A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies
| Autor: | Jong Soon Park, Garth Nicholas, Chandra P. Belani, Eric Sbar, Derek I. Jonker, Catherine Fortin, Ashok Kumar Gupta, Alex A. Adjei, Scott A. Laurie, Laura Q.M. Chow, Steven Zhang, Daniel Patricia, Grace K. Dy |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Maximum Tolerated Dose Paclitaxel Nausea Neutropenia Toxicology Gastroenterology Carboplatin chemistry.chemical_compound Piperidines Pharmacokinetics Neoplasms Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Pyrroles Pharmacology (medical) Neoplasm Metastasis Lung cancer Adverse effect Pharmacology Dose-Response Relationship Drug Triazines business.industry Middle Aged medicine.disease Treatment Outcome Oncology chemistry Area Under Curve Pharmacodynamics Anesthesia Female medicine.symptom business Febrile neutropenia |
| Zdroj: | Cancer Chemotherapy and Pharmacology. 71:1273-1285 |
| ISSN: | 1432-0843 0344-5704 |
| Popis: | A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4–19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types. |
| Databáze: | OpenAIRE |
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