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NCT07875972

PHASE1

Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS)

Sponsor: Liu Qing

View on ClinicalTrials.gov

Summary

This is a single-center, open-label, dose-escalation, investigator-initiated pilot study to evaluate the safety, tolerability, dose-limiting toxicity (DLT), and pharmacodynamic signals of orelabrutinib in patients with amyotrophic lateral sclerosis (ALS). A 12-week run-in observation period will be used to establish each participant's historical ALSFRS-R decline slope. Participants will receive orelabrutinib 50 mg once daily (QD), 100 mg QD, or optional 150 mg QD using a 3+3 dose-escalation design for 24 weeks, followed by a 4-week safety follow-up.

Official title: Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS): A Single-Center, Open-Label, Single-Arm, Dose-Escalation Investigator-Initiated Clinical Study

Key Details

Gender

All

Age Range

18 Years - 75 Years

Study Type

INTERVENTIONAL

Enrollment

Start Date

2026-10

Completion Date

2028-10

Last Updated

2026-10-15

Healthy Volunteers

Conditions

Amyotrophic Lateral Sclerosis (ALS)

Interventions

DRUG

Orelabrutinib

Cohort 1 planned enrollment: 3 participants; may expand to 6 if 1/3 participants experience a dose-limiting toxicity (DLT). Cohort 2 planned enrollment: 3 participants. This cohort will be initiated only after Cohort 1 completes the 28-day DLT observation period and the DSMB approves dose escalation. Cohort 3 (Optional) planned enrollment: 3 participants. This cohort will be initiated only if Cohorts 1 and 2 are safe and if BTK target occupancy / PD signals suggest insufficient target coverage, with written DSMB approval. A traditional 3+3 dose-escalation design is used,. Dose-escalation rules: If 0/3 patients experience a DLT, escalate to the next dose level; if 1/3 patients experience a DLT, expand that dose level to 6 patients; if 1/6 patients experience a DLT, escalation may proceed, whereas if ≥2/6 patients experience a DLT, the dose is deemed intolerable and escalation must stop; if ≥2/3 patients experience a DLT, escalation must stop immediately.

Inclusion Criteria 1. Age 18-75 years, either sex. 2. Confirmed diagnosis of ALS by a neurologist according to the Gold Coast criteria or the revised El Escorial (Airlie House) criteria, with other diseases excluded. 3. Duration from disease onset to enrollment no more than 36 months. 4. ALSFRS-R score ≥ 35 at screening. 5. FVC% predicted ≥ 70% and SVC% predicted ≥ 70%; no resting dyspnea, orthopnea, or need for long-term non-invasive ventilation/oxygen therapy. 6. Participants are able to take medication orally and are independent of enteral nutrition support (e.g., PEG, gastric tube) at screening, as judged by the principal investigator. 7. Stable-dose riluzole (≥ 30 days) and/or edaravone (stable use for one course) is permitted. 8. Assessed as having full capacity to provide informed consent. Exclusion Criteria 1. Tracheostomy or use of non-invasive ventilation (NIV) \> 23 h/day. 2. Abnormal liver function (ALT/AST ≥ 3×ULN), abnormal renal function (eGFR \< 60 mL/min/1.73 m²), absolute neutrophil count (ANC) ≤ 1.5×10⁹/L, platelet count ≤ 100×10⁹/L, or hemoglobin ≤ 100 g/L; international normalized ratio (INR) ≥ 1.5×ULN, activated partial thromboplastin time (APTT) ≥ 1.5×ULN. 3. Unable to swallow or tolerate oral medication at screening. 4. Prior or current malignancy. 5. Known active HBV, HCV, or HIV infection, or any uncontrolled active systemic infection. 6. Major surgery within 6 weeks before screening, or need for major surgery during the study period. 7. Current clinically significant cardiovascular disease, including: NYHA class 3 or 4 heart disease, such as arrhythmia, congestive heart failure, or myocardial infarction, or left ventricular ejection fraction (LVEF) \< 50%; primary cardiomyopathy; history of clinically significant QTc prolongation, or QTc \> 470 ms (women), QTc \> 450 ms (men); uncontrolled hypertension. 8. Bleeding disorders or active bleeding events within 3 months, or current use of anticoagulant/antiplatelet drugs. 9. Diseases significantly affecting gastrointestinal function, such as dysphagia, chronic diarrhea, intestinal obstruction, or gastrectomy. 10. Any history of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary function impairment. 11. Prior exposure to BTK pathway inhibitors. 12. Current use of moderate or strong CYP3A inhibitors or strong CYP3A inducers that cannot be safely discontinued or replaced before screening; moderate CYP3A4 inducers require evaluation by a pharmacist and the investigator. 13. Receipt of a live vaccine within 2 weeks or planned receipt of a live vaccine during the study period (Note: inactivated vaccines may be administered according to local regulations, but the vaccination time and AEs must be recorded). 14. Substance abusers or alcohol abusers. 15. Breastfeeding or pregnant women, or women of childbearing age who are unwilling to use contraceptive measures during the trial and for 180 days after the last dose of study drug. 16. Unable to understand the informed consent form (ICF). 17. Any other relevant medically significant condition that may pose a risk to the participant, interfere with safety assessments, or increase the risk of death during the trial.