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

Abstract

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.

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

“…All patients were hospitalized for the duration of the treatment. The starting dose (81 mg/m 2 ) corresponded to 1 dose level lower than the MTD in humans 9,10 . DRF‐1042 was administered orally in the morning on an empty stomach to the first 3 patients for 5 consecutive days for 2 weeks every 3 weeks.…”

“…In addition, 2 partial responses were documented in 1 patient each with osteosarcoma and breast carcinoma. Four patients also had disease stabilization 9,10 …”

Perspectives on Biologically Active Camptothecin Derivatives

“…For example, 5‐propionyl and 5‐ethoxy derivatives bearing a hydroxy, methoxy, or fluoro group at the β‐position showed good antitumor activity. One of these analogs, DRF‐1042, is currently in phase II clinical trials . These findings prompted other studies to investigate the role of modification at the C‐5 position.…”

“…You et al 46 reported a series of 7-cycloalkylcamptothecin derivatives (53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66). As shown in Table III, many of the compounds exhibited IC 50 values in the low moicromolar-to-nanomolar level and were up to 40-fold more potent than 3, the reference compound.…”

“…One of these analogs, DRF-1042, is currently in phase II clinical trials. 64 These findings prompted other studies to investigate the role of modification at the C-5 position. In 2009, using an enolate chemical protocol, in addition to C5-alkylated derivatives, new C5-fluorinated (96) and C5-aminated analogs (97), along with the first six-membered ring CPT derivative (98) ( Fig.…”