Trial Outcomes & Findings for De-escalation Chemotherapies Versus Escalation in Non Pre-treated Unresectable Patients With Metastatic Colorectal Cancer (NCT NCT02842580)

Last Updated: 2024-07-10

Results Overview

The failure of the strategy is defined by the following events: * Progression (under certain condition) using RECIST version 1.1 and defined as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions * Death (all causes) * Toxicity leading to definitive stop of chemotherapy (oxaliplatine and/or irinotecan).

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

21 participants

Primary outcome timeframe

16 months after randomization

Results posted on

2024-07-10

Participant Flow

Patients were randomized between 15 September 2016 and 10 April 2018 by 9 french centers

Participant milestones

Participant milestones
Measure	Standard Arm (Escalation Strategy - Arm A) LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
Overall Study STARTED	11	10
Overall Study COMPLETED	11	10
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Standard Arm (Escalation Strategy - Arm A) n=11 Participants LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 Participants (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Total n=21 Participants Total of all reporting groups
Age, Continuous	65.70 years STANDARD_DEVIATION 9.14 • n=11 Participants	66.32 years STANDARD_DEVIATION 10.2 • n=10 Participants	65.99 years STANDARD_DEVIATION 9.38 • n=21 Participants
Sex: Female, Male Female	4 Participants n=11 Participants	2 Participants n=10 Participants	6 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=11 Participants	8 Participants n=10 Participants	15 Participants n=21 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment France	11 participants n=11 Participants	10 participants n=10 Participants	21 participants n=21 Participants
kRAS mutation status (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) Mutated	8 Participants n=11 Participants	7 Participants n=10 Participants	15 Participants n=21 Participants
kRAS mutation status (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) Non mutated	3 Participants n=11 Participants	3 Participants n=10 Participants	6 Participants n=21 Participants

PRIMARY outcome

Timeframe: 16 months after randomization

Outcome measures

Outcome measures
Measure	Standard Arm (Escalation Strategy - Arm A) n=11 Participants LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 Participants (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. No strategy failure	7 Participants	4 Participants
The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization. Strategy failure	4 Participants	6 Participants

SECONDARY outcome

Timeframe: At 16 months

Best response derived from all the CT scans performed during treatment and based on RECIST 1.1 definition of response.

Outcome measures

Outcome measures
Measure	Standard Arm (Escalation Strategy - Arm A) n=11 Participants LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 Participants (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
Best Response Rate (Using RECIST Version 1.1) Complete response	0 Participants	1 Participants
Best Response Rate (Using RECIST Version 1.1) Partial response	3 Participants	6 Participants
Best Response Rate (Using RECIST Version 1.1) Stability	7 Participants	2 Participants
Best Response Rate (Using RECIST Version 1.1) Progression	0 Participants	1 Participants
Best Response Rate (Using RECIST Version 1.1) Non evaluable	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Up to 3 years after the treatment start

Overall survival was defined as the time from the date of the patient's inclusion to the patient's death (all causes). For alive patients the date of the latest news was taken into account

Outcome measures

Outcome measures
Measure	Standard Arm (Escalation Strategy - Arm A) n=11 Participants LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 Participants (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
Overall Survival (OS)	31.08 months Interval 15.51 to Upper limit of the confidence interval was not reached at the time of the study analysis because less than 75% of the patients died at the time of the analysis	33.80 months Interval 3.68 to Upper limit of the confidence interval was not reached at the time of the study analysis because less than 75% of the patients died at the time of the analysis

SECONDARY outcome

Timeframe: up to 24 months after randomization

The progression-free survival is the time from inclusion to the first radiological progression or death (all causes). For patients alive without progression date of last news will be considered. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions

Outcome measures

Outcome measures
Measure	Standard Arm (Escalation Strategy - Arm A) n=11 Participants LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 Participants (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
Progression Free Survival (PFS)	8.24 months Interval 4.27 to 12.19	13.22 months Interval 2.27 to 23.49

Adverse Events

Standard Arm (Escalation Strategy - Arm A)

Serious events: 4 serious events

Other events: 10 other events

Deaths: 6 deaths

Experimental Arm (De-escalation Strategy -Arm B)

Serious events: 0 serious events

Other events: 9 other events

Deaths: 5 deaths

Serious adverse events

Serious adverse events
Measure	Standard Arm (Escalation Strategy - Arm A) n=11 participants at risk LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 participants at risk (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
Cardiac disorders Cardiac arrest	9.1% 1/11 • Number of events 1 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
General disorders General physical health deterioration	9.1% 1/11 • Number of events 1 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
General disorders Hyperthermia	9.1% 1/11 • Number of events 1 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	9.1% 1/11 • Number of events 1 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Injury, poisoning and procedural complications Fall	9.1% 1/11 • Number of events 1 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.

Other adverse events

Additional Information

Karine Le Malicot

Fédération Francophone de Cancérologie Digestive

Phone: +33 3 80 39 34 79

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Standard Arm (Escalation Strategy - Arm A) n=11 participants at risk LV5FU2 +avastin then after progression: FOLFIRI + avastin and then after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. 5 FLUOROURACYL: administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). Irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid :administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. bevacizumab: administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy	Experimental Arm (De-escalation Strategy -Arm B) n=10 participants at risk (4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine 5 FLUOROURACYL: Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). acide folinique: 200 mg/m² if Elvorine irinotecan: administered IV at a dose of 180 mg/m² over 90 minutes. Oxaliplatin: administered IV at a dose of 85 mg/m² over 120 minutes. capécitabine: For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle last 21 days. bevacizumab: Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy
Cardiac disorders Hypertension	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	40.0% 4/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Ear and labyrinth disorders Vertigo	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Skin and subcutaneous tissue disorders Alopecia	36.4% 4/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Skin and subcutaneous tissue disorders Dry Skin	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	30.0% 3/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	27.3% 3/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	50.0% 5/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Renal and urinary disorders Proteinuria	36.4% 4/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	40.0% 4/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Nervous system disorders Cephalgia	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Nervous system disorders Sensitive peripheral neuropathy	54.5% 6/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	90.0% 9/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Gastrointestinal disorders Constipation	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	30.0% 3/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Gastrointestinal disorders Diarrhoea	72.7% 8/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	70.0% 7/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Gastrointestinal disorders Mucositis	54.5% 6/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	50.0% 5/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Gastrointestinal disorders Nausea	81.8% 9/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	40.0% 4/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Gastrointestinal disorders Vomiting	45.5% 5/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	30.0% 3/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Psychiatric disorders Anxiety	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Respiratory, thoracic and mediastinal disorders Epistaxis	36.4% 4/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Vascular disorders Thromboembolic event	0.00% 0/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Alanine aminotransferase increased	36.4% 4/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	40.0% 4/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Aspartate aminotransferase increased	45.5% 5/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Anemia	63.6% 7/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	80.0% 8/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Total Bilirubin increased	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Gamma-glutamyltransferase increased	81.8% 9/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	60.0% 6/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations White blood cell count decreased	27.3% 3/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	30.0% 3/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Neutrophils decreased	45.5% 5/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Phosphatases Alcalines increased	72.7% 8/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	60.0% 6/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Investigations Thombopenia	36.4% 4/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Metabolism and nutrition disorders Anorexia	36.4% 4/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Metabolism and nutrition disorders Hyperglycemia	18.2% 2/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	30.0% 3/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Metabolism and nutrition disorders Hyperkaliemia	45.5% 5/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	30.0% 3/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
Metabolism and nutrition disorders Hypoalbuminumia	27.3% 3/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	0.00% 0/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
General disorders Asthenia	72.7% 8/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	80.0% 8/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.
General disorders Fever	27.3% 3/11 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.	20.0% 2/10 • Up to the end of treatment for each patient. The mean time of treatment was 16 months. After patient could have another treatment and patients were followed only for overall survival up to 3 years after the treatment start.