Adverse events include all grades, regardless of severity or possible causality.
Immune system disorders Hypersensitivity	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	8.6% 5/58 • Number of events 6 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Bronchitis	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Fungal infection	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Localised infection	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Rhinitis	10.3% 6/58 • Number of events 9 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Sinusitis	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Upper respiratory tract infection	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Infections and infestations Urinary tract infection	10.3% 6/58 • Number of events 15 Adverse events include all grades, regardless of severity or possible causality.	10.3% 6/58 • Number of events 7 Adverse events include all grades, regardless of severity or possible causality.
Investigations Weight decreased	17.2% 10/58 • Number of events 15 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Metabolism and nutrition disorders Decreased appetite	29.3% 17/58 • Number of events 23 Adverse events include all grades, regardless of severity or possible causality.	31.0% 18/58 • Number of events 25 Adverse events include all grades, regardless of severity or possible causality.
Metabolism and nutrition disorders Dehydration	12.1% 7/58 • Number of events 7 Adverse events include all grades, regardless of severity or possible causality.	17.2% 10/58 • Number of events 13 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Anaemia	36.2% 21/58 • Number of events 48 Adverse events include all grades, regardless of severity or possible causality.	17.2% 10/58 • Number of events 12 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Neutropenia	29.3% 17/58 • Number of events 49 Adverse events include all grades, regardless of severity or possible causality.	24.1% 14/58 • Number of events 21 Adverse events include all grades, regardless of severity or possible causality.
Blood and lymphatic system disorders Thrombocytopenia	19.0% 11/58 • Number of events 32 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Cardiac disorders Palpitations	5.2% 3/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Eye disorders Conjunctivitis	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.
Eye disorders Vision blurred	1.7% 1/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Abdominal pain	10.3% 6/58 • Number of events 6 Adverse events include all grades, regardless of severity or possible causality.	8.6% 5/58 • Number of events 6 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Abdominal pain lower	6.9% 4/58 • Number of events 6 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Abdominal pain upper	6.9% 4/58 • Number of events 5 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Constipation	37.9% 22/58 • Number of events 31 Adverse events include all grades, regardless of severity or possible causality.	27.6% 16/58 • Number of events 20 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Diarrhoea	37.9% 22/58 • Number of events 29 Adverse events include all grades, regardless of severity or possible causality.	24.1% 14/58 • Number of events 27 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Dry mouth	3.4% 2/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Dyspepsia	6.9% 4/58 • Number of events 6 Adverse events include all grades, regardless of severity or possible causality.	15.5% 9/58 • Number of events 9 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Gastrooesophageal reflux disease	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Mouth ulceration	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Nausea	51.7% 30/58 • Number of events 53 Adverse events include all grades, regardless of severity or possible causality.	39.7% 23/58 • Number of events 32 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Rectal haemorrhage	1.7% 1/58 • Number of events 2 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Stomatitis	32.8% 19/58 • Number of events 37 Adverse events include all grades, regardless of severity or possible causality.	39.7% 23/58 • Number of events 29 Adverse events include all grades, regardless of severity or possible causality.
Gastrointestinal disorders Vomiting	20.7% 12/58 • Number of events 18 Adverse events include all grades, regardless of severity or possible causality.	15.5% 9/58 • Number of events 11 Adverse events include all grades, regardless of severity or possible causality.
General disorders Asthenia	12.1% 7/58 • Number of events 7 Adverse events include all grades, regardless of severity or possible causality.	6.9% 4/58 • Number of events 6 Adverse events include all grades, regardless of severity or possible causality.
General disorders Catheter site pain	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.	6.9% 4/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.
General disorders Chills	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.
General disorders Fatigue	55.2% 32/58 • Number of events 61 Adverse events include all grades, regardless of severity or possible causality.	48.3% 28/58 • Number of events 41 Adverse events include all grades, regardless of severity or possible causality.
General disorders Infusion related reaction	1.7% 1/58 • Number of events 1 Adverse events include all grades, regardless of severity or possible causality.	6.9% 4/58 • Number of events 13 Adverse events include all grades, regardless of severity or possible causality.
General disorders Non-cardiac chest pain	5.2% 3/58 • Number of events 3 Adverse events include all grades, regardless of severity or possible causality.	0.00% 0/58 Adverse events include all grades, regardless of severity or possible causality.
Metabolism and nutrition disorders Hyperglycaemia	3.4% 2/58 • Number of events 4 Adverse events include all grades, regardless of severity or possible causality.	5.2% 3/58 • Number of events 5 Adverse events include all grades, regardless of severity or possible causality.