Phase I study of carboplatin in combination with PM00104 (Zalypsis®) in patients with advanced solid tumors

• Published in: Investigational new drugs Vol. 32; no. 4; pp. 644 - 652
• Main Authors: Salazar, Ramón, Calles, Antonio, Gil, Marta, Durán, Ignacio, García, Margarita, Hidalgo, Manuel, Coronado, Cinthya, Alfaro, Vicente, Siguero, Mariano, Fernández-Teruel, Carlos, Prados, Raquel, Calvo, Emiliano
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2014; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Area Under Curve; Bevacizumab; Biological and medical sciences; Bone marrow; Cancer therapies; Carboplatin - administration & dosage; Carboplatin - adverse effects; Carboplatin - pharmacokinetics; Chemotherapy; Clinical trials; Cytotoxicity; Disease; Drug Administration Schedule; Drug dosages; Drug therapy; Electrocardiography; Female; Hematology; Humans; Infusions, Intravenous - methods; Male; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nausea; Neoplasms - drug therapy; Neutropenia; Oncology; Paclitaxel - pharmacokinetics; Paclitaxel - therapeutic use; Patients; Pharmaceuticals; Pharmacokinetics; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phase I Studies; Radiation therapy; Statistical analysis; Tetrahydroisoquinolines - administration & dosage; Tetrahydroisoquinolines - adverse effects; Tetrahydroisoquinolines - pharmacokinetics; Thrombocytopenia; Toxicity; Tumors; Spain; Carboplatin; PM00104; Phase I; Dose-limiting toxicities; Cytotoxic; Antitumor; Antineoplastic agent; Human; Solid tumor; Drug combination; Cytotoxicity; Malignant tumor; Alkaloid; Treatment; Phase I trial; Advanced stage; Dose limiting toxicity; Pharmacokinetics; Cancer; Platinum II Complexes
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0072-y

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 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.