Interleukin-12, Paclitaxel, and Trastuzumab in Treating Patients With Solid Tumors

OBJECTIVES:

I. Determine the maximum tolerated dose of interleukin-12 when given in combination with paclitaxel and trastuzumab (Herceptin®) in patients with HER2/neu-overexpressing malignancies.

II. Determine the response rate and time to progression in patients treated with this regimen.

III. Determine the anti-tumor effect of this regimen in these patients.

OUTLINE: This is a dose-escalation study of interleukin-12.

Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes on days 1, 8, and 15 and paclitaxel IV over 3 hours on day 1 of course 1. Beginning with course 2, patients receive trastuzumab and paclitaxel as in course 1 and interleukin-12 subcutaneously on days 2, 5, 9, 12, 16, and 19. Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of interleukin-12 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed every 3 months for 1 year and then every 6 months thereafter.

Inclusion criteria

• Histologically confirmed HER2/neu-overexpressing (2+ or 3+) malignancy by any standardized assay (fluorescence in-situ hybridization allowed)
• Measurable or evaluable disease
• Failed standard curative therapy
• No brain or CNS metastasis
• Hormone receptor status:

• Not specified
• Male or female
• Performance status - Karnofsky 70-100%
• At least 6 months
• Absolute neutrophil count at least 1,500/mm^3
• Hemoglobin at least 8 g/dL (transfusion or epoetin alfa allowed)
• Platelet count at least 100,000/mm^3
• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST and ALT no greater than 3.0 times ULN
• Hepatitis B surface antigen negative
• Creatinine no greater than 1.5 times ULN
• Calcium no greater than 11 mg/dL (calcium-lowering agents allowed)
• No active or unstable cardiovascular disease
• No cardiac disease requiring drug or device intervention
• No coronary artery disease
• No congestive heart failure
• Cardiac ejection fraction normal by echocardiogram or MUGA scan
• No significant peripheral neuropathy
• No significant CNS disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No serious concurrent infection requiring IV antibiotic therapy
• No clinically significant autoimmune disease (e.g., rheumatoid arthritis)
• No clinically significant gastrointestinal bleeding
• No uncontrolled peptic ulcer disease
• No inflammatory bowel disease
• No other major illness that would preclude study participation
• No other concurrent malignancy except non-melanoma skin cancer or carcinoma in situ of the cervix
• No prior interleukin-12
• No prior trastuzumab (Herceptin®)
• At least 3 weeks since prior chemotherapy
• At least 3 weeks since prior hormonal therapy
• No concurrent systemic corticosteroids
• At least 3 weeks since prior radiotherapy
• At least 3 weeks since prior surgery
• At least 3 weeks since prior investigational drug