FOLFOX/Bevacizumab +/- MK-0646 in Metastatic Colorectal Cancer

Randomized, Double Blind Phase II Study of FOLFOX/Bevacizumab Combined With MK-0646 Versus FOLFOX/Bevacizumab Combined With Placebo in First-Line Treatment of Metastatic Colorectal Cancer

The purpose is to study the efficacy (effectiveness) of a new drug, MK-0646, in metastatic colorectal cancer. MK-0646 is an investigational or experimental anti-cancer agent that has not yet been approved by the U.S. Food and Drug Administration (FDA) for use in metastatic colorectal cancer or any other disease.

This study will assess whether adding MK-0646 to an FDA-approved standard of care chemotherapy improves participants' duration of progression-free survival. MK-0646 is believed to inhibit the receptor of a protein called IGF-1 (Insulin-like Growth Factor) which is thought to contribute to cancer development and growth. However, there is no guarantee that MK-0646 will slow cancer development and growth.

Other purposes of this study include:

• looking at the safety and tolerability of MK-0646
• comparing MK-0646 + standard of care chemotherapy with placebo + standard of care chemotherapy (placebo is a substance that looks like an active drug but has no active ingredient) The standard of care chemotherapy in this study is called FOLFOX 7. FOLFOX 7 includes the drugs oxaliplatin with leucovorin, 5-Fluorouracil (5-FU), and bevacizumab.

Participants randomized to ARM A will receive modified FOLFOX 7 every other week + MK-0646 every week:

5-FU 400 mg/m2 by intravenous infusion over 2-5 minutes Leucovorin 400 mg/m2 by intravenous infusion over 2 hours Oxaliplatin 85 mg/m2 by intravenous infusion over 2 hours (with leucovorin) Bevacizumab 5 mg/kg by intravenous infusion over 30 minutes (+/- 15 minutes) following infusions may be given over 10 minutes (+/- 10 minutes) if the first infusion is tolerated well.

5-FU 2400 mg/m2 by continuous intravenous infusion over 46 hours (may be delivered via automated outpatient pump) Antiemetics (drugs that prevent nausea and vomiting): 5-HT3 receptor antagonist (e.g. ondansetron) and dexamethasone are recommended prior to chemotherapy.

MK-0646 10 mg/kg by intravenous infusion over 60 minutes every week (participants larger than 100 kg [220 pounds] will receive their infusions over 120 minutes).

Participants randomized to ARM B will receive modified FOLFOX 7 every other week + placebo every week:

5-FU 400 mg/m2 by intravenous infusion over 2-5 minutes Leucovorin 400 mg/m2 by intravenous infusion over 2 hours Oxaliplatin 85 mg/m2 by intravenous infusion over 2 hours (with leucovorin) Bevacizumab 5 mg/kg by intravenous infusion over 30 minutes (+/- 15 minutes); following infusions may be given over 10 minutes (+/- 10 minutes) if the first infusion is tolerated well.

5-FU 2400 mg/m2 by continuous intravenous infusion over 46 hours (may be delivered via automated outpatient pump) Antiemetics: 5-HT3 receptor antagonist (e.g. ondansetron) and dexamethasone are recommended prior to chemotherapy Placebo by intravenous infusion over 60 minutes every week (participants larger than 100 kg [220 pounds] will receive their infusions over 120 minutes).

Inclusion Criteria:

• Metastatic colorectal adenocarcinoma.
• Measurable disease by RECIST criteria.
• Adequate hepatic function: total bilirubin ≤2.0 x upper limits of normal (ULN); Aspartate Amino Transferase (AST)/Alanine Amino Transferase (ALT) ≤3.0X upper limits of normal (or ≤5X upper limits of normal if attributable to liver metastases).
• Adequate renal function: serum creatinine ≤2.0 mg/dl.
• Adequate bone marrow function: absolute neutrophil count ≥1,500/mm3; platelets ≥ 100,000/mm3.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) levels ≤1.5 upper limit of normal (unless patients receiving coumadin anticoagulation in which case a stable international normalized ratio (INR) of 2-3 is required).
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Life expectancy ≥ 12 weeks.
• Negative pregnancy test.
• Ability to sign informed consent.

Exclusion Criteria:

• Prior systemic chemotherapy for metastatic colorectal cancer
• Prior oxaliplatin in the adjuvant setting within 12 months
• Uncontrolled central nervous system metastases or carcinomatous meningitis.
• Myocardial infarction in the past 6 months.
• Major surgery within 8 weeks prior to enrollment.
• Uncontrolled serious medical or psychiatric illness.
• Inadequately controlled hypertension (defined as systolic blood pressure >160mmHg, or diastolic blood pressure > 100mmHg).
• Pregnant or lactating women. Both men and women of childbearing potential must be advised of the importance of using effective birth control measures during the course of study.
• Prior experimental therapy targeting the IGF-1 pathway
• Concurrent malignancy (with the exception of squamous or basal cell skin carcinoma)
• Planned surgical metastasectomy
• Patient has known hypersensitivity to components of treatment, their analogs, or drugs of similar chemical or biologic composition