Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS.

Methods and analysis: An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers.

Ethics and dissemination: This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences.

Trial registration number: UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.

Keywords: amyotrophic lateral sclerosis; biomarker; bosutinib; drug repositioning/ repurposing; induced pluripotent stem cell; molecular targeted therapy.

Figure 1

Study schedule of the iDReAM (Induced pluripotent stem cell–based Drug Repurposing for Amyotrophic lateral sclerosis Medicine) study.

Figure 2

3+3 dose escalation study design in the iDReAM (Induced pluripotent stem cell–based Drug Repurposing for Amyotrophic lateral sclerosis Medicine) study. DLT, dose-limiting toxicity.