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.
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/m(2). 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/m(2)/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/m(2)/day.
Chatterjee
Arani
A
Dr. Reddy's Laboratories, Discovery Research, Bollaram Road, Miyapur, Hyderabad-500 049, India.
Digumarti
Raghunadharao
R
Mamidi
Rao N V S
RN
Katneni
Kasiram
K
Upreti
Vijay V
VV
Surath
Anjna
A
Srinivas
Maddali L
ML
Uppalapati
Srihari
S
Jiwatani
Sangeeta
S
Subramaniam
Swaminathan
S
Srinivas
Nuggehally R
NR
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents; C484816:DRF-1042; D002166:Camptothecin