Summary
A phase I trial of vincristine and etoposide was designed following the identification of a potentially synergistic antitumor effect in a murine model. The dose of vincristine was fixed (0.5 mg daily for 3 days). Etoposide was given at 1 of 3 total dose levels (250, 500, or 750 mg/m2) per treatment. Each dose was given in 3 equal fractions and each fraction was given daily for 3 days, i.e., 83.3 mg/m2/d × 3d, 166.7 mg/m2/d × 3d, or 250 mg/m2/d × 3d. A total of 31 patients were entered into study including 10, 18, and 3 patients treated at the 250, 500, and 750 mg/m2 dose levels, respectively. Dose-limiting toxicity occurred at the 750 mg/m2 level, in which Grade 4 myelosuppression developed in all of the patients. Life-threatening gram negative sepsis occurred in two of these patients and both required platelet transfusions. Grade 3–4 WBC toxicity was observed in 9 of 16 (56%) evaluable patients treated at the 500 mg/m2 level, but reversal of toxicity was generally rapid with repeat courses given at 3 week intervals in most patients. Non-hematologic toxicity was negligible. Objective responses were observed in 2 of 4 patients with Hodgkin's disease. The starting dose of etoposide recommended for phase II trials of this agent in combination with vincristine is 500 mg/m2; dose escalation may be possible in some patients.
Similar content being viewed by others
References
Jackson Jr DV, Long TR, Trahey TT, Morgan TM: Synergistic antitumor activity of vincristine and VP-16–213. Cancer Chemother Pharmacol 13:176–180, 1984
Jackson Jr DV, Long TR, Rice DG, Morgan TM: Combination of vincristine and VP-16–213: Evaluation of drug sequence. Cancer Biochem Biophys 8:265–275, 1986
Wolff SN, Fer MF, McKay CM, Hande KR, Hainsworth JD, Greco FA: High dose VP-16–213 and autologous bone marrow transplantation for refractory malignancies: A phase I study. J Clin Oncol 1:701–705, 1983
Johnson DH, Hande KR, Hainsworth JD, Greco FA: High dose etoposide as single-agent chemotherapy for small cell carcinoma of the lung. Cancer Treat Rep 67:957, 1983
Postmus PE, Mulder NH, Sleijfer DT, Meinesz AF, Vriesendorp R, deVries EGE: High-dose etoposide for refractory malignancies: A phase I study. Cancer Treat Report 68:1471–1474, 1985
Miller AB, Hoogstraten B, Staquet M, Winkler A: Reporting results of cancer treatment. Cancer 47:207, 1981
Jackson Jr DV, Wells HB, White DR, Muss HB, Richards II F, Cooper MR, Stuart JJ, Pope EK, Spurr CL: Lack of potentiation of vincristine induced neurotoxicity by VP-16–213. Am J Clin Oncol 6:327–330, 1983
Thant M, Hawley J, Smith MT, Cohen MH, Minna JD, Bunn PA, Ihde DC, West W, Matthews MJ: Possible enhancement of vincristine neuropathy by VP-16. Cancer 49:859–864, 1982
Jackson Jr DV, Bender RA: The clinical pharmacology of the vinca alkaloids, epipodophyllotoxins, and maytansine. In: Pinedo HM, Clinical Pharmacology of Anti-Neoplastic Drugs, New York, NY: Elsevier/North-Holland Biomedical Press B.V., 277–294, 1978
O'Dwyer PJ, Leyland-Jones B, Alonso MT, Marsoni S, Wittes RE: Drug therapy. Etoposide (VP-16–213). Current status of an active anticancer drug. N Engl J Med 312: 692–700, 1985
Jackson DV, Castel MC, Bender RA: Biliary excretion of [3H]-vincristine in man. Clin Pharmacol Ther 24:101–107, 1978
Hande KR, Wedlund PJ, Noone RM: Pharmacokinetics of high-dose etoposide (VP-16–213) administered to cancer patients. Cancer Research 44:379–382, 1984
Dombernowsky P, Nissen NI: Schedule dependency of the antileukemic activity of the podophyllotoxin-derivative VP-16–213 (NSC-141540) in L1210 leukemia. Acta Path Microbiol Scan 5:715–724, 1973
Jackson DV, Bender RA: Cytotoxic thresholds of vincristine in a murine and human leukemia cell line in vitro. Cancer Res 39:4346–4349, 1979
Radice PA, Bunn Jr PA, Ihde DC: Therapeutic trials with VP-16–213 and VM-26: active agents in small cell lung cancer, non-Hodgkin's lymphomas, and other malignancies. Cancer Treat Rep 63:1231–1239, 1979
Jackson DV: Periwinkle alkaloids II: vincristine. In: Lockich JJ, Cancer Chemotherapy by Infusion. Chicago: Precept Press, 181–199, 1987
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jackson, D.V., Cruz, J.M., Zekan, P.J. et al. Phase I study of vincristine and escalating doses of etoposide. Invest New Drugs 7, 203–207 (1989). https://doi.org/10.1007/BF00170858
Issue Date:
DOI: https://doi.org/10.1007/BF00170858