Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors
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This phase I trial determined the recommended dose for phase II trials (RD) of carboplatin 1-h intravenous (i.v.) infusion followed by PM00104 1-h i.v. infusion on Day 1 every 3 weeks (q3wk) in adult patients with advanced solid tumors. A toxicity-guided, dose-escalation design was used. Patients were stratified and divided into heavily (n = 6) or mildly pretreated (n = 14) groups. Transient grade 4 thrombocytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m2 was the RD in both groups. At this RD, the carboplatin AUC was equal to ~60 % the target AUC used in other combinations, and the PM00104 dose intensity was 56–67 % of the value achieved at the RD for single-agent PM00104 given as 1-h infusion q3wk. Most treatment-related adverse events were grade 1/2. They mainly consisted of gastrointestinal and general symptoms, such as fatigue, anorexia, mucosal inflammation or nausea. Transient neutropenia (50 % of patients) and thrombocytopenia (33–38 %) were the most common severe hematological abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. Partial response was found in one patient with triple negative breast cancer pretreated with paclitaxel/bevacizumab. Three patients with colorectal cancer, head and neck cancer, and tumor of unknown origin had disease stabilization for ≥3 months. In conclusion, no optimal dose was reached due to overlapping myelosuppression despite stratification according to prior treatment. Therefore, this carboplatin plus PM00104 combination was not selected for further clinical research.
KeywordsPhase I PM00104 Carboplatin Antitumor Cytotoxic Dose-limiting toxicities
This study was supported by Pharma Mar, S.A., and presented in part at the following events:
American Society of Clinical Oncology (ASCO), 47th Annual Meeting, June 3–7, 2011. Chicago, Illinois (J Clin Oncol 29: 2011 suppl; abstr e13085). Phase I study of PM00104 in combination with carboplatin (C) in patients (pts) with advanced solid tumors. Calvo, E.; Gil, M.; Coronado, C.; Valer, A.; Duran, I.; Hidalgo, M.; Pardo, B.; Calles, A.; García, M.; Morelli, P.; Kahatt, C.M.; Prados, R.; Fernandez, C.; Salazar, R.
American Association for Cancer Research (AACR) Annual Meeting; March 31–April 4, 2012. Chicago, IL (abstract 5587). Phase I study of PM00104 in combination with carboplatin in patients (pts) with advanced solid tumors. Calvo, E.; Gil, M.; Coronado, C.; Valer, A.; Duran, I.; Hidalgo, M.; Pardo, B.; Calles, A.; Garcia, M.; Morelli, P.; Kahatt, C.; Prados, R.; Fernandez, C.; Salazar, R.
Conflict of interest
Cinthya Coronado, Vicente Alfaro, Mariano Siguero, Carlos Fernández-Teruel and Raquel Prados are employees of PharmaMar.
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