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

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of interleukin-12, paclitaxel, and trastuzumab in treating patients who have solid tumors. 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. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as trastuzumab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining interleukin-12, chemotherapy, and monoclonal antibody therapy may kill more tumor cells.

Detailed Description
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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.

Official Title
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Phase I Trial of Interleukin-12 in Combination With Paclitaxel Plus Herceptin in Patients With Her2-positive Malignancies

Conditions
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Male Breast Cancer, Recurrent Breast Cancer, Recurrent Endometrial Carcinoma, Recurrent Gastric Cancer, Recurrent Non-small Cell Lung Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Small Cell Lung Cancer

Intervention / Treatment
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* Biological: trastuzumab
* Drug: paclitaxel
* Biological: recombinant interleukin-12


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Biological: trastuzumab<br>* Given IV<br>* Other names: MOAB HER2;Drug: paclitaxel<br>* Given IV<br>* Other names: Taxol;Biological: recombinant interleukin-12<br>* Given SC<br>* Other names: Ro 24-7472;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of IL-12, defined as the dose level one level beneath that dose at which 2 or more of 6 patients showed DLT, based on the NCI CTC version 2.0 |  | Up to 21 days |