ORIGINAL ARTICLE A phase I pharmacokinetic study of PM00104 (Zalypsis Ò ) administered as a 24-h intravenous infusion every 3 weeks in patients with advanced solid tumors J. Capdevila • S. Clive • E. Casado • C. Michie • A. Piera • E. Sicart • M. J. Carreras • C. Coronado • C. Kahatt • A. Soto Matos-Pita • C. Fernandez Teruel • M. Siguero • M. Cullell-Young • J. Tabernero Received: 15 November 2012 / Accepted: 1 February 2013 / Published online: 2 March 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Purpose PM00104 (Zalypsis Ò ) is a synthetic tetrahydro- isoquinoline alkaloid with potent antiproliferative activity against tumor cell lines. This phase I study evaluated the safety, dose-limiting toxicities (DLTs), recommended dose for phase II trials (RD), pharmacokinetics (PK) and pre- liminary antitumor activity of PM00104 as a 24-h intra- venous (i.v.) infusion every 3 weeks (q3wk). Methods Thirty-seven patients with refractory advanced solid tumors received PM00104 in a toxicity-guided dose escalation study design (3 ? 3 patients per cohort). Plasma samples were collected for PK analysis. Results DLTs comprised severe neutropenia lasting [ 5 days (n = 4 patients), vomiting, thrombocytopenia, transaminase increases (n = 2 each), fatigue, tumor pain, myalgia, muscle stiffness, creatine phosphokinase increase and dosing delay [ 2 weeks due to moderate fatigue (n = 1 each). The RD was 4.0 mg/m 2 . Most PM00104-related adverse events at the RD were mild or moderate; the most common were nausea, vomiting and fatigue. Myelosup- pression and transaminase increases were transient and manageable. PK parameters increased linearly with dose. Higher PM00104 PK exposure was related to a decrease in hemoglobin, neutrophils, platelets and white blood cells. Area under the curve was directly correlated with both incidence and severity of nausea and vomiting. Three patients with hepatocellular carcinoma, esophageal adeno- carcinoma and prostate adenocarcinoma had response eval- uation criteria in solid tumors stable disease C3 months. Conclusions PM00104 given as 24-h i.v. infusion q3wk has predictable and manageable toxicity, but resulted in more myelotoxicity (because of the higher dose level achieved as the RD) and a similar drug clearance compared to 1-h infusion schedules. Preliminary evidence of antitu- mor activity was observed. Keywords PM00104 Á Tetrahydroisoquinoline Á Pharmacokinetics Á Phase I study Introduction PM00104 (Zalypsis Ò ) is a novel synthetic tetrahydroiso- quinoline alkaloid related to jorumycin, renieramycins, safracins and saframycins [1] with potent antiproliferative activity in vitro against solid and non-solid tumor cell lines. Half-maximal inhibitory concentrations (IC 50 ) were in the low nanomolar range [2]. In vivo, significant tumor growth inhibition was found in several murine xenograft models, especially against gastric cancer and multiple myeloma cell lines [1–5]. PM00104 binds covalently to the DNA minor groove [2]. The resulting PM00104-DNA adducts are transformed into double-strand DNA breaks [1, 6] which arrest the cell cycle, activate DNA replication checkpoints and induce caspase-dependent apoptotic cell death [1, 2, 7]. J. Capdevila Á E. Casado Á A. Piera Á E. Sicart Á M. J. Carreras Á J. Tabernero (&) Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Universitat Auto `noma de Barcelona, Pg. Vall d’Hebron, 119-129, 08035 Barcelona, Spain e-mail: jtabernero@vhio.net S. Clive Á C. Michie Edinburgh Cancer Centre, Western General Hospital, Edinburgh, UK C. Coronado Á C. Kahatt Á A. Soto Matos-Pita Á C. Fernandez Teruel Á M. Siguero Á M. Cullell-Young Pharma Mar, S.A., Colmenar Viejo, Madrid, Spain 123 Cancer Chemother Pharmacol (2013) 71:1247–1254 DOI 10.1007/s00280-013-2119-8