Phase I and Pharmacokinetic Study of BMS-188797, a New Taxane Analog, Administered on a Weekly Schedule in Patients with Advanced Malignancies

• Published in: Clinical cancer research Vol. 9; no. 14; pp. 5187 - 5194
• Main Authors: ADVANI, Ranjana, FISHER, George A, LUM, Bert L, JAMBALOS, Charro, CHO, Cheryl D, COHEN, Marvin, GOLLERKERI, Ashwin, SIKIC, Branimir I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.11.2003
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Agents, Phytogenic - toxicity; Area Under Curve; Biological and medical sciences; Chemotherapy; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Medical sciences; Middle Aged; Neoplasms - drug therapy; Neoplasms - metabolism; Pharmacology. Drug treatments; Safety; Salvage Therapy; Taxoids - administration & dosage; Taxoids - pharmacokinetics; Taxoids - toxicity; Antineoplastic agent; Human; Solid tumor; Intravenous administration; Administration schedule; Malignant tumor; Blood plasma; Chemotherapy; Treatment; Analog; Taxane derivatives; Phase I trial; Advanced stage; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265

Purpose: The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly. Experimental Design: Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797. Results: Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m 2 . The number of patients evaluated at each dose level was as follows: 35 mg/m 2 ( n = 3); 50 mg/m 2 ( n = 9); and 65 mg/m 2 ( n = 6). At 65 mg/m 2 , three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m 2 dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration ( C max ) and area under the curve (AUC 0–48 ) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC. Conclusions: The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m 2 . The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.