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

JRCT ID: jRCT2051190001

Registered date:01/04/2019

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: amyotrophic lateral sclerosis
• Date of first enrollment: 29/03/2019
• Target sample size: 24
• Study type: Interventional

Intervention(s)

The study consists of a 12-week observation period, a 1-week (5- to 9-day) transitional period, a 12-week study treatment period, and a 4-week follow-up period.
3 to 6 ALS patients will be enrolled in each of the 4 bosutinib dose levels [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.

Outcome(s)

• Primary Outcome: Dose limiting toxicity (DLT) for 4 weeks after initiating bosutinib and during all treatment period (12 weeks).

Secondary Outcome

Secondary Endpoint(s): Adverse events (AEs), laboratory abnormality, vital signs (blood pressure, pulse rate, body temperature), electrocardiogram (ECG), chest X-ray findings AEs will be graded according to the Common Terminology Criteria for Adverse Events ver. 4.03 (CTCAE v.4.03).

Exploratory Endpoints:
Changes from baseline in total ALSFRS-R score, %FVC and grip strength.
Changes in blood neurofilament L and phosphorylated neurofilament H during the observation period and the study treatment period.

Key inclusion & exclusion criteria

• Age minimum: 20age
• Age maximum: 79age
• Gender: Both

Include 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 additionally signed by a delegate signer if the subject is unable to handwrite.
2. 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
3. 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
4. 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
5. Patients who can visit hospital regularly as outpatients
6. Patients with change in total ALSFRS-R score during the observation period are -1 to -3 points
7. Urine pregnancy test (for females of childbearing potential) negative at screening
8. Patients with appropriate renal function at the time of the first and second registrations
9. Patients with appropriate hepatic function at the time of the first and second registrations
10. Able to take oral tablets
etc.

Exclude 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 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
10. Uncontrolled hypomagnesemia or uncorrected hypokalemia due to potential effects on the QT interval
11. History of malignancy within 5 years prior to registration
12. Known prior or suspected severe hypersensitivity to study drugs or any component in their formulations
13. 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
14. Recent or ongoing clinically significant GI disorder
15. Patients with chronic obstructive pulmonary disease
etc.

Related Information

• Primary Sponsor: Inoue Haruhisa
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development