PHASE I STUDIES Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors Ramón Salazar & Antonio Calles & Marta Gil & Ignacio Durán & Margarita García & Manuel Hidalgo & Cinthya Coronado & Vicente Alfaro & Mariano Siguero & Carlos Fernández-Teruel & Raquel Prados & Emiliano Calvo Received: 18 November 2013 /Accepted: 5 February 2014 # Springer Science+Business Media New York 2014 Summary 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 thrombo- cytopenia (in one heavily and three mildly pretreated patients) was the only dose-limiting toxicity (DLT) observed. Carboplatin AUC3-PM00104 2.0 mg/m 2 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 abnor- malities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations oc- curred. 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. Keywords Phase I . PM00104 . Carboplatin . Antitumor . Cytotoxic . Dose-limiting toxicities Introduction PM00104 (Zalypsis®) is a synthetic cytotoxic alkaloid struc- turally related to marine compounds jorumycins and renieramycins [1–3]. The antitumor effects of PM00104 are exerted through covalent modification of guanines in the DNA minor groove. This results in double-strand DNA breaks, S-phase arrest and apoptosis in cancer cells [4–7]. Preclinical studies showed promising antitumor activity and acceptable pharmacokinetic (PK) and toxicity profiles [4, 7–15]. Based on these findings, several phase I clinical trials have evaluated different single-agent schedules [16–18]. One of these trials evaluated a 1-h intravenous (i.v.) infu- sion every 3 weeks (q3wk) schedule. The most common PM00104-related adverse events (AEs) were mild-moderate nausea and fatigue. The most frequent severe hematological abnormalities were transient neutropenia and leukopenia. No dose-limiting toxicities (DLTs) occurred at the recommended dose for phase II trials (RD) of 3.0 mg/m 2 [16]. Overall, relevant tumor shrinkage was found in one patient with urothelial carcinoma [16] and prolonged disease stabilizations in several patients with difficult-to-treat diseases [16–18]. Phase II clinical trials are assessing PM00104 in patients with advanced endometrial/cervical cancer [19], advanced Ewing R. Salazar : M. Gil : M. García Instituto Catalán de Oncología, L ’Hospitalet de Llobregat, Barcelona, Spain A. Calles : I. Durán : M. Hidalgo : E. Calvo (*) START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte Sanchinarro, C/Oña 10, 28050 Madrid, Spain e-mail: emiliano.calvo@start.stoh.com C. Coronado : V. Alfaro : M. Siguero : C. Fernández-Teruel : R. Prados PharmaMar, Clinical R&D, Colmenar Viejo, Madrid, Spain Invest New Drugs DOI 10.1007/s10637-014-0072-y