Abstract
Purpose: 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. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. Methods: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. Results: Five dose levels of MAC-321 ranging from 25 to 75 mg/m2 were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m2). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m2; one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m2 had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C max value of less than 1 h. Mean C max and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). 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 subjects had disease stabilization.
Original language | English (US) |
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Pages (from-to) | 203-209 |
Number of pages | 7 |
Journal | Cancer Chemotherapy And Pharmacology |
Volume | 60 |
Issue number | 2 |
DOIs | |
State | Published - Jul 2007 |
Externally published | Yes |
Keywords
- Clinical trial
- Docetaxel
- MAC-321
- Paclitaxel
- Phase I
ASJC Scopus subject areas
- Oncology
- Toxicology
- Pharmacology
- Cancer Research
- Pharmacology (medical)