Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies

Robert J. Morgan, Edward M. Newman, Lawrence Sowers, Kevin Scanlon, Jonathan Harrison, Steven Akman, Lucille Leong, Kim Margolin, Joyce Niland, James Raschko, George Somlo, Mary Carroll, Warren Chow, Merry Tetef, Victor Hamasaki, Yun Yen, James H. Doroshow

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Purpose: Azidothymidine (AZT, zidovudine) has been shown to reverse cisplatin resistance in cell culture. This phase I study was performed to determine the maximally tolerated dose (MTD) and dose-limiting toxicities of AZT when administered by continuous intravenous infusion in combination with cisplatin (CDDP), and to evaluate the pharmacokinetics of AZT in this setting. Patients and methods: Entered in the study were 61 patients with advanced, histologically confirmed malignancies which were unresponsive to or for which no "standard" chemotherapeutic regimen existed. AZT was administered as a 72-h infusion on days 1-3 and 14-16 of a 28-day cycle at dose levels from 400 through 14,364 mg/m2 per day. CDDP at dose levels of 30, 45, or 60 mg/m2 was administered at hour 36 of each AZT infusion. The plasma pharmacokinetics of AZT were determined in patients treated at representative dose levels. Results: Of the 61 patients who completed 125 courses of therapy, 21 had stable disease for a median of four cycles (range two to eight), 33 progressed on therapy, and 7 were not assessable for response. The major observed toxicity was myelosuppression. The MTD of AZT was 8135 mg/m2 per day when administered on this schedule. Escalation of CDDP did not result in additive toxicity. The mean steady-state level of AZT at the MTD was 44 μM (range 35-51 μM). Conclusions: Steady-state concentrations of AZT increased with dose. The plasma levels achieved at the MTD exceeded those required for drug resistance reversal in vitro. The administration of CDDP had no effect on AZT steady-state levels. The dose-limiting toxicity of this drug combination is myelosuppression. AZT may be useful in further studies utilizing combination therapy to achieve increased chemotherapy effectiveness.

Original languageEnglish
Pages (from-to)459-464
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume51
Issue number6
Publication statusPublished - Jun 1 2003
Externally publishedYes

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Maximum Tolerated Dose
Zidovudine
Toxicity
Pharmacokinetics
Cisplatin
Neoplasms
Plasmas
Chemotherapy
Drug Combinations
Therapeutics
Cell culture
Drug Resistance
Intravenous Infusions
Appointments and Schedules
Cell Culture Techniques
Drug Therapy
Pharmaceutical Preparations

Keywords

  • Azidothymidine
  • AZT
  • Cisplatin
  • Phase I trial

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Morgan, R. J., Newman, E. M., Sowers, L., Scanlon, K., Harrison, J., Akman, S., ... Doroshow, J. H. (2003). Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies. Cancer Chemotherapy and Pharmacology, 51(6), 459-464.

Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies. / Morgan, Robert J.; Newman, Edward M.; Sowers, Lawrence; Scanlon, Kevin; Harrison, Jonathan; Akman, Steven; Leong, Lucille; Margolin, Kim; Niland, Joyce; Raschko, James; Somlo, George; Carroll, Mary; Chow, Warren; Tetef, Merry; Hamasaki, Victor; Yen, Yun; Doroshow, James H.

In: Cancer Chemotherapy and Pharmacology, Vol. 51, No. 6, 01.06.2003, p. 459-464.

Research output: Contribution to journalArticle

Morgan, RJ, Newman, EM, Sowers, L, Scanlon, K, Harrison, J, Akman, S, Leong, L, Margolin, K, Niland, J, Raschko, J, Somlo, G, Carroll, M, Chow, W, Tetef, M, Hamasaki, V, Yen, Y & Doroshow, JH 2003, 'Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies', Cancer Chemotherapy and Pharmacology, vol. 51, no. 6, pp. 459-464.
Morgan, Robert J. ; Newman, Edward M. ; Sowers, Lawrence ; Scanlon, Kevin ; Harrison, Jonathan ; Akman, Steven ; Leong, Lucille ; Margolin, Kim ; Niland, Joyce ; Raschko, James ; Somlo, George ; Carroll, Mary ; Chow, Warren ; Tetef, Merry ; Hamasaki, Victor ; Yen, Yun ; Doroshow, James H. / Phase I study of cisdiamminedichloroplatinum in combination with azidothymidine in the treatment of patients with advanced malignancies. In: Cancer Chemotherapy and Pharmacology. 2003 ; Vol. 51, No. 6. pp. 459-464.
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AU - Sowers, Lawrence

AU - Scanlon, Kevin

AU - Harrison, Jonathan

AU - Akman, Steven

AU - Leong, Lucille

AU - Margolin, Kim

AU - Niland, Joyce

AU - Raschko, James

AU - Somlo, George

AU - Carroll, Mary

AU - Chow, Warren

AU - Tetef, Merry

AU - Hamasaki, Victor

AU - Yen, Yun

AU - Doroshow, James H.

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N2 - Purpose: Azidothymidine (AZT, zidovudine) has been shown to reverse cisplatin resistance in cell culture. This phase I study was performed to determine the maximally tolerated dose (MTD) and dose-limiting toxicities of AZT when administered by continuous intravenous infusion in combination with cisplatin (CDDP), and to evaluate the pharmacokinetics of AZT in this setting. Patients and methods: Entered in the study were 61 patients with advanced, histologically confirmed malignancies which were unresponsive to or for which no "standard" chemotherapeutic regimen existed. AZT was administered as a 72-h infusion on days 1-3 and 14-16 of a 28-day cycle at dose levels from 400 through 14,364 mg/m2 per day. CDDP at dose levels of 30, 45, or 60 mg/m2 was administered at hour 36 of each AZT infusion. The plasma pharmacokinetics of AZT were determined in patients treated at representative dose levels. Results: Of the 61 patients who completed 125 courses of therapy, 21 had stable disease for a median of four cycles (range two to eight), 33 progressed on therapy, and 7 were not assessable for response. The major observed toxicity was myelosuppression. The MTD of AZT was 8135 mg/m2 per day when administered on this schedule. Escalation of CDDP did not result in additive toxicity. The mean steady-state level of AZT at the MTD was 44 μM (range 35-51 μM). Conclusions: Steady-state concentrations of AZT increased with dose. The plasma levels achieved at the MTD exceeded those required for drug resistance reversal in vitro. The administration of CDDP had no effect on AZT steady-state levels. The dose-limiting toxicity of this drug combination is myelosuppression. AZT may be useful in further studies utilizing combination therapy to achieve increased chemotherapy effectiveness.

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