Dataset Information

A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs.

ABSTRACT: Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. A total of 233 patients were randomized to asciminib (n = 157) or bosutinib (n = 76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% confidence interval, 2.19-22.30; 2-sided P = .029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant/intolerant to ≥2 prior TKIs. This trial was registered at www.clinicaltrials.gov as #NCT03106779.

SUBMITTER: Rea D

PROVIDER: S-EPMC9728405 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs.

Réa Delphine D Mauro Michael J MJ Boquimpani Carla C Minami Yosuke Y Lomaia Elza E Voloshin Sergey S Turkina Anna A Kim Dong-Wook DW Apperley Jane F JF Abdo Andre A Fogliatto Laura Maria LM Kim Dennis Dong Hwan DDH le Coutre Philipp P Saussele Susanne S Annunziata Mario M Hughes Timothy P TP Chaudhri Naeem N Sasaki Koji K Chee Lynette L García-Gutiérrez Valentin V Cortes Jorge E JE Aimone Paola P Allepuz Alex A Quenet Sara S Bédoucha Véronique V Hochhaus Andreas A

Blood 20211101 21

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant/intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes because of disease biology and inadequate efficacy and/or safety of current therapies. Asciminib, a first-in-class BCR-ABL1 inhibitor Specifically Targeting the ABL Myristoyl Pocket (STAMP), has the potential to overcome resistance/intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previousl ...[more]

PMID: 34407542

Similar Datasets

Project description:BackgroundHealth-related quality of life (HRQOL) in patients with chronic-phase chronic myeloid leukemia (CML) is important because of the requirement for long-term treatment. This study assessed HRQOL in bosutinib-treated patients with Philadelphia chromosome-positive CML and resistance or intolerance to 1 (chronic-phase second-line [CP2L]) or more (chronic-phase third-line [CP3L]) tyrosine kinase inhibitors who had 264 weeks or more of follow-up (ClinicalTrials.gov identifier NCT00261846).MethodsPatient-reported HRQOL was assessed with the EuroQol 5-Dimensions Questionnaire (EQ-5D) and the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu).ResultsIn total, 284 and 119 patients composed the CP2L and CP3L cohorts, respectively. At treatment completion, more than 50% of the patients in the CP2L and CP3L cohorts completed the EQ-5D and FACT-Leu assessments. The EQ-5D and EQ-5D visual analog scale scores were stable in both cohorts throughout treatment. The mean FACT-Leu scores were generally stable over time but were lower in magnitude in the CP3L cohort versus the CP2L cohort. The FACT-Leu scale scores of a subset of patients with chronic diarrhea (CP2L, n = 101; CP3L, n = 30) were similar to the scores of the larger cohorts. Minimally important differences (MIDs) from baseline for the FACT-Leu scale scores were observed for the following: emotional well-being (EWB), Functional Assessment of Cancer Therapy-General (FACT-G) Total, FACT-Leu Total, and Functional Assessment of Cancer Therapy Trial Outcome Index (FACT-TOI) in the CP2L cohort and FACT-Leu Total in the CP3L cohort. Among patients with chronic diarrhea, MIDs were observed for EWB, FACT-G Total, FACT-Leu Total, and FACT-TOI in the CP2L cohort and for EWB, FACT-G Total, and FACT-Leu Total in the CP3L cohort.ConclusionsHRQOL was maintained with long-term bosutinib treatment for patients with CP2L and CP3L CML. Cancer 2018;124:587-95. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Project description:BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS.MethodsAn open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1-3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study.FindingsBetween March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg-400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib.InterpretationThis is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required.FundingAMED and iPS Cell Research Fund.

Dataset Information

A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs.

Publications

A phase 3, open-label, randomized study of asciminib, a STAMP inhibitor, vs bosutinib in CML after 2 or more prior TKIs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets