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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of an Orally Active Novel Camptothecin Analog, DRF-1042, in Refractory Cancer Patients in a Phase I Dose Escalation Study

From Dr. Reddy's Laboratories Ltd., Hyderabad, India (A. Chatterjee, R. N. V. S. Mamidi, K. Katneni, V. V. Upreti, S. Subramaniam, N. R. Srinivas) and Nizam's Institute of Medical Sciences, Hyderabad, India (R. Digumarti, A. Surath, M. L. Srinivas, S. Uppalapati, S. Jiwatani). Source of research support: Dr. Reddy's Laboratories Ltd., Hyderabad, India.

The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m². Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m²/day. AUC increased approximately linearly with dose. The t_1/2 for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m²/day.

Key Words: DRF-1042 • camptothecin • pharmacokinetics • pharmacodynamics • maximum tolerated dose • dose-limiting toxicities • cancer

Address for reprints: Dr. Nuggehally R. Srinivas, FCP, Dr. Reddy's Laboratories, Discovery Research, Bollaram Road, Miyapur, Hyderabad—500 049, India.

This article has been cited by other articles:

				A. Chatterjee, R. Digumarti, K. Katneni, V. V. Upreti, R. N. V. S. Mamidi, R. Mullangi, A. Surath, M. L. Srinivas, S. Uppalapati, S. Jiwatani, et al. Safety, Tolerability, and Pharmacokinetics of a Capsule Formulation of DRF-1042, a Novel Camptothecin Analog, in Refractory Cancer Patients in a Bridging Phase I Study J. Clin. Pharmacol., April 1, 2005; 45(4): 453 - 460. [Abstract] [Full Text] [PDF]