Sant P Chawla 1 , Sanjay Goel 2 , Warren Chow 3 , Fadi Braiteh 4 , Arun S Singh 5 , Juneko E Grilley Olson 6 , Atsushi Osada 7 , Iulian Bobe 7 , Richard F Riedel 8 Show Affiliations »
Abstract
PURPOSE: NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas. PATIENTS AND METHODS: This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated. RESULTS: Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations. CONCLUSIONS: NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma. ©2020 American Association for Cancer Research.
PURPOSE: NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin . It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors , including soft-tissue sarcomas . PATIENTS AND METHODS: This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin -equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated. RESULTS: Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma , one with osteosarcoma , and 11 with other solid tumors . Observed dose-limiting toxicities included thrombocytopenia , stomatitis , lung infection , and febrile neutropenia . The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma . A dose-dependent increase was observed in both total and released epirubicin concentrations. CONCLUSIONS: NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma . NC-6300 warrants further investigation in patients with advanced solid tumors , including sarcoma . ©2020 American Association for Cancer Research.
Entities: Chemical
Disease
Species
Year: 2020
PMID： 32381487 DOI： 10.1158/1078-0432.CCR-20-0591
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531