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

Sponsor
Atara Biotherapeutics (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03283826
Collaborator
(none)
265
34
2
118.4
7.8
0.1

Study Details

Study Description

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]).

Condition or Disease Intervention/Treatment Phase
  • Biological: ATA188
  • Drug: Placebo
Phase 1/Phase 2

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 in 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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
265 participants
Allocation:
Randomized
Intervention Model:
Sequential Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2, Two-part, Open-label Dose-escalation and Double-blind, Placebo-controlled Dose-expansion Study With an Open-label Extension to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis
Actual Study Start Date :
Oct 19, 2017
Anticipated Primary Completion Date :
Jul 1, 2023
Anticipated Study Completion Date :
Sep 1, 2027

Arms and Interventions

Arm Intervention/Treatment
Experimental: ATA188

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

Biological: ATA188
ATA188 is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ progressive multiple sclerosis.
Other Names:
  • Epstein-Barr Virus-directed cytotoxic T lymphocytes (CTLs)
  • EBV-CTLs
  • EBV-targeted T-cell
  • Placebo Comparator: 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).

    Drug: Placebo
    Placebo matching to ATA188

    Outcome Measures

    Primary Outcome Measures

    1. Part 1: Incidence of adverse events [At 12 months after the first dose of study drug]

    2. 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]

    3. 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)]

    4. 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 Outcome Measures

    1. Part 1: Change from baseline in EDSS score [At 12 months after the first dose of study drug]

    2. Part 2: Percentage of participants with confirmed EDSS improvement at 15 months [At 15 months after the first dose of study drug]

    3. 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]

    4. Part 2: Percentage of participants with SDI at 15 months [At 15 months after the first dose of study drug]

    5. Part 2: Change from baseline in immunoglobulin G (IgG) index [At 9 months after the first dose of study drug]

    Other Outcome Measures

    1. Change from baseline in cervical spinal cord volume on MRI scans [At 12 months after the first dose of study drug]

    2. Change from baseline in whole brain volume on MRI scans [At 12 months after the first dose of study drug]

    3. 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]

    4. Change from baseline in IgG production [At 12 months after the first dose of study drug]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • For Part 1: 18 to < 66 years of age

    • For Part 1: History of progressive forms of MS as defined by the 2010 Revised McDonald criteria for the diagnosis of MS

    • For Part 1: EDSS scores of 3.0 to 7.0

    • For Part 2: 18 to < 61 years of age

    • For Part 2: Current diagnosis of a progressive form of MS as defined by the 2017 Revised McDonald criteria

    • For Part 2: EDSS scores of 3.0 to 6.5

    • Positive EBV serology

    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

    • 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

    • 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)

    • 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 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

    • Any previous treatment with alemtuzumab, ablative stem cell transplant, or EBV T-cell therapy for both parts and cladribine for Part 2

    • Unwilling to use protocol specified contraceptive methods

    • Women who are breastfeeding

    • Pregnancy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of California, San Diego La Jolla California United States 92037
    2 Kaiser Permanente MS Clinic Los Angeles Los Angeles California United States 90027
    3 Stanford University Palo Alto California United States 94304
    4 University of California San Francisco San Francisco California United States 94158
    5 University of Colorado Aurora Colorado United States 80045
    6 Advanced Neurology Fort Collins Colorado United States 80528
    7 Neurology Associates, PA-Maitland Maitland Florida United States 32751
    8 University of South Florida, Morsani College of Medicine Tampa Florida United States 33612
    9 Fort Wayne Neurological Center Fort Wayne Indiana United States 46825
    10 University of Kansas Medical Center KUMC - Multiple Sclerosis MS Center Kansas City Kansas United States 66160
    11 University of Kentucky Lexington Kentucky United States 40536
    12 Ochsner Clinic Foundation New Orleans Louisiana United States 70121
    13 Dragonfly Research Wellesley Massachusetts United States 02481
    14 Washington University in St. Louis Saint Louis Missouri United States 63110
    15 Neurosciences Institute at Hackensack University Medical Center Hackensack New Jersey United States 07601
    16 Dent Neurologic Institute Amherst New York United States 14226
    17 Columbia University Medical Center-The Neurological Institute of New York New York New York United States 10032
    18 University of Rochester Medical Center - URMC Rochester New York United States 14642
    19 PMG Research of Piedmont Healthcare Mooresville North Carolina United States 28117
    20 University of Cincinnati Cincinnati Ohio United States 45219
    21 University of Pennsylvania Philadelphia Pennsylvania United States 19104-5127
    22 Premier Neurology P.C. Greer South Carolina United States 29650
    23 Advanced Neurosciences Institute ANI - Franklin Franklin Tennessee United States 37064
    24 Vanderbilt University Medical Center VUMC Nashville Tennessee United States 37215
    25 The University of Texas Health Science Center at Houston Houston Texas United States 77030
    26 MS Center of Greater Washington Vienna Virginia United States 22182
    27 Inland Northwest Research LLC Spokane Washington United States 99202
    28 Medical College of Wisconsin Milwaukee Wisconsin United States 53226
    29 Liverpool Hospital Liverpool New South Wales Australia 2170
    30 Royal Brisbane and Women's Hospital Brisbane Queensland Australia 4029
    31 Griffith University, School of Medicine Southport Queensland Australia 4222
    32 Fraser Health Multiple Sclerosis Clinic Burnaby British Columbia Canada V5G 2X6
    33 Unity Health Toronto/St. Michael's Hospital Toronto Ontario Canada M5B1W8
    34 Recherche Sepmus Inc. Greenfield Park Quebec Canada J4V2J2

    Sponsors and Collaborators

    • Atara Biotherapeutics

    Investigators

    • Study Director: Kiren Kresa-Reahl, MD, Atara Biotherapeutics

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Atara Biotherapeutics
    ClinicalTrials.gov Identifier:
    NCT03283826
    Other Study ID Numbers:
    • ATA188-MS-101
    First Posted:
    Sep 14, 2017
    Last Update Posted:
    Jul 25, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Atara Biotherapeutics
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 25, 2022