Phase 1/2 Study to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis

NCT ID: NCT03283826

Last Updated: 2024-02-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 134 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-19
• Study Completion Date: 2024-01-17

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of ATA188 as a monotherapy in Parts 1 and 2, to determine the recommended Part 2 dose (RP2D) of ATA188 as monotherapy in Part 1, and to evaluate the effect of ATA188 treatment on clinical disability, as assessed by confirmed Expanded Disability Status Scale (EDSS) improvement at 12 months in Part 2 in participants with progressive forms of multiple sclerosis (MS) (primary progressive multiple sclerosis [PPMS] and secondary progressive multiple sclerosis [SPMS]).

Detailed Description

This is a multicenter, 2 part study in adult participants with progressive forms of MS (PPMS/SPMS) with an open-label, single-arm, sequential dose-escalation period (Part 1) and a double-blind, randomized, placebo-controlled dose-expansion period (Part 2) followed by open-label extension (OLE) period. Part 2 and the OLE have been initiated by the sponsor's discretion based on a review of data from the dose-escalation cohorts.

This study will evaluate the safety and efficacy of ATA188 administered by intravenous (IV) infusion. ATA188 will be selected for each participant based on matching 2 or more human leukocyte antigen (HLA) alleles shared between ATA188 and the participant, at least 1 of which is a HLA-restricting allele.

In Part 1, participants received 2 cycles of ATA188 and entered 12 months follow-up period after the last dose of ATA188. Participants who completed at least the first year of the dose-escalation period and were active in the study have entered the OLE period. In OLE period, participants will receive the same RP2D assigned to Part 2 participants at the time of the Part 1 participant's first dose in each year of the OLE. In OLE period, participants will receive 1 cycle of ATA188 treatment every 12 months (Q12M) for up to 4 years (ie, Years 2 to 5). Otherwise, end of study (EOS) visit will be conducted at 24 months after Cycle 1 Day 1.

In Part 2, participants will be randomized in 1:1 ratio to receive ATA188 at the RP2D or matching placebo, stratified by progressive MS diagnosis (PPMS vs SPMS) and any prior exposure to anti-CD20 therapy (yes vs no). Participants will receive 2 cycles of ATA188 at the RP2D or matching placebo and will be followed for at least 12 months after the first dose of study drug (ie, Year 1). In second year (Year 2), participants who received placebo in Year 1 will receive 2 cycles of ATA188 at the RP2D assigned at randomization and participants who received ATA188 at the RP2D in Year 1 will receive 1 cycle of ATA188 (at the RP2D assigned at randomization) and 1 cycle of placebo to maintain the blind. Participants who complete Year 2 will enter the OLE period to receive ATA188 Q12M for up to 3 years (ie, Years 3 to 5) at the RP2D that was last selected by the sponsor for Part 2. The end of study visit will be scheduled at 5 years (60 months) after the first dose of study drug (ie, Cycle 1 Day 1).

Based on interim analysis, the recruitment for Parts 1and 2 have completed.

Conditions

Primary Progressive Multiple Sclerosis; Secondary Progressive Multiple Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

ATA188

Participants in Parts 1 and 2 will receive ATA188 intravenously as described in the Detailed Description.

Group Type: EXPERIMENTAL

ATA188

Intervention Type: BIOLOGICAL

ATA188 is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ progressive multiple sclerosis.

Placebo

Participants in Part 2 will receive placebo matching to ATA188 intravenously as described in the Detailed Description (i.e., will receive placebo only in the first year, and thereafter will receive ATA188 for the remainder of the study).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo matching to ATA188

Interventions

ATA188

ATA188 is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ progressive multiple sclerosis.

Intervention Type: BIOLOGICAL

Placebo

Placebo matching to ATA188

Intervention Type: DRUG

Other Intervention Names

Epstein-Barr Virus-directed cytotoxic T lymphocytes (CTLs); EBV-CTLs; EBV-targeted T-cell

Eligibility Criteria

Inclusion Criteria

• For Part 1: History of progressive forms of MS (PPMS or SPMS), as defined by the 2010 Revised McDonald criteria for the diagnosis of MS
• For Part 1: 18 to < 66 years of age
• For Part 1: EDSS scores of 3.0 to 7.0. Participants with EDSS scores of 6.5 to 7.0 must retain measurable upper limb function as assessed by the 9-hole Peg Test (9HPT).
• For Part 2: Current diagnosis of a progressive form of MS (PPMS or SPMS) as defined by the 2017 Revised McDonald criteria
• For Part 2:18 to < 61 years of age
• For Part 2:EDSS scores of 3.0 to 6.5
• Positive EBV serology
• Willing and able to provide written informed consent

Exclusion Criteria

• Clinical relapse as follows: For Part 1: Active clinical relapse between providing informed consent and the first dose of study drug. For Part 2: Documented clinical and/or radiological relapse for 2 years prior to screening, including gadolinium (Gd)-enhancing lesion(s) on any brain MRI scans available during this period (A participant will also be considered ineligible if any clinical and/or radiological relapse is reported between screening and the first dose of study drug.)
• Concurrent serious uncontrolled or unresolved medical condition, such as infection, limiting protocol compliance or exposing the subject to unacceptable risk
• Positive serology and/or nucleic acid testing (NAT) for human immunodeficiency virus (HIV), active hepatitis B virus (HBV) infection or carrier status for HBV, active hepatitis C virus (HCV) infection
• For Part 1: Positive serology for syphilis or human T cell lymphotrophic virus I/II
• Uncontrolled psychosis, uncontrolled depression or suicide risk, substance dependence, or any other psychiatric condition that may compromise the ability to participate in this trial
• Clinically significant abnormalities of full blood count, renal function, or hepatic function
• Any contraindication to MRI and/or Gd, eg., any object that is reactive to strong static magnetic, pulsed-gradient fields including any metallic fragments or foreign body (eg, aneurysm clip[s], pacemakers, electronic implants, shunts)
• Any history of cancer (as exceptions, successfully treated non-melanoma skin cancer or carcinoma in situ of the cervix with a < 5% chance of recurrence within 12 months of providing informed consent are allowed.)
• Prior therapy with corticosteroids (within 2 weeks before Cycle 1 Day 1)
• Prior therapy (30 days) B-cell depleting agent (eg, anti-CD20 agents such as ocrelizumab); participant must be progressing despite therapy to be eligible
• For Part 1: Prior therapy (6 half-lives or 30 days whichever is longer) with cladribine, glatiramer acetate, interferon β, dimethyl fumarate, methotrexate, azathioprine, cyclosporine, fingolimod, natalizumab, teriflunomide, mitoxantrone, cyclophosphamide, any other immunosuppressant or cytotoxic therapy (other than steroids), antithymocyte globulin or similar anti-T-cell antibody therapy, or any other investigational product
• For Part 1: Any previous treatment with alemtuzumab, ablative stem cell transplant, or EBV T-cell therapy
• For Part 2: Prior therapy (6 half-lives or 30 days whichever is longer) with IV immunoglobin, plasmapheresis, Bruton's tyrosine kinase inhibitors, all sphingosine 1-phosphate receptor modulators (eg, fingolimod), glatiramer acetate, interferon β, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators (eg, dimethyl fumarate), methotrexate, azathioprine, cyclosporine, natalizumab, teriflunomide, mitoxantrone, cyclophosphamide, any other immunosuppressant or cytotoxic therapy (other than steroids), antithymocyte globulin or similar anti-T-cell antibody therapy, or any other investigational product
• For Part 2: Any previous treatment with cladribine, alemtuzumab, ablative stem cell transplant, or EBV T-cell therapy
• Unresolved reactions from previous therapies that may, in the investigator's opinion, impact the safety of the participant or the conduct of this study
• Unwilling to use protocol specified contraceptive methods
• Women who are breastfeeding
• Pregnancy
• Inability or unwillingness to comply with study procedures

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Atara Biotherapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Kiren Kresa-Reahl, MD

Role: STUDY_DIRECTOR

Atara Biotherapeutics

Locations

University of California, San Diego

La Jolla, California, United States

Kaiser Permanente MS Clinic Los Angeles

Los Angeles, California, United States

Stanford University

Palo Alto, California, United States

University of California San Francisco

San Francisco, California, United States

University of Colorado

Aurora, Colorado, United States

Advanced Neurology

Fort Collins, Colorado, United States

Neurology Associates, PA-Maitland

Maitland, Florida, United States

University of South Florida, Morsani College of Medicine

Tampa, Florida, United States

Fort Wayne Neurological Center

Fort Wayne, Indiana, United States

University of Kansas Medical Center KUMC - Multiple Sclerosis MS Center

Kansas City, Kansas, United States

Ochsner Clinic Foundation

New Orleans, Louisiana, United States

Dragonfly Research

Wellesley, Massachusetts, United States

Washington University in St. Louis

St Louis, Missouri, United States

Dent Neurologic Institute

Amherst, New York, United States

Columbia University Medical Center-The Neurological Institute of New York

New York, New York, United States

University of Rochester Medical Center - URMC

Rochester, New York, United States

PMG Research of Piedmont Healthcare

Mooresville, North Carolina, United States

University of Pennsylvania

Philadelphia, Pennsylvania, United States

Premier Neurology P.C.

Greer, South Carolina, United States

Advanced Neurosciences Institute ANI - Franklin

Franklin, Tennessee, United States

Vanderbilt Comprehensive Multiple Sclerosis Center

Nashville, Tennessee, United States

The University of Texas Health Science Center at Houston

Houston, Texas, United States

MS Center of Greater Washington

Vienna, Virginia, United States

Inland Northwest Research LLC

Spokane, Washington, United States

Medical College of Wisconsin

Milwaukee, Wisconsin, United States

Liverpool Hospital

Liverpool, New South Wales, Australia

Royal Brisbane and Women's Hospital

Brisbane, Queensland, Australia

Griffith University, School of Medicine

Southport, Queensland, Australia

Fraser Health Multiple Sclerosis Clinic

Burnaby, British Columbia, Canada

Unity Health Toronto/St. Michael's Hospital

Toronto, Ontario, Canada

Recherche Sepmus Inc.

Greenfield Park, Quebec, Canada

Countries

United States; Australia; Canada

References

Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR, Khanna R. Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult Scler. 2014 Oct;20(11):1541-4. doi: 10.1177/1352458514521888. Epub 2014 Feb 3.

Reference Type: BACKGROUND

PMID: 24493474 (View on PubMed)

Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunology. 2017 Jan 20;6(1):e126. doi: 10.1038/cti.2016.87. eCollection 2017 Jan.

Reference Type: BACKGROUND

PMID: 28197337 (View on PubMed)

Drosu N, Bjornevik K, Bilodeau PA, Yeh A, Lechner-Scott J, Hawkes CH, Giovannoni G, Levy M. In the era of antiviral trials for MS, the answer lies in the details. Mult Scler Relat Disord. 2024 Feb;82:105444. doi: 10.1016/j.msard.2024.105444. Epub 2024 Jan 12. No abstract available.

Reference Type: DERIVED

PMID: 38241758 (View on PubMed)

Giovannoni G, Hawkes CH, Lechner-Scott J, Levy M, Yeh EA. Emboldened or not: The potential fall-out of a failed anti-EBV trial in multiple sclerosis. Mult Scler Relat Disord. 2024 Jan;81:105364. doi: 10.1016/j.msard.2023.105364. Epub 2023 Dec 10. No abstract available.

Reference Type: DERIVED

PMID: 38104476 (View on PubMed)

Other Identifiers

NCT03283826

Identifier Type: REGISTRY

Identifier Source: secondary_id

ATA188-MS-101

Identifier Type: -

Identifier Source: org_study_id