RAPA-501 Therapy for ALS EAP

Study Overview
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Brief Summary
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RAPA-501-ALS is an Intermediate-Size Expanded Access Trial of RAPA-501 autologous hybrid TREG/Th2 cells in patients living with amyotrophic lateral sclerosis (pwALS).

Detailed Description
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This is an open-label, non-randomized, multi-center intermediate size expanded access clinical trial of single-agent RAPA-501 cells in patients with high-risk ALS who are not eligible for other ALS clinical trials. 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 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 for several months to capture major clinical events and to assess survival. The total duration of RAPA-501 therapy and follow-up interval on this protocol is approximately 8-months (250 days). The primary objective in the expanded access cohort is to determine the feasibility and safety of the highest-dose established safe dose of RAPA-501 (80 x 10 6 cells per infusion). Secondary study objectives relate to determining the ALS disease activity pre-therapy, during study interventions, and throughout the post-therapy observation interval of RAPA-501 therapy through the monitoring of ALSFRS-R scores, SVC values, hand grip strength, and ROADS Scale. In addition, secondary study objectives relate to characterizing immune system parameters pre- and post- therapy and the potential effect of RAPA-501 therapy on serum markers of neurodegeneration. 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.

Official Title
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Intermediate-Size Expanded Access Trial of Autologous Hybrid T REG /Th2 Cell Therapy (RAPA-501) of Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Biological: RAPA-501 Autologous T cells


Participation Criteria
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Eligibility Criteria
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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. Pulmonary slow vital capacity (SVC) < 50% of predicted normal. 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 who are taking riluzole (Rilutek), edaravone (Radicava), and/or sodium phenylbutyrate/taurursodial (Relyvrio) are eligible if taking the drug for at least 30 days prior to the screening visit. Patients must be ≥ two (2) weeks removed from major surgery, or investigational therapy. Patients must have no ongoing, unstable serious illness other than ALS, as determined by the Site Investigator. 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). 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 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. HIV, hepatitis B, or hepatitis C seropositive. Pregnant or breastfeeding subjects. Subjects of childbearing age, or males who have a partner of childbearing potential, who are unwilling to practice contraception. Subjects may be excluded at the Principal Investigator discretion or if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: RAPA-501 Autologous T cells|Experimental: Intermediate size expanded access cohort. Single-agent RAPA-501 T cells, 80 x 10EE6 cells per infusion.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amyotrophic Lateral Sclerosis, Autologous TREG/Th2 cell therapy, RAPA-501