Interleukin-12 and Trastuzumab in Treating Patients With Cancer That Has High Levels of HER2/Neu

A Phase I Trial of Herceptin and Interleukin-12

Interleukin-12 may kill tumor cells by stopping blood flow to the tumor and by stimulating a person's white blood cells to kill cancer cells. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Phase I trial to study the effectiveness of interleukin-12 and trastuzumab in treating patients who have cancer that has high levels of HER2/neu and has not responded to previous therapy

OBJECTIVES:

I. Determine the maximum tolerated dose of interleukin-12 (IL-12) when combined with trastuzumab in patients with HER2-Neu overexpressing malignancies.

II. Determine the safety of this regimen in these patients.

III. Analyze any expression of interferon-inducible genes in tumor tissues of these patients after receiving this regimen.

IV. Characterize natural killer cytokine production in patients treated with this regimen.

V. Determine serum interferon gamma levels in patients treated with this regimen.

OUTLINE:

This is a dose escalation study of interleukin-12 (IL-12).

Patients receive an initial loading dose of trastuzumab IV over 90 minutes on day 1 of the first week and a maintenance dose of trastuzumab IV over 30-90 minutes on day 1 of each subsequent week. Patients receive IL-12 IV on days 2 and 5 beginning on week 3. Treatment with maintenance trastuzumab and IL-12 repeats weekly for 14 weeks in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease continue treatment for up to 38 additional weeks.

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

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

PROJECTED ACCRUAL: A total of 15 patients will be accrued for this study within 6 months.

Inclusion Criteria:

• Patients must have a histologically proven Her2 overexpressing malignancy as determined by any standardized assay currently in clinical use
• Patients must have measurable or evaluable disease
• The patient must have failed standard curative and/or palliative therapies for their disease
• Life expectancy of at least 6 months
• No concurrent malignancy other than non-melanoma skin carcinoma
• Adequate hematopoietic, cardiac, renal, and hepatic function
• Calculated creatinine clearance will be used to assess renal function
• Karnofsky Performance Status index >= 70%
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; a woman of childbearing potential is defined as a female who is biologically capable of becoming pregnant
• Normal cardiac ejection fraction by echocardiogram or MUGA (i.e., greater than OSU lower limit of normal)
• Written signed informed consent; the patient must be aware that his/her disease is neoplastic in nature and willingly consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts

Exclusion Criteria:

• History of significant peripheral neuropathy or significant central nervous system disease
• Brain or central nervous system metastasis at entry
• Active or unstable cardiovascular disease or cardiac disease requiring drug or device intervention; history of coronary artery disease or congestive heart failure
• Pregnant or nursing women
• Surgery, radiotherapy, chemotherapy, or hormonal therapy during the three weeks prior to the initiation of therapy
• Exposure to any investigational drug within three weeks prior to the start of dosing
• Concurrent use of systemic corticosteroids
• Known seropositive for hepatitis B surface antigen
• Known seropositive for HIV antibody
• Serious concurrent infection requiring intravenous antibiotic therapy
• Clinically significant autoimmune disease (e.g., rheumatoid arthritis)
• Clinically significant gastrointestinal bleeding or uncontrolled peptic ulcer disease
• History of inflammatory bowel disease
• Any other major illness which, in the investigator's judgment, will substantially increase the risk associated with the patient's participation in this study
• Prior therapy with Herceptin