A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors.

Autor: Ghalib MH; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA.; Now at Rutgers Cancer Institute, New Brunswick, NJ, USA., Pulla MP; Dept. Servicio de Oncología Médica, University Hospital Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain., De Miguel Luken MJ; Early Phase Clinical Trial Unit, Hospital Madrid Norte San Chinarro - Centro Integral Oncologico Clara Campal, Madrid, Spain., de Juan VC; Medical Oncology Department, University Hospital Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain., Chaudhary I; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA., Hammami MB; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA., Vikash S; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA., Maitra R; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA., Martinez S; Clinical Development, PharmaMar, Colmenar Viejo, Madrid, S.A, Spain., Kahatt C; Clinical Development, PharmaMar, Colmenar Viejo, Madrid, S.A, Spain., Extremera S; Clinical Development, PharmaMar, Colmenar Viejo, Madrid, S.A, Spain., Fudio S; Clinical Development, PharmaMar, Colmenar Viejo, Madrid, S.A, Spain., Goel S; Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, USA. sanjay.goel@rutgers.edu.; Now at Rutgers Cancer Institute, New Brunswick, NJ, USA. sanjay.goel@rutgers.edu.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2024 Oct; Vol. 42 (5), pp. 481-491. Date of Electronic Publication: 2024 Aug 03.
DOI: 10.1007/s10637-024-01458-8
Abstrakt: Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m 2 /Gem 1000 mg/m 2 ) was the MTD. Accrual into DL7 (Plo 10.0 mg/m 2 /Gem 1000 mg/m 2 ) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m 2 /Gem 1000 mg/m 2 . No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.
Competing Interests: Declarations. Ethics approval and consent to participate: The entire study was performed in compliance with Institutional and Federal guidelines for clinical research. The study was approved by the ethics committee of each participating institution. Disclosure of potential conflicts of interest: SM, CK, SE and SF report personal fees for salary as full-time employee and stock ownership from Pharma Mar, outside the submitted work. Presentations: Presented in part at the Annual Meetings of the European Society of Medical Oncology (ESMO) in 2023, Madrid, Spain.
(© 2024. The Author(s).)
Databáze: MEDLINE
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