A Trial Evaluating Raltitrexed, Oxaliplatin and Bevacizumab Combination Versus FOLFOX6 Plus Bevacizumab in 2nd-line Treatment of Metastatic Colorectal Cancer (BEVATOMOX)

• Treatment-related toxicity [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  Treatment-related toxicity is evaluated according to the NCI-CTCAE v.4 criteria.
• Objective response rate [ Time Frame: Every 9 weeks ] [ Designated as safety issue: No ]
  Objective response rate is evaluated according to the RECIST V 1.1 criteria.
• Overall survival [ Time Frame: unk ] [ Designated as safety issue: No ]
  OS is estimated from the date of randomization until the date of death from any cause
• Cost-effectiveness study [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  The cost-effectiveness study includes the number of hospital stays (treatment and toxicity), the global cost of treatments, and the cost of hospital stays due to treatment-induced toxicity
• Quality of life [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Quality of life is measured using the QLQ-C30 questionnaire

This phase 2 trial aims to evaluate the continued use of bevacizumab with raltitrexed and oxaliplatin combination versus FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer whose disease has progressed after irinotecan-based chemotherapy.

Eligible patients are randomly allocated to receive either bevacizumab with raltitrexed and oxaliplatin combination or bevacizumab with FOLFOX 6 combination. Random allocation schedule is performed using a minimization technique for the following stratification factors:

• Center
• Number of metastatic sites: 1 versus > 1
• Bevacizumab-based first-line therapy: Yes versus No

• Drug: bevacizumab, oxaliplatin and 5FU combination

  Bevacizumab 5 mg/kg administered as an iv infusion for 1h30, then for 1h and for 30 min. at the following cycles, respectively.

  Oxaliplatin 85 mg/m² administered as an iv infusion for 2h Elvorine 200 mg/m² administered as an iv infusion for 2h 5FU 400 mg/m2 bolus then 5FU 2,400 mg/m² iv infusion for 46h D1=D15 (12 cycles)

• Drug: Bevacizumab, oxaliplatin and raltitrexed combination

  Bevacizumab 7.5 mg/kg administered as an iv infusion for 1h30, then administered for 1h and 30 min at the following cycles, respectively.

  Oxaliplatin 130 mg/m² administered as an iv infusion for 2h Raltitrexed 3 mg/m² administered as an iv infusion for 15 min

• Experimental: Arm A
  FOLFOX6 + bevacizumab (D1=D15, 12 cycles)
  Intervention: Drug: bevacizumab, oxaliplatin and 5FU combination
• Experimental: Arm B
  Raltitrexed + Oxaliplatin + Bevacizumab (D1=D21, 8 cycles)
  Intervention: Drug: Bevacizumab, oxaliplatin and raltitrexed combination

Inclusion Criteria:

• Histologically proven colorectal cancer
• Resected or asymptomatic primary tumor
• Metastatic colorectal cancer not eligible for curative surgery
• No major surgery within four weeks of the start of study treatment
• At least one target lesion unidimensionally measurable on cross-sectional imaging according to RECIST criteria (v1.1)
• Disease progression after failure of irinotecan-based chemotherapy
• Bone metastases are allowed if there is at least one other measurable metastatic site
• CT scan of the abdomen, chest and pelvis within 3 weeks of the start of study treatment
• WHO PS ≤ 2
• Platelet count >= 100,000 mm3
• Hemoglobin > 10g/dl
• Bilirubin < 1.5 ULN, AST/ALT < 5 ULN
• Serum creatinine < 1.5 ULN, creatinine clearance > 60 ml/min (Cockcroft)
• A time period of 4 weeks should be respected between the end of previous treatments and study enrollment
• Negative pregnancy test in women of childbearing potential
• Male or female using an effective contraceptive method
• Absence of known or symptomatic brain metastases
• Life expectancy > 3 months
• Informed consent signed prior any study specific procedures

Exclusion Criteria:

• Prior raltitrexed-based chemotherapy
• Prior oxaliplatin-based chemotherapy (except for adjuvant treatment completed for more than 6 months)
• Uncontrolled arterial hypertension defined as systolic pressure > 150 mm Hg or diastolic pressure > 100 mm Hg
• Malignant hypertension or hypertensive encephalopathy
• Myocardial infarction, pulmonary embolism, or severe vascular disease within 6 months prior to study entry
• Hemorrhagic diathesis or significant pathology of coagulation
• Peripheral neuropathy grade>2 (NCI-CTC v4.0)
• Hemoptysis < 1 month
• Venous access device (PAC) or any other minor surgery such as a biopsy within the last 7 days
• Symptomatic brain metastases or carcinomatous meningitis
• History or presence of other cancer within the past 5 years (except curatively treated nonmelanoma skin cancer and in situ cervical cancer)
• Severe bacterial or fungal infection (Grade > 2 NCI-CTCAE v.4.0)
• Known or suspected sensitivity to one of the study drugs
• Pregnant or breastfeeding women
• Previous enrollment in an investigational drug study within the last 4 weeks
• Psychological, social, geographical disorders or any other condition that would preclude study compliance (treatment administration and study follow-up)