Abstract
Background: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. Methods: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. Results: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m-2) and 20 patients on the 3-h schedule (1.8-3.5 mg m-2). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m-2. With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m -2. Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. Conclusion: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.
Original language | English (US) |
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Pages (from-to) | 1379-1385 |
Number of pages | 7 |
Journal | British Journal of Cancer |
Volume | 106 |
Issue number | 8 |
DOIs | |
State | Published - Apr 10 2012 |
Externally published | Yes |
Keywords
- cytotoxic
- novel marine-derived compound
- phase I
- PM00104
ASJC Scopus subject areas
- Oncology
- Cancer Research