Monoclonal Antibody Therapy in Treating Patients With Advanced Colorectal Cancer

Phase I/II Study of MEDI-522, A Humanized Monoclonal Antibody Directed Against the Human Alpha V Beta 3 Integrin, in Patients With Irinotecan-Refractory Advanced Colorectal Cancer

RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells.

PURPOSE: Phase I/II trial to study the effectiveness of monoclonal antibody therapy in treating patients who have advanced colorectal cancer that has not responded to irinotecan.

OBJECTIVES:

• Determine the recommended phase II dose of monoclonal antibody anti-anb3 integrin in patients with irinotecan-refractory advanced colorectal cancer.
• Determine the safety and tolerance of this drug in these patients.
• Determine any antitumor activity of this drug in these patients.
• Determine the objective response rate, response duration, and time to progression in patients treated with this drug.
• Determine the pharmacokinetics of this drug in these patients.

OUTLINE: This is a dose-escalation study.

Patients receive monoclonal antibody anti-anb3 integrin IV over 30 minutes once weekly on weeks 1-52 in the absence of disease progression or unacceptable toxicity. Patients with responding disease may continue therapy.

Cohort of 4-6 patients receive escalating doses of monoclonal antibody anti-anb3 integrin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 4 or 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are treated at that dose in the phase II portion of the study.

Patients are followed every 3 months for 2 years.

PROJECTED ACCRUAL: A total of 4-24 patients will be accrued for phase I of this study and a total of 40 patients will be accrued for phase II of this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed advanced colorectal cancer

• Disease progression while receiving an irinotecan-containing regimen for metastatic colorectal cancer OR

• Disease recurrence within 6 months after completing an irinotecan-containing regimen in the adjuvant setting

• At least 1 measurable lesion (for phase II only)

  • At least 20 mm by x-ray, CT scan, MRI, or photograph

  • Recurrent disease after surgery or radiotherapy is considered measurable if it has been at least 4 weeks since treatment and measurable disease is outside the port of prior radiotherapy or there is evidence of disease progression within the port of prior radiotherapy

  • The following are not considered measurable:

    • Pleural effusion
    • Ascites
    • Osteoblastic lesion or evidence of disease on bone scan alone
    • Progressive irradiated lesions alone
    • Bone marrow involvement
    • Brain metastases
    • Malignant hepatomegaly by physical exam alone
    • Chemical markers (e.g., carcinoembryonic antigen)

• No known brain metastases or primary brain tumors

• No symptomatic pleural effusion or ascites requiring paracentesis

• No clinical evidence of bowel obstruction

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin greater than 10.0 g/dL

Hepatic:

• Bilirubin no greater than 2.0 mg/dL
• AST/ALT no greater than 5 times upper limit of normal (ULN)
• PT/PTT less than ULN OR
• INR less than 1.12
• No hepatitis virus infection

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance greater than 50 mL/min

Cardiovascular:

• No prior myocardial infarction
• No angina
• No uncontrolled hypertension (systolic blood pressure greater than 150 mm Hg)
• No prior cerebrovascular accident or transient ischemic attack

Pulmonary:

• No respiratory insufficiency requiring oxygen treatment
• No lymphangitic involvement of lungs

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 30 days before, during, and for 30 days after study
• Thyroxine and thyroid-stimulating hormone normal
• No hematemesis, melena, hematochezia, or gross hematuria
• No prior significant adverse reaction to a humanized monoclonal antibody
• No known HIV infection
• No active infection requiring systemic anti-infective therapy
• No other medical or psychological condition or behavior, including substance dependence or abuse, that would preclude study
• No other malignancy within the past 5 years except basal cell skin cancer or completely excised carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Prior immunotherapy with approved agents allowed
• No prior monoclonal antibody anti-anb3 integrin or its precursor (MEDI-523)
• No other concurrent immunotherapy

Chemotherapy:

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy
• No concurrent palliative chemotherapy

Endocrine therapy:

• No concurrent hormonal therapy

Radiotherapy:

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy

Surgery:

• See Disease Characteristics
• At least 4 weeks since prior surgery and surgical wounds must have healed

Other:

• Recovered from all prior therapy
• At least 4 weeks since prior investigational agents