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A Phase I Trial of ISIS 2503, an Antisense Inhibitor of H-ras, in Combination with Gemcitabine in Patients with Advanced Cancer¹

Departments of Oncology [A. A. A., C. E., J. M. R., J. A. S., H. C. P., S. R. A., R. M. G., L. J. H., P. J. A.] and Medicine [G. K. D.], Mayo Clinic and Foundation, Rochester, Minnesota 55905, and ISIS Pharmaceuticals, Carlsbad, California 92008 [T. W., R. S. G., J. H., F. A. D.]

Purpose: The purpose of this study was to define the toxicity, pharmacokinetics, and clinical activity of the combination of ISIS 2503, an oligodeoxynucleotide antisense inhibitor of H-ras, and gemcitabine in patients with advanced solid tumors.

Experimental Design: The target dose of ISIS 2503 on this study was 6 mg/kg/day. Twenty-seven patients (16 male, 11 female) received 97 treatment courses (median, 2; range, 1–13). Nineteen patients were treated with a fixed gemcitabine dose of 1000 mg/m² on days 1 and 8 and two escalating doses of ISIS 2503 (4 and 6 mg/kg/day) as a 14-day continuous infusion starting on day 1. In addition, 8 patients (5 male, 3 female) received a flat dose of ISIS 2503 based on ideal body weight. Cycles were repeated every 3 weeks. Toxicities, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded as maximum grade/patient for all treatment cycles. Pharmacokinetic analyses were performed to evaluate any interaction between these two agents.

Results: The most common nondose-limiting toxicity was hematological, manifested as neutropenia (5 grade 2, 7 grade 3, and 1 grade 4) and thrombocytopenia (10 grade 1, 5 grade 2, 5 grade 3, and 1 grade 4). Nonhematological toxicities included anorexia (7 grade 1, 3 grade 2, and 1 grade 3), nausea (10 grade 1 and 1 grade 3), fatigue (6 grade 1, 5 grade 2, and 3 grade 3), fever (6 grade 1, 2 grade 2, 1 and grade 3), and thrombosis associated with central lines (5). The plasma concentration of gemcitabine at the end of infusion was altered in the presence of ISIS 2503, leading to alterations on other pharmacokinetic parameters, but the observed differences were not clinically relevant. The plasma disposition of ISIS 2503 was not altered by gemcitabine coadministration. One partial response was documented in a heavily pretreated patient with metastatic breast cancer. Disease stabilization for greater than six cycles of treatment was observed in 5 patients.

Conclusions: The combination of gemcitabine and ISIS 2503 was well tolerated and clinically active in this group of heavily pretreated patients. The recommended Phase II dose of gemcitabine (1000 mg/m²) and ISIS 2503 (6 mg/kg/day) warrants additional evaluation.

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