This is a Phase Ib, open-label, multicenter, dose-escalation study designed to assess if PRO95780 in combination with two different irinotecan-containing regimens is safe and tolerable in patients with metastatic colorectal cancer (mCRC) who have progressed following, or cannot tolerate, first-line therapy with 5-fluorouracil-, oxaliplatin-, and bevacizumab-containing regimens. This study will also make a preliminary assessment of the anti-tumor activity of PRO95780 in combination with irinotecan and cetuximab or the FOLFIRI regimen plus bevacizumab.

Inclusion Criteria:

• Signed informed consent
• Age ≥ 18 years
• Histologically confirmed CRC with evidence of metastases and measurable tumor lesions
• Documented disease progression following, or intolerance to, treatment with 5-fluorouracil, oxaliplatin, and bevacizumab-based therapy
• Life expectancy > 3 months
• For patients of reproductive potential (males and females), use of reliable means for contraception (e.g., contraceptive pill, intrauterine device [IUD], physical barrier) throughout the trial and for 6 months following their final exposure to study treatment
• Willingness and capability to be accessible for study follow-up

Exclusion Criteria:

• Patients who have a Kras mutation will be excluded from receiving cetuximab-containing regimens
• Prior radiotherapy to a measurable metastatic lesion(s) to be used for response assessment, unless the lesion has progressed subsequent to the radiotherapy
• Recent radiotherapy to a peripheral lesion, thoracic, abdominal, or pelvic field
• Recent chemotherapy, hormonal therapy, or immunotherapy
• Evidence of clinically detectable ascites
• Other invasive malignancies within 5 years
• History or evidence of active central nervous system (CNS) disease
• Current or recent participation in another experimental drug study
• Clinically significant cardiovascular disease
• Active infection requiring parenteral antibiotics
• Recent major surgical procedure, open biopsy, significant traumatic injury, fine needle aspirations, or anticipation of need for major surgical procedure during the course of the study
• Known or suspected to be positive for the human immunodeficiency virus (HIV)
• Known to be positive for hepatitis C or hepatitis B surface antigen
• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or specified study treatment
• Pregnancy (positive pregnancy test) or breast feeding
• Serious, non-healing wound, ulcer, or bone fracture
• Known sensitivity to any of the products administered during the study
• Any disorder that compromises the ability of the patient to provide written informed consent and/or comply with study procedures