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A Randomized Phase I Trial of Chronic Oral Etoposide with or without Granulocyte-Macrophage Colony-stimulating Factor in Patients with Advanced Malignancies¹

Brooke Army Medical Center, Fort Sam Houston, Texas 78234-6200 [D. S., S., H. A. B., D. A. R., K. J. B.]; Cancer Therapy and Research Center of South Texas, San Antonio, Texas 78229 [L. S. S., J. R. E., S. M. F., G. R. W., D. D. V. H.]; and the University of Texas Health Science Center, San Antonio, Texas 78284 [G. M. C., J. G. K., D. D. V. H.]

Data from an in vitro human tumor-cloning assay suggested synergistic cytotoxicity when etoposide (VP16) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined. To explore this potential, we undertook a prospectively randomized three-arm trial in a phase I setting with various schedules of VP16 and GM-CSF. Thirty-one patients were enrolled in the three-arm trial. Arm A consisted of oral VP16 daily for up to 21 days with cycles repeated every 35 days. Arm B included oral VP16 daily for up to 21 days plus concomitant GM-CSF at 5 µg/kg/day s.c. days 1–10. Arm C included oral VP16 daily for up to 21 days plus pretreatment with GM-CSF at the same dose for 5 days (days –6 to –2). VP16 was begun at 25 mg/m²/day on level 1 and increased to 50 mg/m²/day on level 2. Twenty-seven patients were evaluable for toxicity, nine on each arm (six patients on each arm on level 1, three patients on each arm on level 2). Neutropenia on arm B (concomitant VP16 and GM-CSF) was earlier and more profound than on arm A or C. The median absolute neutrophil count and day of nadir for arms A, B, and C were 3295, 988, and 1600/mm³ and days 23, 15, and 26, respectively. Thrombocytopenia was generally uncommon except on arm C level 2, where the median platelet count was 26,000/mm³. One partial response (arm B) in a patient with non-small cell lung cancer was seen. Dose intensity favored arm A. Neither concomitant therapy with VP16 and GM-CSF (arm B) nor pretreatment with GM-CSF (arm C) improved dose intensity over VP16 alone (arm A), and arms B and C were complicated by increased neutropenia and thrombocytopenia.

¹ Supported in part by a grant from Schering-Plough Corporation and Cancer Center Support Grant 5P01-CA54-174-02. Presented in part at the 83rd Annual Meeting of the American Association of Cancer Research.

² To whom requests for reprints should be addressed, at Cancer Therapy and Research Center, 8122 Datapoint Drive, Suite 700, San Antonio, TX 78229.

Received 8/ 5/93. Accepted 10/12/93.

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