First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours

T. A. Yap, H. Cortes-Funes, H. Shaw, R. Rodriguez, D. Olmos, R. Lal, P. C. Fong, D. S. Tan, D. Harris, J. Capdevila, C. Coronado, V. Alfaro, A. Soto-Matos, C. Fernández-Teruel, M. Siguero, J. M. Tabernero, L. Paz-Ares, J. S. De Bono, J. A. López-Martin

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16 Citations (Scopus)

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. © 2012 Cancer Research UK.
Original languageEnglish
Pages (from-to)1379-1385
JournalBritish Journal of Cancer
Volume106
Issue number8
DOIs
Publication statusPublished - 10 Apr 2012

Keywords

  • cytotoxic
  • novel marine-derived compound
  • phase I
  • PM00104

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