IMC-A12 in Treating Patients With Advanced Liver Cancer

PRIMARY OBJECTIVES:

I. To determine the progression-free survival (PFS) at 4 months in patients with advanced hepatocellular carcinoma (HCC) treated with anti-IGF-1R recombinant monoclonal antibody IMC-A12.

II. To determine the best overall response rate in patients treated with this drug.

SECONDARY OBJECTIVES:

I. To determine the median overall survival of patients treated with this drug. II. To evaluate the safety, tolerability, and adverse events profile of this drug in these patients.

III. To perform a subgroup analysis to compare PFS of patients with advanced HCC who are hepatitis B positive/hepatitis C negative versus patients who are hepatitis B negative/hepatitis C positive treated with this drug.

IV. To store pre-therapy paraffin embedded tumor tissue for future tissue-based correlative studies.

V. To evaluate tumor necrotic areas using a new volumetric method of assessing non-viable tumor as a correlate for response.

VI. To prospectively validate and compare the CLIP and the GDETCH staging systems and additional prognostic factors.

OUTLINE: Patients receive anti-IGF-1R recombinant monoclonal antibody IMC-A12 IV over 1 hour once weekly. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo serum sample collection at baseline for future tissue-based correlative studies. Previously collected paraffin embedded tumor tissue samples are also stored for future correlative studies.

After completion of study treatment, patients are followed every 3 months for at least 1 year.

Inclusion criteria

• Histologically or cytologically confirmed hepatocellular carcinoma

• Unresectable, locally advanced, or metastatic disease
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
• Child's Pugh score A5, A6, B7, or B8
• No known brain metastases
• No history of primary CNS tumors
• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 3 months
• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 75,000/mcL
• Total bilirubin ≤ 2 times upper limit of normal (ULN)
• AST/ALT ≤ 2.5 times ULN
• PT/INR ≤ 1.7 times ULN
• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min
• Fasting serum glucose ≤ 125 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No clinical encephalopathy
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to anti-IGF-1R recombinant monoclonal antibody IMC-A12
• No poorly controlled diabetes mellitus

• Patients with a history of diabetes mellitus are eligible provided their blood glucose is within normal range (fasting blood glucose < 120 mg/dL OR below ULN) and patient is on a stable dietary or therapeutic regimen for this condition
• No concurrent uncontrolled illness including, but not limited to, any of the following:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness or social situation that would preclude compliance with study requirements
• No history of seizures not well controlled with standard medical therapy
• No history of stroke
• No history of another primary cancer except for the following:

• Curatively resected nonmelanoma skin cancer
• Curatively treated carcinoma in situ of the cervix
• Other primary solid tumor with no known active disease present that in the opinion of the investigator would not affect treatment outcome
• Prior local therapy (i.e., surgery, radiotherapy, hepatic arterial embolization, radiofrequency ablation, percutaneous ethanol injection, or cryoablation) allowed provided the target lesion has not been treated with local therapy and/or the target lesion within the field of local therapy has shown an increase of ≥ 25% in size

• At least 4 weeks since prior local therapy
• No prior systemic therapy except for sorafenib tosylate
• No prior agents targeting the IGF or IGF-1R pathway
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No concurrent anticancer therapy