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Phase 1 Trial Of Oral MAC-321 In Subjects With Advanced Malignant Solid Tumors.

A. Zhu, R. Bukowski, A. Lockhart, K. Wang, W. Cooper, J. Grover, M. Cohen, L. Appleman, M. Shapiro, M. Rothenberg
Published 2004 · Medicine

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2040 Background: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. METHODS This phase 1 ascending-dose study was performed to determine the safety and tolerability of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Key eligibility criteria included adult patients with refractory solid tumors, good performance status (ECOG ≤ 2), and adequate hematologic, hepatic, and renal function. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. RESULTS 18 patients (4 females, 14 males) were evaluated at 5 dose levels ranging from 25 to 75 mg/m2. Treatment was well tolerated at the first 3 dose levels (25, 37, 50 mg/m2). Two patients developed dose-limiting toxicities (DLTs) at 75 mg/m2 (1 patient with grade 3 neutropenia with fever, another patient had grade 4 neutropenia with fever). Three patients were treated at an intermediate dose level of 60 mg/m2 without DLTs. Other common toxicities included grade 1-2 fatigue and grade 1-2 diarrhea. Disease stabilization was seen in 4 patients with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). There was substantial interpatient variability in the PK parameters. MAC-321 was absorbed rapidly with mean Tmax less than 1 hour. Mean Cmax and AUC values generally increased in a dose-related manner. The elimination half-life ranged from 20-228 hours. CONCLUSIONS MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m2. The major DLT was neutropenic fever. Four patients had disease stabilization. This study is ongoing to confirm 60 mg/m2 as the maximum tolerated dose and to determine the oral bioavailability of MAC-321. [Table: see text].



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