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Phase I study of the taxane BMS-188797 in combination with carboplatin administered every 3 weeks in patients with
Mayer N Fishman1, Christopher R Garrett, George R Simon
1Experimental Therapeutics and Phase I Programs, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA..
Rationale:
BMS-188797 is one of several novel taxanes in ongoing clinical development. It has superior activity in experimental tumor models when compared with paclitaxel. BMS-188797 has a single C-4 modification, a 4-desacetyl-4-methylcarbonate, compared with paclitaxel.
Methods:
We did a phase I study, in which a fixed dose of carboplatin was combined with a dose escalation schedule of BMS-188797, both administered once every 3 weeks, in patients with advanced solid malignancies.
Results:
Thirty patients were treated, 11 at the proposed recommended phase II dose. The dose-limiting toxicity was myelosuppression. There was a linear relationship between administered dose of BMS-188797 and the measured area under the curve (AUC). There was significant interpatient variability of BMS-188797 AUC at the maximum tolerated dose. Two radiographic partial responses were observed: one patient with duodenal adenocarcinoma and one patient with esophageal adenocarcinoma (time on study, 19 and 30 weeks, respectively).
Conclusion:
The recommended phase II dose for BMS-188797 and carboplatin administered on a once-every-3 week schedule is carboplatin AUC = 5 mg min/mL and BMS-188797 at a dose of 135 mg/m(2).
Insights
This Phase I trial determined the recommended dose for BMS-188797, a novel taxane, combined with carboplatin for advanced cancers. The recommended Phase II dose was established as carboplatin AUC 5 mg min/mL and BMS-188797 135 mg/m².
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- BMS-188797 is a novel taxane derivative with demonstrated superior preclinical activity compared to paclitaxel.
- The drug features a unique C-4 modification (4-desacetyl-4-methylcarbonate).
Purpose of the Study:
- To evaluate the safety and determine the recommended Phase II dose of BMS-188797 in combination with carboplatin.
- To assess the pharmacokinetic profile of BMS-188797 in patients with advanced solid malignancies.
Main Methods:
- A Phase I clinical study involving dose escalation of BMS-188797 with a fixed dose of carboplatin.
- Both agents were administered intravenously every 3 weeks to patients with advanced solid tumors.
Main Results:
- Thirty patients were enrolled; 11 reached the proposed Phase II dose.
- Myelosuppression was the dose-limiting toxicity.
- A linear dose-exposure relationship was observed for BMS-188797, with significant interpatient variability in AUC at the maximum tolerated dose.
- Two partial responses were noted in patients with duodenal and esophageal adenocarcinoma.
Conclusions:
- The recommended Phase II dose for the combination regimen is carboplatin AUC 5 mg min/mL and BMS-188797 135 mg/m².
- This dose is to be administered on a 3-week schedule for patients with advanced solid malignancies.
