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

Phase 1 Dose Escalation Study of Bosutinib in Patients With Amyotrophic Lateral Sclerosis (ALS)

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.

Study Overview

• Status: Recruiting
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Bosutinib

Detailed Description

The study consists of a 12-week observation period, a 1-week (acceptable window: 5-9 days) transitional period, a 12-week study treatment period, and a 4-week follow-up period. Subjects who have been receiving riluzole since before the enrollment are allowed to continuously receive riluzole during the 12-week observation period (with the dosage remaining unchanged), and stop receiving riluzole from the beginning of the 1-week (acceptable window: 5-9 days) transitional period. After the completion of the transitional period, subjects whose total ALSFRS-R score decreased by 1 to 3 points during the 12-week observation period will receive bosutinib for 12 weeks to evaluate the safety and tolerability of bosutinib in ALS patients. All ALS drugs including riluzole will be prohibited during the bosutinib treatment period.

In this study, 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. RP2D will be determined by the safety assessment committee upon completion of 12-week study treatment in all subjects in all dose levels.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Haruhisa Inoue; Phone Number: 0753667360; Email: prj-als_bosutinib@cira.kyoto-u.ac.jp

Study Locations

• Japan
  • Kyoto, Japan
    • Recruiting
    • Kyoto University
    • Contact: Haruhisa Inoue
  • Sagamihara, Japan
    • Recruiting
    • Kitasato University
    • Contact: Makiko Nagai
  • Tokushima, Japan
    • Recruiting
    • Tokushima University
    • Contact: Yuishin Izumi
  • Yonago, Japan
    • Recruiting
    • Tottori University
    • Contact: Yasuhiro Watanabe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. 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.
2. Patients aged ≥20 years and <80 years at the time of informed consent
3. 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
4. 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
5. 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
6. Patients who can visit hospital regularly as outpatients
7. Patients with change in total ALSFRS-R score during the observation period are -1 to -3 points

8. 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:

   1. 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;
   2. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
   3. 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.

9. 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.

10. Patients with appropriate hepatic function as defined as follows at the time of the first and second registrations b. Total serum bilirubin ≤1.5 × ULN unless the patient has documented Gilbert syndrome; c. AST and ALT ≤2.5 × ULN
11. Able to take oral tablets
12. Patients whose acute effect of previous treatment has recovered to the baseline or CTCAE v.4.03 ≤ Grade 1 at the time of the first and second registrations
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

Exclusion criteria:

1. Patients with tracheostomy
2. Patients who have used non-invasive ventilation due to ALS symptoms
3. Patients whose %FVCs are less than 70% at the time of first and second registrations
4. Patients who have nerve conduction study findings of demyelination such as conduction block
5. 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
6. Patients with bulbar type ALS with dysphagia and dysarthria
7. Patients with cognitive impairment
8. 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

9. 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
10. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on the QT interval

11. Patient who is taking the following medicines during study drugs administration.

    a Combination of warfarin or other anticoagulation. Combination of therapeutic anticoagulant therapy with low molecular weight heparin is acceptable b Src or c-Abl inhibitors c Other treatments for cancer d Drugs known to prolong the QT interval or predispose to Torsades de Pointe e Current or anticipated use of a strong or moderate CYP3A inhibitor and inducer f Drugs affecting gastric pH such as Proton pump inhibitors (e.g., lansoprazole)

12. History of malignancy within 5 years prior to registration with the exception of basal cell carcinoma or cervical carcinoma in situ or Stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least 12 months
13. Patients who were enrolled in other clinical study within 12 weeks before the first registration, or are expected to be enrolled in other clinical study using a study drug during this study
14. Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations
15. Patients with active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
16. Recent or ongoing clinically significant GI disorder (eg, Crohn's disease, ulcerative colitis, or prior total or partial gastrectomy).
17. Patients with chronic obstructive pulmonary disease
18. Major surgery or radiotherapy within 14 days prior to registration at the time of the first registration

19. Patient who fulfills the conditions:

    1. Neutrophil count (ANC) <1,500/mm3 or white blood cell <3,000/mm3 at the time of the first and second registration
    2. Hemoglobin <9.0 g/dL at the time of the first and second registrations
    3. Platelet count <100,000/L at the time of the first and second registrations
20. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study
21. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Drug: Bosutinib; 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; Subjects will receive 100 mg, 200mg, 300mg or 400 mg of bosutinib once daily, orally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose-limiting toxicity (DLT)	During the first 4 weeks of treatment with bosutinib
Dose-limiting toxicity (DLT)	Up to 12 weeks of treatment with bosutinib

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Adverse events are graded based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03.	Up to 12 weeks of treatment with bosutinib
Incidence of abnormal laboratory test results	Hematology, Blood chemistry, Coagulation test, etc.	Up to 12 weeks of treatment with bosutinib
Incidence of abnormal vital signs	Blood pressure, Pulse rate, Body temperature	Up to 12 weeks of treatment with bosutinib
Incidence of abnormal ECG recordings	ECG; electrocardiogram	Up to 12 weeks of treatment with bosutinib
Incidence of abnormal X-ray findings		Up to 12 weeks of treatment with bosutinib

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total ALSFRS-R score	ALSFRS-R score; ALS Functional Rating Scale-Revised score, the maximum points 48, the minimum points 0, higher scores mean a better outcome.	Up to 12 weeks of treatment with bosutinib
Change in the Japan ALS severity classification	Grade 1 to Grade 5, lower grade means a better outcome.	Up to 12 weeks of treatment with bosutinib
Change in %FVC	FVC; Forced Vital Capacity	Up to 12 weeks of treatment with bosutinib
Change in grip power		Up to 12 weeks of treatment with bosutinib
Change in blood neurofilament L		Up to 12 weeks of treatment with bosutinib
Change in blood phosphorylated neurofilament H		Up to 12 weeks of treatment with bosutinib

Collaborators and Investigators

• Sponsor: Kyoto University
• Collaborators: Pfizer; Kitasato University; Tokushima University; Tottori University
• Investigators: Principal Investigator: Haruhisa Inoue, Kyoto University

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2019
• Primary Completion (Anticipated): March 31, 2022
• Study Completion (Anticipated): March 31, 2022

Study Registration Dates

• First Submitted: January 9, 2021
• First Submitted That Met QC Criteria: February 3, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Actual): February 9, 2021
• Last Update Submitted That Met QC Criteria: February 3, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: sporadic ALS, SOD1
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: WI240618

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No