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Phase I Trial of Consensus Interferon in Patients with Metastatic Renal Cell Carcinoma

Toxicity and Immunological Effects¹

Experimental Therapeutics Program [T. E. H., T. M., P. E., J. F., C. T., R. D., T. O., R. M. B.] and Center for Drug Development [E. B.], Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, and Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation [L. M., J. F., C. T., R. M. B.], Cleveland, Ohio 44195

Purpose: The purpose of our study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and effects on chemokine/cytokine gene expression in peripheral blood mononuclear cells (PBMCs) of consensus IFN (CIFN).

Experimental Design: Cohorts of three to six patients with metastatic renal cell carcinoma (RCC) were treated with escalating doses of CIFN (dose level I, 9.0 µg/m²; dose level II, 15.0 µg/m²; dose level III, 21.0 µg/m²) given s.c. three times weekly in 4-week cycles until progression. The cohort treated at the maximum tolerated dose was expanded to further define toxicity. An additional three patients were treated with i.v. CIFN (15.0 µg/m²) to evaluate route-related differences in gene expression. Cytokine and chemokine gene expression in PBMCs was assessed by reverse transcription-PCR.

Results: A total of 25 patients (18 men and 7 women) were enrolled between January 28, 1999, and November 1, 2000, at dose levels I (n = 4), II (n = 14), and III (n = 7). Dose-limiting toxicity occurred at dose level III (21 µg/m²) and included grade-3 or -4 respiratory distress/failure (n = 3) and hypocalcemia (n = 1) occurring within the first cycle of treatment. Other severe toxicities included grade-3 neutropenia, thrombocytopenia, fatigue, and nausea/vomiting. Studies of cytokine and chemokine gene expression in PBMCs from eight patients revealed induction of IFN-, IP-10, and Mig. I.V. administration was associated with a faster induction, but of shorter duration. There were no responses; however, 24 patients had stable disease of variable duration (4–32 weeks) and received a median of three cycles of treatment (range, 1–8 cycles). Overall median survival was 13.5 months, and was 12.7 months in the previously treated patients.

Conclusion: CIFN was safely administered s.c. three times weekly at doses up to 15.0 µg/m². Although there were no responses, the median survival was longer than expected in a previously treated patient population with metastatic RCC.

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