title: Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors.
abstract: 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 thrombocytopenia (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 abnormalities; their incidence was higher than with single-agent PM00104. No pharmacokinetic drug-drug alterations occurred. 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.
authors.affiliation: Instituto Catalán de Oncología, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Salazar
authors.forename: Antonio
authors.initials: A
authors.lastname: Calles
authors.forename: Marta
authors.initials: M
authors.lastname: Gil
authors.forename: Ignacio
authors.initials: I
authors.lastname: Durán
authors.forename: Margarita
authors.initials: M
authors.lastname: García
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Cinthya
authors.initials: C
authors.lastname: Coronado
authors.forename: Vicente
authors.initials: V
authors.lastname: Alfaro
authors.forename: Mariano
authors.initials: M
authors.lastname: Siguero
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Teruel
authors.forename: Raquel
authors.initials: R
authors.lastname: Prados
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D000068258:Bevacizumab; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C500383:PM 00104; D044005:Tetrahydroisoquinolines; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel