A Translational Study of Avastin (Bevacizumab) in Patients With Metastatic Colorectal Cancer (ASCENT)

• Progression-free survival during Phase A [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Progression-free survival during Phase B [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Time to failure of strategy [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Duration of disease control [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Overall survival from the start of treatment to study completion [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Survival beyond 1st progression [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Overall survival during Phase B [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Overall response rate [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Rate of liver resection [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Safety: incidence of adverse events [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]

This open-label, prospective, single-arm, multicenter study will evaluate the relationship of the markers of inflammation and progression-free survival in patients with previously untreated metastatic colorectal cancer. The study consists of two phases: Phase A treatment: XELOX plus Avastin (bevacizumab), or mFOLFOX6 plus Avastin administered until first disease progression. Patients will then continue with Phase B treatment: FOLFIRI plus Avastin until second disease progression. The anticipated time on study treatment is 4 years.

• Drug: bevacizumab [Avastin]
  7.5 mg/kg intravenously on Day 1 of every 3 weeks cycle until 1st disease progression
• Drug: XELOX
  Oxaliplatin 130 mg/m2 intravenously on Day 1, capecitabine 1000 mg/m2 orally twice daily on Days 1-14 of every 3 weeks cycle until 1st disease progression
• Drug: bevacizumab [Avastin]
  5.0 mg/kg intravenously on Day 1 every 2 weeks until 1st disease progression
• Drug: mFOLFOX6
  Oxaliplatin 85 mg/m2 intravenously on Day 1, leucovorin 400 mg/m2 intravenously on Day 1, fluorouracil 400 mg/m2 on Day 1, fluorouracil 2400 mg/m2 intravenous infusion on Day 1 every two weeks until 1st disease progression
• Drug: bevacizumab [Avastin]
  5.0 mg/kg intravenously on Day 1 every 2 weeks until 2nd disease progression
• Drug: FOLFIRI
  Irinotecan 180 mg/m2 intravenously on Day 1, leucovorin 400 mg/m2 on Day 1, fluorouracil 400 mg/m2 on Day 1, fluorouracil 2400 mg/m2 intravenous infusion on Day 1 every 2 weeks until 2nd disease progression

• Experimental: Phase A Treatment
  Interventions:

  • Drug: bevacizumab [Avastin]
  • Drug: XELOX
• Experimental: Alternative Phase A Treatment
  Interventions:

  • Drug: bevacizumab [Avastin]
  • Drug: mFOLFOX6
• Experimental: Phase B Treatment
  Interventions:

  • Drug: bevacizumab [Avastin]
  • Drug: FOLFIRI

Inclusion Criteria:

Resected primary tumor patients, and patients with primary tumor in situ:

• Adult patients, >/= 18 years of age
• Previously untreated metastatic colorectal cancer and not a candidate for curative resection
• WHO performance status of 0-1
• Life expectancy of >/= 3 months
• Eligible for XELOX, mFOLFOX6, FOLFIRI and Avastin treatment in accordance with local standards of care and pharmaceutical benefits scheme

Additional inclusion criteria for patients with primary tumor in situ:

• Intact primary tumor of the colon or the rectum not requiring surgical intervention prior to study start
• Minimal or asymptomatic primary tumor

Exclusion Criteria:

Resected primary tumor patients, and patients with primary tumor in situ:

• Previous chemotherapy for metastatic colorectal cancer
• Previous neoadjuvant or adjuvant chemotherapy less than 6 months prior to study start
• Radiotherapy within 28 days prior to enrolment or not recovered from a radiotherapy
• History of non-colorectal cancer (patients are eligible if disease-free for more than 5 years and the risk of recurrence is deemed low)
• Presence of active inflammatory bowel disease
• History of gastrointestinal perforations
• Peritoneal disease
• History of significant bleeding event
• Significant vascular disease
• Peripheral arterial thrombosis or other thrombotic event within 6 months before study start

Additional exclusion criteria for patients with primary tumor in situ:

• Prior endoscopic management of the current tumor
• Acute diverticulitis
• Presence of intra-abdominal abscess
• Active gastroduodenal ulcer