EMBOLD: Phase 1/2 Study to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis
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 |
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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
Arms and Interventions
Arm | Intervention/Treatment |
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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:
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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
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Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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 Outcome Measures
- 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]
- Change from baseline in IgG production [At 12 months after the first dose of study drug]
Eligibility Criteria
Criteria
Inclusion Criteria:
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For Part 1: 18 to < 66 years of age
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For Part 1: History of progressive forms of MS as defined by the 2010 Revised McDonald criteria for the diagnosis of MS
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For Part 1: EDSS scores of 3.0 to 7.0
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For Part 2: 18 to < 61 years of age
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For Part 2: Current diagnosis of a progressive form of MS as defined by the 2017 Revised McDonald criteria
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For Part 2: EDSS scores of 3.0 to 6.5
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Positive EBV serology
Exclusion Criteria:
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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.)
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Concurrent serious uncontrolled or unresolved medical condition
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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
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For Part 1: Positive serology for syphilis or human T cell lymphotrophic virus I/II
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Clinically significant abnormalities of full blood count, renal function, or hepatic function
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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)
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Prior therapy with corticosteroids (within 2 weeks before Cycle 1 Day 1)
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Prior therapy (30 days) B-cell depleting agent (eg, anti-CD20 agents such as ocrelizumab); participant must be progressing despite therapy to be eligible
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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
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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
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Any previous treatment with alemtuzumab, ablative stem cell transplant, or EBV T-cell therapy for both parts and cladribine for Part 2
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Unwilling to use protocol specified contraceptive methods
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Women who are breastfeeding
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Pregnancy
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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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
- 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. Erratum in: Clin Transl Immunology. 2017 Jun 16;6(6):e147.
- 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.
- ATA188-MS-101