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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
Author(s) -
Chatterjee Arani,
Digumarti Raghunadharao,
Mamidi Rao N. V. S.,
Katneni Kasiram,
Upreti Vijay V.,
Surath Anjna,
Srinivas Maddali L.,
Uppalapati Srihari,
Jiwatani Sangeeta,
Subramaniam Swaminathan,
Srinivas Nuggehally R.
Publication year - 2004
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270004265647
Subject(s) - pharmacokinetics , medicine , camptothecin , tolerability , pharmacodynamics , refractory (planetary science) , diarrhea , adverse effect , pharmacology , cmax , gastroenterology , chemistry , physics , organic chemistry , astrobiology
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.