iPSC-based Drug Repurposing for ALS Medicine (iDReAM) Study

NCT04744532 | Unknown Phase 1 DMC

• 1 other identifier: WI240618
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 7

Brief Summary

This study consists of a phase 1 part and a phase 2 part. Phase 1 part: This is a phase 1, open-label, multicenter, dose escalation study to evaluate the safety and tolerability of bosutinib to determine the maximum tolerated dose(MTD) and a recommended phase 2 dose (RP2D) of bosutinib for treatment of ALS patients. Also, efficacy will be evaluated exploratory. Phase 2 part: This is an open label, multicenter, phase 2 part whose purpose is to evaluate the efficacy exploratorily and the long-term (for 24 weeks) safety of bosutinib for the treatment of ALS patients.

Conditions

Amyotrophic Lateral Sclerosis

Keywords

sporadic ALS, SOD1

Outcome Measures

Primary Outcomes (8)

• Phase 1 part: Dose-limiting toxicity (DLT)

  Dose limiting toxity (DLT) for 4 weeks after initiating bosutinib

  During the first 4 weeks of treatment with bosutinib

• Phase 1 part: Dose-limiting toxicity (DLT)

  Dose limiting toxity (DLT) during all treatment period (12 weeks)

  Up to 12 weeks of treatment with bosutinib

• Phase 2 part: Change in ALSFRS-R from baseline to week 24 in each 200mg and 300mg group compared with the external published data of placebo group

  Change from baseline in ALSFRS-R at week 24 in each 200mg and 300mg group will be compared with the external published data of placebo group excluded bulbar-onset type in edaravone study (MCI186-19)

  Up to 24 weeks of treatment with bosutinib

• Phase 2 part: Adverse events

  Safety in each dose group and pooled dose group during 24 weeks of treatment. Adverse events will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.4.03).

  Up to 24 weeks of treatment with bosutinib

• Phase 2 part: Incidence of abnormal laboratory test results

  Hematology, Blood chemistry, Coagulation test, etc.

  Up to 24 weeks of treatment with bosutinib

• Phase 2 part: Incidence of abnormal vital signs

  Blood pressure, Pulse rate, Body temperature

  Up to 24 weeks of treatment with bosutinib

• Phase 2 part: Incidence of abnormal ECG recordings

  ECG; electrocardiogram

  Up to 24 weeks of treatment with bosutinib

• Phase 2 part: Incidence of abnormal X-ray findings

  chest X-ray examination

  Up to 24 weeks of treatment with bosutinib

Secondary Outcomes (7)

• Phase 1 part: Adverse events

  Up to 12 weeks of treatment with bosutinib

• Phase 1 part: Incidence of abnormal laboratory test results

  Up to 12 weeks of treatment with bosutinib

• Phase 1 part: Incidence of abnormal vital signs

  Up to 12 weeks of treatment with bosutinib

• Phase 1 part: Incidence of abnormal ECG recordings

  Up to 12 weeks of treatment with bosutinib

• Phase 1 part: Incidence of abnormal X-ray findings

  Up to 12 weeks of treatment with bosutinib

Other Outcomes (12)

• Phase 1 part: Change in total ALSFRS-R score

  Up to 12 weeks of treatment with bosutinib

• Phase 1 part: Change in the Japan ALS severity classification

  Up to 12 weeks of treatment with bosutinib

• Phase 1 part: Change in %FVC

  Up to 12 weeks of treatment with bosutinib

Study Arms (2)

Drug: Bosutinib (Phase 1 part)

EXPERIMENTAL

Phase 1 part: 3 to 6 ALS patients will be enrolled in each of the 4 bosutinib dose lelvels \[100 mg/day (dose level 1), 200 mg/day (dose level 2), 300 mg/day (dose level 3), or 400mg/day (dose level 4)\] to evaluate the safety and tolerability of the investigational drug (bosutinib) under a 3+3 dose escalation study design. The dose will be escalated by 1 dose level at a time; no skipping will be allowed. Dose escalation and MTD will be determined by the safety assessment committee comprising oncologist, hematologist, ALS Expert based on the incidence of DLT in 4 weeks of treatment among 3 subjects enrolled (6 subjects if additionaly enrolled) in each dose level.

Drug: Bosutinib (Phase 1 part)

Drug: Bosutinib (Phase 2 part)

EXPERIMENTAL

Phase 2 part: 25 ALS patients will be enrolled; patients will be randomly assigned to the following groups: 13 patients in 300mg/day group and 12 patients in 200mg/day group of the investigational drug (bosutinib). The efficacy and the safety of bosutinib in ALS patients for 24 weeks will be assessed.

Drug: Bosutinib (Phase 2 part)

Interventions

Bosutinib (Phase 1 part) DRUG

Subjects will receive 100 mg, 200mg, 300mg or 400 mg of bosutinib once daily, orally.

Also known as: PF-05208763

Drug: Bosutinib (Phase 1 part)

Bosutinib (Phase 2 part) DRUG

Subjects will receive 200mg/day or 300mg/day of bosutinib once daily, orally.

Also known as: PF-05208763

Drug: Bosutinib (Phase 2 part)

Eligibility Criteria

• Age: 20 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study. To be additionaly signed by a delegate signer if the subject is unable to handwrite.
• Patients aged ≥20 years and \<80 years at the time of informed consent
• Patients with positive already-reported SOD1 gene mutation and progressive muscle weakness; sporadic ALS patients who are categorized as either "Definite ALS" or "Probable ALS" or "Probable-laboratory supported ALS" in the Updated Awaji Criteria for the diagnosis of ALS
• Patients at Grade 1 or 2 in the Japan ALS Severity Scale of the grant-in-aid program for chronic diseases from the Japanese Ministry of Health, Labour and Welfare; patients with positive SOD1 mutation of Grade 1, 2 or 3
• Patients with ALS that occurred within 2 years at the time of the first registration; patients with positive SOD1 mutation within 5 years after disease onset
• Patients who can visit hospital regularly as outpatients
• Patients with change in total ALSFRS-R score during the observation period are -1 to -3 points
• Urine pregnancy test (for females of childbearing potential) negative at screening
• Female patients of nonchildbearing potential must meet at least 1 of the following criteria:
• Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle stimulating hormone (FSH) level confirming the postmenopausal state;
• Have undergone a documented hysterectomy and/or bilateral oophorectomy;
• Have medically confirmed ovarian failure. All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
• Male and female patients of childbearing potential must agree to use one highly effective method of contraception as outlined in this protocol, throughout the study and for at least 28 days after the last dose of investigational product.
• Patients with appropriate renal function as defined as follows at the time of the first and second registrations
• a. Serum creatinine ≤1.5 × upper limit of normal (ULN) or estimated creatinine clearance ≥60 mL/min as calculated using the method standard for the institution.

You may not qualify if:

• Patients with tracheostomy
• Patients who have used non-invasive ventilation due to ALS symptoms
• Patients whose %FVCs are less than 70% at the time of first and second registrations
• Patients who have nerve conduction study findings of demyelination such as conduction block
• Patients who are taking edaravone; patients who started riluzole or edaravone after start of the observation period; patients who changed the dosage of riluzole after start of the observation period
• Patients with bulbar type ALS with dysphagia and dysarthria
• Patients with cognitive impairment
• Pregnant female patients; breastfeeding female patients; fertile male and female patients of childbearing potential who are unwilling or unable to use 1 highly effective methods of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product
• History of clinically significant or uncontrolled cardiac disease including:
• History of, or active, congestive heart failure;
• Uncontrolled angina or hypertension within 3 months prior to registration;
• Myocardial infarction within 12 months prior to registration;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
• Diagnosed or suspected congenital or acquired prolonged QT interval history or prolonged QTc (QTcF should not exceed 500 msec);
• Unexplained syncope

Sponsors & Collaborators

• Kyoto University: lead
• Tokushima University: collaborator
• Kitasato University: collaborator
• Tottori University: collaborator
• Nara Medical University: collaborator
• Toho University: collaborator
• Hiroshima University: collaborator
• Pfizer: collaborator

Study Sites (7)

Hiroshima University

Hiroshima, Japan

RECRUITING

Nara Medical University

Kashihara, Japan

RECRUITING

Kyoto University

Kyoto, Japan

RECRUITING

Kitasato University

Sagamihara, Japan

RECRUITING

Tokushima university

Tokushima, Japan

RECRUITING

Toho University

Tokyo, Japan

RECRUITING

Tottori University

Yonago, Japan

RECRUITING

Related Publications (2)

• Imamura K, Izumi Y, Egawa N, Ayaki T, Nagai M, Nishiyama K, Watanabe Y, Murakami T, Hanajima R, Kataoka H, Kiriyama T, Nanaura H, Sugie K, Hirayama T, Kano O, Nakamori M, Maruyama H, Haji S, Fujita K, Atsuta N, Tatebe H, Tokuda T, Takahashi N, Morinaga A, Tabuchi R, Oe M, Kobayashi M, Lobello K, Morita S, Sobue G, Takahashi R, Inoue H. Protocol for a phase 2 study of bosutinib for amyotrophic lateral sclerosis using real-world data: induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study. BMJ Open. 2024 Oct 26;14(10):e082142. doi: 10.1136/bmjopen-2023-082142.

  PMID: 39461864 DERIVED

• Imamura K, Izumi Y, Nagai M, Nishiyama K, Watanabe Y, Hanajima R, Egawa N, Ayaki T, Oki R, Fujita K, Uozumi R, Morinaga A, Hirohashi T, Fujii Y, Yamamoto T, Tatebe H, Tokuda T, Takahashi N, Morita S, Takahashi R, Inoue H. Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial. EClinicalMedicine. 2022 Oct 25;53:101707. doi: 10.1016/j.eclinm.2022.101707. eCollection 2022 Nov.

  PMID: 36467452 DERIVED

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Interventions

bosutinib

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Haruhisa Inoue

  Kyoto University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Haruhisa Inoue

CONTACT

0753667360; prj-als_bosutinib@cira.kyoto-u.ac.jp

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: January 9, 2021
• First Posted: February 9, 2021
• Study Start: March 19, 2019
• Primary Completion: March 31, 2024
• Study Completion: March 31, 2024
• Last Updated: March 8, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: After completion of the study
• Access Criteria: Requests for clinical data should be emailed to the corresponding author and should include a brief description of the proposed analysis. Requests for data access will be reviewed individually, and a decision will be communicated

Locations

JP (7)