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

NCT03283826 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: ATA188-MS-101NCT03283826
• Study Type: interventional
• Target: 134
• Locations: 3 countries
• Sites: 31

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 \[SPMS\]).

Conditions

Primary Progressive Multiple Sclerosis; Secondary Progressive Multiple Sclerosis

Keywords

Multiple Sclerosis (MS); Primary Progressive Multiple Sclerosis; Secondary Progressive Multiple Sclerosis; Epstein-Barr Virus (EBV); EBV-associated Multiple Sclerosis; Inflammation; Central Nervous System; Autoimmune Disease; Autoimmunity; Demyelination; Cell Therapy; T-cell; Allogeneic; EBV viremia; Off-the-shelf (T cells)

Outcome Measures

Primary Outcomes (4)

• Part 1: Incidence of adverse events

  At 12 months after the first dose of study drug

• Part 1: Incidence of clinically significant changes in laboratory tests, electrocardiograms (ECGs), and vital signs

  At 12 months after the first dose of study drug

• Part 1: Recommended Part 2 dose of ATA188 monotherapy

  Day 1 to Day 35 of Cycle 1 for each participant in dose escalation part (approximately 1 year)

• Part 2: Percentage of participants with confirmed expanded disability status scale (EDSS) improvement at 12 months

  At 12 months after the first dose of study drug

Secondary Outcomes (5)

• Part 1: Change from baseline in EDSS score

  At 12 months after the first dose of study drug

• Part 2: Percentage of participants with confirmed EDSS improvement at 15 months

  At 15 months after the first dose of study drug

• Part 2: Percentage of participants with sustained disability improvement (SDI; ie, confirmed EDSS improvement or 20% decrease in timed 25-foot walk [T25W]) at 12 months

  At 12 months after the first dose of study drug

• Part 2: Percentage of participants with SDI at 15 months

  At 15 months after the first dose of study drug

• Part 2: Change from baseline in immunoglobulin G (IgG) index

  At 9 months after the first dose of study drug

Other Outcomes (4)

• Change from baseline in cervical spinal cord volume on MRI scans

  At 12 months after the first dose of study drug

• Change from baseline in whole brain volume on MRI scans

  At 12 months after the first dose of study drug

• Change from baseline in number of Gd-enhancing and new or enlarging T2 lesions on brain MRI scans

  At 12 months after the first dose of study drug

Study Arms (2)

ATA188

EXPERIMENTAL

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

Biological: ATA188

Placebo

PLACEBO COMPARATOR

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).

Drug: Placebo

Interventions

ATA188 BIOLOGICAL

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

Also known as: Epstein-Barr Virus-directed cytotoxic T lymphocytes (CTLs), EBV-CTLs, EBV-targeted T-cell

ATA188

Placebo DRUG

Placebo matching to ATA188

Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Atara Biotherapeutics: lead

Study Sites (31)

University of California, San Diego

La Jolla, California, 92037, United States

Location

Kaiser Permanente MS Clinic Los Angeles

Los Angeles, California, 90027, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

University of California San Francisco

San Francisco, California, 94158, United States

Location

University of Colorado

Aurora, Colorado, 80045, United States

Location

Advanced Neurology

Fort Collins, Colorado, 80528, United States

Location

Neurology Associates, PA-Maitland

Maitland, Florida, 32751, United States

Location

University of South Florida, Morsani College of Medicine

Tampa, Florida, 33612, United States

Location

Fort Wayne Neurological Center

Fort Wayne, Indiana, 46825, United States

Location

University of Kansas Medical Center KUMC - Multiple Sclerosis MS Center

Kansas City, Kansas, 66160, United States

Location

Ochsner Clinic Foundation

New Orleans, Louisiana, 70121, United States

Location

Dragonfly Research

Wellesley, Massachusetts, 02481, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Dent Neurologic Institute

Amherst, New York, 14226, United States

Location

Columbia University Medical Center-The Neurological Institute of New York

New York, New York, 10032, United States

Location

University of Rochester Medical Center - URMC

Rochester, New York, 14642, United States

Location

PMG Research of Piedmont Healthcare

Mooresville, North Carolina, 28117, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104-5127, United States

Location

Premier Neurology P.C.

Greer, South Carolina, 29650, United States

Location

Advanced Neurosciences Institute ANI - Franklin

Franklin, Tennessee, 37064, United States

Location

Vanderbilt Comprehensive Multiple Sclerosis Center

Nashville, Tennessee, 37215, United States

Location

The University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

MS Center of Greater Washington

Vienna, Virginia, 22182, United States

Location

Inland Northwest Research LLC

Spokane, Washington, 99202, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Liverpool Hospital

Liverpool, New South Wales, 2170, Australia

Location

Royal Brisbane and Women's Hospital

Brisbane, Queensland, 4029, Australia

Location

Griffith University, School of Medicine

Southport, Queensland, 4222, Australia

Location

Fraser Health Multiple Sclerosis Clinic

Burnaby, British Columbia, V5G 2X6, Canada

Location

Unity Health Toronto/St. Michael's Hospital

Toronto, Ontario, M5B1W8, Canada

Location

Recherche Sepmus Inc.

Greenfield Park, Quebec, J4V2J2, Canada

Location

Related Publications (4)

• 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.

  PMID: 24493474 BACKGROUND

• 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.

  PMID: 28197337 BACKGROUND

• 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.

  PMID: 38241758 DERIVED

• 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.

  PMID: 38104476 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis; Epstein-Barr Virus Infections; Inflammation; Autoimmune Diseases; Demyelinating Diseases

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Study Officials

• Kiren Kresa-Reahl, MD

  Atara Biotherapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 13, 2017
• First Posted: September 14, 2017
• Study Start: October 19, 2017
• Primary Completion: November 9, 2023
• Study Completion: January 17, 2024
• Last Updated: February 23, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3); US (25); CA (3)