Regulatory T Cells for Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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Phase 1 Safety Run-in Study of 6 patients followed by Phase 1b Randomized, Double Blind, Placebo Control Trial of CK0803, neurotropic, allogeneic, umbilical cord blood derived T regulatory (Treg) cells in additional 60 patients with Amyotrophic Lateral Sclerosis.

Detailed Description
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CK0803, neurotrophic allogenic T regulatory Cells (Treg), utilizes Cellenkos' proprietary CRANE technology to generate disease specific products. The primary objective of the upcoming phase 1 study is to establish safety and tolerability of multiple doses of CK0803 in ALS patients. The goal of the phase 1b study is to extend safety and establish efficacy of CK0803 in ALS using the combined assessment of function and survival (CAFS) that ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score.

Official Title
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Phase 1 Safety Run-in Study and Phase 1b Randomized, Double Blinded, Placebo Controlled Trial

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Biological: CK0803
* Other: Excipient


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability of the subject or his/her legally authorized representative to provide informed consent. Adult ALS subjects (≥18 years of age) Diagnosis of ALS, according to the Revised El Escorial Criteria for ALS Subjects with disease onset ≤ 5 years Upright (sitting position) Slow Vital Capacity (SVC) as adjusted for sex, age and height ≥ 50% predicted Subjects must have documented ALSFRSR score of 36-45 at baseline. Subjects taking concomitant Riluzole or Edaravone or Albrioza at study entry must be on a stable dose for ≥ 30 days prior to the first dose of study treatment (Day 1). Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (APTT) should be within normal ranges. Agree to practice highly effective contraception during the study and continue contraception for 90 days after their last dose of study treatment. Exclusion Criteria: Uncontrolled infection, not responding to appropriate antimicrobial agents after seven days of therapy. The Protocol medical monitor is the final arbiter of eligibility. Antiplatelet or anticoagulant therapy within the 14 days prior to Day 1 or anticipated use during the study, including but not limited to daily aspirin including low dose aspirin (defined as ≤ 150 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban Clinically significant low platelet count (defined as < 100,000/mm3), coagulation tests, or laboratory abnormalities that would render a subject unsuitable for inclusion Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator Have any other conditions, which, in the opinion of the Investigator would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study Concurrent participation in any other interventional clinical study Treatment with another investigational drug, biological agent, or device, including, but not limited to sodium phenylbutyrate, within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer Treatment of cancer in the last 5 years (except in situ carcinoma of the cervix or basal cell carcinoma) Female subjects who are pregnant or currently breastfeeding Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject unsuitable for enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a randomized two-arm, multi-center phase Ib trial of CK0803 (cryopreserved, allogeneic, cord blood derived T regulatory cells that express neurotropic homing markers) versus placebo for treatment of adults with amyotrophic lateral sclerosis (ALS) having onset within 5 years of trial entry. This trial will consist of a 6-patient safety run-in followed by a randomized comparative trial with up to two stages (stages 1 and 2), each stage of size 30 patients, with a safety rule applied after stage 1 that may terminate the trial early, for a maximum total sample size of 6+30+30 = 66 patients.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CK0803<br>CK0803 (cryopreserved, allogeneic, cord blood derived T regulatory cells that express neurotropic homing markers) will be administered intravenously Dose: 100 million Treg cells (fixed dose) Dose regimen: Induction: one infusion every 7 days (+/-3) x 4 doses Consolidation: one infusion every 28 days (+/-3) x 5 doses | Biological: CK0803<br>* CK0803 (cryopreserved, allogeneic, cord blood derived T regulatory cells that express neurotropic homing markers) will be administered intravenously<br>|
| Placebo Comparator: Placebo<br>Excipient | Other: Excipient<br>* Excipient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Limiting Toxicity (TLT) | TLT of CK0803 as assessed by the incidence and severity of AE and SAEs using NCI-CTCAE Version 5.0 criteria. TLT is a primary endpoint for bothe phase 1 safety run-in and phase 1b RCT part | 28 days | 
| Combined assessment of function and survival (CAFS) | CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score where score = 0 is worst and score = 48 is best. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of all cause AEs and SAEs | Treatment limiting toxicities of CK0803 as assessed by the incidence and severity of AE and SAEs using NCI-CTCAE Version 5.0 criteria. | baseline and at weeks 1, 2, 3, 4, 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at end of treatment (EOT) | 
| ALS Functional Rating Scale-Revised (ALSFRS-R) Score | Longitudinal processes of ALSFRS-R score measured at baseline and different time points. ALSFRS-R score 0=worst; 48=best | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT | 
| Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) | Each item of the ALSSQOL-R is rated by the individual using a 0 to 10 point Likert scale, with 0 being the least desirable situation, and 10 being the most desirable. | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT | 
| Slow Vital Capacity (SVC) | SVC is the volume of air expired, on a low complete expiration after a maximal inspiration without forced or rapid effort. | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT | 
| Handheld dynamometer (HHD) | HHD allows for objective measurement of muscle strength | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT | 
| Nfl CSF | Neurofilament light chain level in the CSF | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT | 
| Nfl Serum | Neurofilament light chain level in the Serum | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT12 months | 
| Ventilation assistance-free survival (VAFS) | VAFS is defined as the time to the earliest occurrence of 1 of the following events: i) Death, or ii) Permanent ventilation (> 22 hours of mechanical ventilation [invasive or non-invasive] per day for > 21 consecutive days in the absence of an acute potentially reversible event) | Each measured at baseline and at weeks 5, 8, 12 and/or 13, 16, 20, 24 and/or 25, 36 and 48 from first infusion and/or at EOT | 
| Overall Survival (OS) | OS defined as the length of time from the start of treatment that patients are still alive. | 24 weeks and 48 weeks from first infusion and/or at EOT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ALS, Cellenkos, T Regulatory Cells, Randomized Placebo Control Trial, Umbilical cord blood, Amyotrophic Lateral Sclerosis