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RAPA-501 Therapy for ALS

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ClinicalTrials.gov Identifier: NCT04220190
Recruitment Status : Recruiting
First Posted : January 7, 2020
Last Update Posted : July 27, 2021
Sponsor:
Collaborators:
Massachusetts General Hospital
Hackensack Meridian Health
Information provided by (Responsible Party):
Rapa Therapeutics LLC

Brief Summary:
RAPA-501-ALS is an open-label, dose escalation, Phase 1/2 study of RAPA-501 autologous T cells in adults with amyotrophic lateral sclerosis (ALS).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Biological: RAPA-501 Autologous T cells Phase 1 Phase 2

Detailed Description:

This is an open-label, non-randomized, multi-center Phase 1/2 study evaluating RAPA-501 T cells in subjects with amyotrophic lateral sclerosis.

After a subject consents to the study, an apheresis procedure will be performed to collect cells to manufacture the investigational product, RAPA-501 T cells.

This study consists of three cohorts. Cohorts 1 and 2 will evaluate a 6-month regimen of four (4) cycles of RAPA-501 T cell therapy without the pentostatin-cyclophosphamide host conditioning regimen (PC regimen). Cohorts 1 and 2 will evaluate two different doses: Cohort 1 - 40 x 10^6 cells/infusion and Cohort 2 - 160 x 10^6 cells/infusion. Both cohorts will evaluate a 6-month regimen of four cycles of the RAPA-501 cell therapy.

Cohort 3 will evaluate the highest safe dose of RAPA-501 cells (from Cohort 1 and Cohort 2) in combination with the PC regimen. Cohort 3 will evaluate a 6-month regimen of 4 cycles of RAPA-501 cells administered after the PC regimen. The PC regimen will be 7 days in duration and the RAPA-501 cell therapy will take place on Day 8.

All subjects who complete active treatment on each cohort will then complete the follow-up portion of the study (approximately 6-months in duration).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Masking Description: No masking
Primary Purpose: Treatment
Official Title: Phase I Trial of Autologous Hybrid TREG/Th2 Cell (RAPA-501) Therapy for Amyotrophic Lateral Sclerosis
Actual Study Start Date : December 15, 2020
Estimated Primary Completion Date : December 15, 2023
Estimated Study Completion Date : December 15, 2023


Arm Intervention/treatment
Experimental: Single agent RAPA-501 T cells (dose level 1)
Dose level 1 is 40 x 10^6 cells/infusion
Biological: RAPA-501 Autologous T cells
TREG/Th2 cells
Other Name: RAPA-501 cells

Experimental: Single agent RAPA-501 T cells (dose level 2)
Dose level 2 is 160 x 10^6 cells/infusion
Biological: RAPA-501 Autologous T cells
TREG/Th2 cells
Other Name: RAPA-501 cells

Experimental: RAPA-501 + PC Regimen
RAPA-501 T cell therapy preceded by the pentostatin-cyclophosphamide (PC) regimen
Biological: RAPA-501 Autologous T cells
TREG/Th2 cells
Other Name: RAPA-501 cells




Primary Outcome Measures :
  1. Dose safety of single-agent RAPA-501 T cells [ Time Frame: 30 days after the first infusion of RAPA-501 T cells. ]
    To determine the safety of single-agent RAPA-501 T cells administered intravenously (i.v.) at dose level 1 and dose level 2.

  2. Highest tolerated dose of RAPA-501 T cells [ Time Frame: 30 days after the first infusion of RAPA-501 T cells. ]
    Determine the safety of the highest tolerated dose of RAPA-501 T cells in combination with pentostatin and cyclophosphamide host conditioning (PC regimen).


Secondary Outcome Measures :
  1. Effect of therapy on disease status [ Time Frame: One year after treatment initiation. ]
    To determine the ALS disease activity score (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and Rasch Overall ALS Disability Scale [ROADS]) for each study cohort pre-therapy, during study interventions, and after the post-therapy observation interval.

  2. Characterize immune system parameters [ Time Frame: One year after treatment initiation. ]
    Determine whether therapy increases the number of circulating Th2 and TREG cells, as measured by T cells that express the transcription factors GATA3 and FOXP3 by flow cytometry, respectively. The absolute number of GATA3+ and FOXP3+ T cells will be determined pre- and post-therapy (unit of measurement for both GATA3 and FOP3: absolute number of positive cells per microliter of blood).

  3. Characterize immune system parameters [ Time Frame: One year after treatment initiation. ]
    Determine whether therapy reduces the number of circulating Th1 cells, as measured by T cells that express the transcription factor TBET by flow cytometry, respectively. The absolute number of TBET+ cells will be determined pre- and post-therapy (unit of measure for TBET: number of positive cells per microliter of blood).

  4. Characterize pulmonary function test parameters [ Time Frame: One year after treatment initiation. ]
    Determine whether therapy increases pulmonary function, as determined by measurement of pre- and post-therapy measures of Slow Vital Capacity (SVC) (unit of measurement: percent of age-predicted value).

  5. Characterize hand grip strength [ Time Frame: One year after treatment initiation. ]
    Characterize hand grip strength pre- and post-therapy using hand-held dynamometry.


Other Outcome Measures:
  1. Cerebrospinal fluid assessment [ Time Frame: Six months after treatment initiation. ]
    To assess cerebrospinal fluid pre- and post- therapy for content of inflammation molecules and neurodegeneration molecules.

  2. Neuroinflammation assessment [ Time Frame: Six months after treatment initiation. ]
    Assess neuroinflammation in vivo using PET scan that incorporates a translocator protein radiotracer.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female patients ≥ 18 years of age.
  2. Patients with sporadic or familial amyotrophic lateral sclerosis (ALS) diagnosed as laboratory-supported possible, probable, or definite according to World Federation of Neurology El Escorial Criteria.
  3. Must have a source of autologous T cells potentially sufficient to manufacture RAPA-501 cells, as defined by a peripheral CD3+ T cell count ≥ 800 cells per μl.
  4. Patients may continue riluzole (Rilutek®) and/or edaravone (Radicava®) therapy if on a stable dose for ≥ one month prior to study entry.
  5. Patients must be ≥ two weeks from major surgery, from edaravone therapy, and from participation in investigational trials.
  6. Patients must have recovered from clinical toxicities (resolution of CTCAE [version 5] toxicity to a value of ≤ 2).
  7. Serum creatinine ≤ less than or equal to 2.0 mg/dL.
  8. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal.
  9. Bilirubin ≤ 1.5 (except if due to Gilbert's disease).
  10. Pulmonary slow vital capacity (SVC) ≥ 50% of predicted normal.
  11. No history of abnormal bleeding tendency.
  12. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future care.

    For accrual to Cohort 3, additional eligibility inclusion criteria are as follows:

  13. Ejection fraction by MUGA or 2-D echocardiogram within institution normal limits (applies only to study participants on cohort).

Exclusion Criteria:

  1. Active uncontrolled infection.
  2. Hypertension not adequately controlled by ≤ 3 medications.
  3. History of documented pulmonary embolus within 6 months of enrollment.
  4. Clinically significant cardiac pathology, as defined by: myocardial infarction within 6 months prior to enrollment, Class III or IV heart failure according to NYHA, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
  5. Patients with history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis.
  6. HIV, hepatitis B, or hepatitis C seropositive.
  7. Pregnancy or breastfeeding patients.
  8. Patients of childbearing age, or males who have a partner of childbearing potential, who are unwilling to practice contraception.
  9. Patients may be excluded at the discretion of the PI or if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

    For accrual to Cohort 3, additional eligibility exclusion criteria are as follows:

  10. Calculated creatinine clearance value of < 70 mL/min/1.73 m2, as calculated by the Cockcroft-Gault formula.
  11. Diagnosis of malignancy (active).
  12. Urinary obstruction.
  13. Hypersensitivity to the agents in the PC regimen (pentostatin, cyclophosphamide).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04220190


Contacts
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Contact: Jennifer Gough Clinical Regulatory Coordinator 617-285-4774 jgough@rapatherapeutics.com

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Kelly Fisher    617-726-9094    kefisher@mgh.harvard.edu   
Principal Investigator: James Berry, M.D.         
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Michele Donato Principal Investigator    551-996-5855    michele.donato@hackensackmeridian.org   
Principal Investigator: Michele Donato         
Sponsors and Collaborators
Rapa Therapeutics LLC
Massachusetts General Hospital
Hackensack Meridian Health
Investigators
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Study Director: Daniel Fowler, M.D. Rapa Therapeutics LLC
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Responsible Party: Rapa Therapeutics LLC
ClinicalTrials.gov Identifier: NCT04220190    
Other Study ID Numbers: RAPA-501-ALS
First Posted: January 7, 2020    Key Record Dates
Last Update Posted: July 27, 2021
Last Verified: July 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Rapa Therapeutics LLC:
Amyotrophic Lateral Sclerosis
Autologous TREG/Th2 cell therapy
RAPA-501
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases