search
Back to results

RAPA-501 Therapy for ALS

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
RAPA-501 Autologous T cells
Sponsored by
Rapa Therapeutics LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic Lateral Sclerosis, Autologous TREG/Th2 cell therapy, RAPA-501

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future care.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, 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).

Sites / Locations

  • Massachusetts General HospitalRecruiting
  • Hackensack University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase 2/3 Expansion Cohort, Single-agent RAPA-501 T cells

Phase 1/2 Only, Single-agent RAPA-501 T cells (dose level Arm 1)

: Phase 1/2 Only, Single-agent RAPA-501 T cells (dose level Arm 2)

Phase 1/2 Only, RAPA-501 + PC Regimen (Arm 3A)

Arm Description

80 x 10^6 cells per infusion (no host conditioning)

Dose level 1 is 20 x 10^6 cells/infusion

Dose level 2 is 80 x 10^6 cells/infusion

RAPA-501 T cell therapy preceded by the 3-day pentostatin-cyclophosphamide (PC) regimen

Outcomes

Primary Outcome Measures

In the expansion cohort enrolling standard-risk pwALS, determine the feasibility and safety of the highest established safe dose of RAPA-501 (80 x 10^6 cells per infusion).

Secondary Outcome Measures

Characterize immune system parameters pre- and post-therapy.
Specifically, relative to pretreatment patient peripheral blood values, determine whether study interventions: (a) increase circulating Th2 and TREG cells; (b) reduce circulating Th1 cells; (c) increase T cell expression of programmed death-1 (PD-1); and (d) reduce inflammatory cytokines IL-1-beta, IL-6, and TNF-alpha.
Relative to pretreatment values, characterize the potential effect of RAPA-501 therapy on serum markers of neurodegeneration (neurofilament light, NfL).
Relative to pretreatment values, characterize the potential effect of RAPA-501 therapy on pulmonary function, as measured by slow vital capacity measurements (SVC, percent of predicted normal).
Relative to pretreatment values, characterize the potential effect of RAPA-501 therapy on hand grip strength using hand-held dynamometry.
Using a virtual control cohort and prognostic matching comparator arm (Origent algorithm), determine the potential effect of RAPA-501 therapy on disease progression (ALSFRS-R), pulmonary function (SVC), time to King's stage transition, and survival.

Full Information

First Posted
January 3, 2020
Last Updated
August 25, 2023
Sponsor
Rapa Therapeutics LLC
Collaborators
Massachusetts General Hospital, Hackensack Meridian Health
search

1. Study Identification

Unique Protocol Identification Number
NCT04220190
Brief Title
RAPA-501 Therapy for ALS
Official Title
Phase 2/3 Trial of Autologous Hybrid TREG/Th2 Cell (RAPA-501) Therapy for Amyotrophic Lateral Sclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 15, 2020 (Actual)
Primary Completion Date
July 1, 2025 (Anticipated)
Study Completion Date
July 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rapa Therapeutics LLC
Collaborators
Massachusetts General Hospital, Hackensack Meridian Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RAPA-501-ALS is a phase 2/3 expansion cohort study of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).
Detailed Description
This is an open-label, non-randomized, multi-center phase 2/3 study evaluating RAPA-501 T cell therapy in pwALS on an expansion cohort. 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. RAPA-501 cells are manufactured ex vivo using epigenetic reprogramming to yield a T cell population that is enriched for a dual anti-inflammatory phenotype based on hybrid TREG and Th2 differentiation. RAPA-501 cells express both the TREG and Th2 transcription factors FOXP3 and GATA3, are enriched for expression of the ATP ectonucleotidase molecules CD39 and CD73, are enriched for the T cell homing molecule CD103, and suppress both effector T cell inflammatory molecules and CNS microglial cell inflammatory molecules. This study consists of a phase 2/3 expansion cohort that is evaluating RAPA-501 T cell therapy at the dose of 80 x 10EE6 cells per infusion, with up to 4 infusions separated by six weeks between doses (infusion at time 0, and then after week 6, 12, and 18). Study subjects are then followed at the treatment site at 24 weeks and 30 weeks on-study; then, subjects are followed remotely using surveys for two years to capture major clinical events and assess survival. The primary objective in the expansion cohort is to determine the feasibility and safety of the highest established safe dose of RAPA-501 (80 x 10EE6 cells per infusion) in patients with standard-risk ALS (as defining by study entry values of: SVC greater than or equal to 70% of predicted normal; time interval since first ALS symptom, 24 months or less; and ALSFRS-R score between 34 and 45). Secondary study objectives relate to assessing the potential efficacy of RAPA-501 therapy through monitoring of ALSFRS-R scores, SVC values, time to King's stage transition, and survival. To enhance an ability to determine potential efficacy, these parameters will be compared to two comparator arms using machine learning algorithms developed by Origent Data Sciences, namely: (1) a virtual intra-patient control cohort (patient serves as own control); and (2) a comparator arm developed by prognostic mapping to the PRO-ACT database. In addition, secondary study objectives relate to study of pre- and post-therapy blood samples (serum and cells) for markers of inflammation and neurodegeneration. In the initial phase 1/2 study design, patients received therapy on Cohort 1 (low-dose RAPA-501; 20 x 10EE6 cells per infusion), Cohort 2 (high-dose RAPA-501; 80 x 10EE6 cells per infusion), and Cohort 3A (low-dose RAPA-501 when administered after a 3-day host conditioning regimen consisting of pentostatin plus cyclophosphamide. At the time of study amendment to add the expansion cohort, some patients already enrolled to the phase 1/2 aspect of the trial will continue to receive their initially designated cohort therapy and follow-up evaluation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
Amyotrophic Lateral Sclerosis, Autologous TREG/Th2 cell therapy, RAPA-501

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Masking Description
No masking
Allocation
Non-Randomized
Enrollment
41 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 2/3 Expansion Cohort, Single-agent RAPA-501 T cells
Arm Type
Experimental
Arm Description
80 x 10^6 cells per infusion (no host conditioning)
Arm Title
Phase 1/2 Only, Single-agent RAPA-501 T cells (dose level Arm 1)
Arm Type
Experimental
Arm Description
Dose level 1 is 20 x 10^6 cells/infusion
Arm Title
: Phase 1/2 Only, Single-agent RAPA-501 T cells (dose level Arm 2)
Arm Type
Experimental
Arm Description
Dose level 2 is 80 x 10^6 cells/infusion
Arm Title
Phase 1/2 Only, RAPA-501 + PC Regimen (Arm 3A)
Arm Type
Experimental
Arm Description
RAPA-501 T cell therapy preceded by the 3-day pentostatin-cyclophosphamide (PC) regimen
Intervention Type
Biological
Intervention Name(s)
RAPA-501 Autologous T cells
Other Intervention Name(s)
RAPA-501 cells
Intervention Description
TREG/Th2 cells
Primary Outcome Measure Information:
Title
In the expansion cohort enrolling standard-risk pwALS, determine the feasibility and safety of the highest established safe dose of RAPA-501 (80 x 10^6 cells per infusion).
Time Frame
Through 30 Weeks On-Study
Secondary Outcome Measure Information:
Title
Characterize immune system parameters pre- and post-therapy.
Description
Specifically, relative to pretreatment patient peripheral blood values, determine whether study interventions: (a) increase circulating Th2 and TREG cells; (b) reduce circulating Th1 cells; (c) increase T cell expression of programmed death-1 (PD-1); and (d) reduce inflammatory cytokines IL-1-beta, IL-6, and TNF-alpha.
Time Frame
Through 30 Weeks On-Study
Title
Relative to pretreatment values, characterize the potential effect of RAPA-501 therapy on serum markers of neurodegeneration (neurofilament light, NfL).
Time Frame
Through 30 Weeks On-Study
Title
Relative to pretreatment values, characterize the potential effect of RAPA-501 therapy on pulmonary function, as measured by slow vital capacity measurements (SVC, percent of predicted normal).
Time Frame
Through 30 Weeks On-Study
Title
Relative to pretreatment values, characterize the potential effect of RAPA-501 therapy on hand grip strength using hand-held dynamometry.
Time Frame
Through 30 Weeks On-Study
Title
Using a virtual control cohort and prognostic matching comparator arm (Origent algorithm), determine the potential effect of RAPA-501 therapy on disease progression (ALSFRS-R), pulmonary function (SVC), time to King's stage transition, and survival.
Time Frame
Through 2 Years and 30 Weeks On-Study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female patients ≥ 18 years of age. 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. . Less than or equal to 24 months since ALS symptom onset. Total ALSFRS-R score between 34 and 45. Must have a source of autologous T cells potentially sufficient to manufacture RAPA-501 cells, as defined by a peripheral CD3+ T cell count ≥ 500 cells per μl. Patients may continue riluzole (Rilutek®), and/or edaravone (Radicava®), and/or sodium phenylbutyrate/taurusodial (Relyvrio™) if on a stable dose for at least 30 days prior to the screening visit. Patients must be ≥ 2 two weeks removed from major surgery or investigational therapy. Patients must have recovered from clinical toxicities ([resolution of CTCAE(v5) [version 5] toxicity to a value of ≤ 2].). Serum creatinine ≤ less than or equal to 2.0 mg/dL. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN). Bilirubin ≤ 1.5 (except if due to Gilbert's disease). Pulmonary slow vital capacity (SVC) ≥ 70% of predicted normal. No history of abnormal bleeding tendency. 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 patient participant at any time without prejudice to future medical care. Exclusion Criteria: Active uncontrolled infection. Hypertension not adequately controlled by ≤ 3 medications. History of documented pulmonary embolus within 6 months of enrollment. 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. Patients with history of coronary artery bypass grafting or angioplasty will receive a cardiology evaluation and be considered on a case-by-case basis. HIV, hepatitis B, or hepatitis C seropositive. Pregnancy or breastfeeding patients. Patients of Subjects of childbearing age, or males who have a partner of childbearing potential, who are unwilling to practice contraception. Patients Subjects may be excluded at the Principal Investigator discretion of the PI or if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Daniel Fowler, M.D. Chief Medical Officer, RAPA Therapeutics, LLC
Phone
(301) 518-3104
Email
dan@rapatherapeutics.com
First Name & Middle Initial & Last Name or Official Title & Degree
Jennifer Sunga Regulatory Affairs Associate, RAPA Therapeutics, LLC
Phone
(571) 277-4916
Email
jsunga@rapatherapeutics.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Fowler, M.D.
Organizational Affiliation
Rapa Therapeutics LLC
Official's Role
Study Director
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jacqueline Topping
Phone
617-643-6036
Email
JTOPPING@mgh.harvard.edu
First Name & Middle Initial & Last Name & Degree
Lisa Lichtenegger
Phone
617-643-9005
Email
llichtenegger@mgh.harvard.edu
First Name & Middle Initial & Last Name & Degree
James Berry, M.D.
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michele Donato Principal Investigator
Phone
551-996-5855
Email
michele.donato@hackensackmeridian.org
First Name & Middle Initial & Last Name & Degree
Michele Donato, M.D

12. IPD Sharing Statement

Learn more about this trial

RAPA-501 Therapy for ALS

We'll reach out to this number within 24 hrs