An Open-Label Phase 1 Study to Evaluate the Safety of ATA188 in Subjects With Progressive and Relapsing-Remitting Multiple Sclerosis

Phase 1 Study to Evaluate the Safety of ATA188 in Subjects With Progressive and Relapsing-Remitting Multiple Sclerosis



Sponsors

Lead Sponsor



Source

Atara Biotherapeutics

Oversight Info

Has Dmc

No

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No


Brief Summary

This is a multicenter, open-label, two-population, single-arm study with a sequential
dose-escalation and dose-expansion in adult subjects with progressive forms of multiple
sclerosis (MS) and an in adult subjects with relapsed remitting multiple sclerosis (RRMS).

Detailed Description

This is a multicenter, open-label, two-population, single-arm study with a sequential
dose-escalation and dose expansion in adult subjects with progressive forms of MS (Population
A) and in adult subjects with RRMS (Population B).

This study will evaluate the safety of ATA188 administered by intravenous (IV) infusion.
ATA188 will be selected for each subject based on matching at least 2 human leukocyte antigen
(HLA) alleles shared between ATA188 and the subject including at least 1 HLA-restricting
allele.

Subjects will receive 2 cycles of treatment with each cycle consisting of a 15-day treatment
period (with 3 infusions, each given approximately 7 days apart, on Days 1, 8 [±2 days], and
15 [±2 days]). After the third infusion of Cycle 1, subjects will enter a 20-day observation
period with weekly visits, and after the third infusion of Cycle 2, subjects will enter a
follow-up period with 11 monthly (every 28 ±5 days) visits. Together, subjects will be
observed for at least 1 year after the first dose of ATA188.

Overall Status

Recruiting

Start Date

2017-10-19

Completion Date

2020-03-01

Primary Completion Date

2019-02-01

Phase

Phase 1

Study Type

Interventional

Primary Outcome

Measure

Time Frame

Incidence of adverse events and clinically significant changes in laboratory tests, ECGs, and vital signs
Approximately 2 months per subject
Recommended Phase 2 dose of ATA188 monotherapy
Approximately 1 year

Secondary Outcome

Measure

Time Frame

Change from baseline in the number of Gd-enhancing and new or enlarging T2 lesions on brain MRI scans for subjects with RRMS
Approximately 9 months per subject
Change from baseline in expanded disability status scale (EDSS) score
Approximately 9 months per subject
Change from baseline in annualized relapse rate (ARR) for subjects with RRMS
Approximately 9 months per subject

Enrollment

60

Conditions


Intervention

Intervention Type

Drug

Intervention Name


Description

Allogeneic EBV-directed T-cell therapy

Arm Group Label

Progressive or RRMS

Other Name

EBV-CTLs

Epstein-Barr Virus-directed cytotoxic T lymphocytes (CTLs)

EBV-targeted T-cell



Eligibility

Criteria

Inclusion Criteria:

A subject will be considered eligible to participate in this study if all of the following
are satisfied:

1. History of MS, with progressive forms of MS or RRMS as defined by the 2010 Revised
McDonald criteria [53] for the diagnosis of MS.

1. Subjects with progressive forms of MS must have no new Gd-enhancing lesions
within 12 months of providing informed consent

2. Subjects with RRMS must have failed a health authority approved treatment

2. Positive EBV serology

3. Availability of appropriate partially HLA-matched and restricted ATA188 cell product

4. Males and females of the following ages:

1. 18 to 65 years of age for subjects with progressive forms of MS

2. 18 to 45 years of age for subjects with RRMS

5. EDSS scores as follows:

1. 3.0 to 6.5 for subjects with progressive forms of MS

2. 2.0 to 5.5 for subjects with RRMS

6. Willing and able to provide written informed consent

Exclusion Criteria:

A subject will not be eligible to participate in the study if any of the following criteria
are met:

1. Active clinical relapse between providing informed consent and enrollment (ie, date of
the first dose of ATA188)

2. Concurrent serious uncontrolled or unresolved medical condition, such as infection,
limiting protocol compliance or exposing the subject to unacceptable risk

3. Positive serology and/or nucleic acid testing (NAT) for human immunodeficiency virus
(HIV)

4. Serology and/or NAT indicating active hepatitis B virus (HBV) infection or carrier
status for HBV (Note: A positive serology for HBV indicating a previous but cleared
infection with HBV is not an exclusion criterion)

5. Serology and/or NAT indicating active hepatitis C virus (HCV) infection

6. Positive serology for syphilis or human T cell lymphotrophic virus I/II (HTLV)

7. Significant non-malignant disease (eg, severe cardiac or respiratory dysfunction)

8. Uncontrolled psychosis, uncontrolled depression or suicide risk, substance dependence,
or any other psychiatric condition that may compromise the ability to participate in
this trial

9. Clinically significant abnormalities of full blood count, renal function, or hepatic
function:

- Elevated liver function tests, including total bilirubin (TBILI) > 1.5× the upper
limit of normal (ULN; unless subject has documented Gilbert's disease), aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) > 3.0×ULN

- Subjects with both a creatinine > 1.5×ULN and an estimated creatinine clearance
of < 60 mL/min (using the Cockcroft-Gault equation)

- Hemoglobin < 10 g/dL; platelet < 100×109/L; absolute neutrophil count < 1.5×109/L

10. 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)

11. Prior cancers, except 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

12. Immunomodulatory therapy as follows:

1. Any previous treatment with a B-cell depleting agent

2. Any previous treatment with alemtuzumab

3. Treatment with corticosteroids within 2 weeks of providing informed
consentTreatment with glatiramer acetate or interferon (IFN)β within 4 weeks of
providing informed consent

4. Treatment with dimethyl fumarate within 4 weeks of providing informed consent

5. Treatment with fingolimod within 2 months of providing informed consent

6. Treatment with natalizumab, methotrexate, azathioprine, or cyclosporine within 6
months of providing informed consent

7. Treatment with teriflunomide within 12 months of providing informed consent
unless patient has completed an accelerated clearance with cholestyramine

8. Treatment with mitoxantrone, cyclophosphamide, cladribine, rituximab or any other
immunosuppressant or cytotoxic therapy (other than steroids) within 12 months of
providing informed consent, or determined by the treating physician to have
residual immune suppression from these treatments

13. Antithymocyte globulin or similar anti-T cell antibody therapy ≤ 4 weeks of providing
informed consent

14. Female of childbearing potential unwilling to use a highly effective method of
contraception (ie, one that results in pregnancy less than 1% per year when used
consistently and correctly), eg, implants, injectables, combined oral contraceptives,
some intrauterine contraceptive devices, sexual abstinence, or a vasectomized partner,
and/or unwilling to refrain from donating eggs while undergoing treatment with ATA188
and for 3 months after the last dose OR Men with a female partner of childbearing
potential unwilling to use a highly effective contraceptive measure and/or unwilling
to refrain from donating sperm while undergoing treatment with ATA188 and for 3 months
after the last dose

15. Women who are breastfeeding

16. Pregnancy

17. Inability to comply with study procedures

18. Previous treatment with EBV T cell therapy

Gender

All

Minimum Age

18 Years

Maximum Age

65 Years

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Tap Maniar, MD
Study Director
Atara Biotherapeutics
Kanya Rajangam, MD, PhD
Study Director
Atara Biotherapeutics

Overall Contact

Last Name

Atara Biotherapeutics

Phone

(805) 603-4856

Email



Location

Facility

Status

Contact

Investigator

Royal Brisbane and Women's Hospital
Herston Queensland 4029 Australia
Recruiting
Last Name: Nanette Douglas
Phone: (07) 3646 2548
Email: [email protected]
Last Name: Michael Pender, MD, PhD
Role: Principal Investigator

Location Countries

Country

Australia


Verification Date

2017-10-01

Lastchanged Date

2017-10-19

Firstreceived Date

2017-09-13

Responsible Party

Responsible Party Type

Sponsor


Keywords


Has Expanded Access

No

Condition Browse


Number Of Arms

1

Arm Group

Arm Group Label

Progressive or RRMS

Arm Group Type

Experimental

Description

Adult subjects with either progressive forms of MS (Population A) or with Relapsing Remitting Multiple Sclerosis (Population B) will be enrolled. Subjects will receive 2 cycles of treatment with each cycle consisting of a 15-day treatment period (with 3 infusions, each given approximately 7 days apart, on Days 1, 8 [±2 days], and 15 [±2 days]). After the third infusion of Cycle 1, subjects will enter a 20-day observation period with weekly visits, and after the third infusion of Cycle 2, subjects will enter a follow-up period with 11 monthly (every 28 ±5 days) visits. Together, subjects will be observed for at least 1 year after the first dose of ATA188.


Firstreceived Results Date

N/A

Reference

Citation

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


Citation

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.

PMID

28197337



Firstreceived Results Disposition Date

N/A

Study Design Info

Intervention Model

Sequential Assignment

Primary Purpose

Treatment

Masking

None (Open Label)


Study First Submitted

September 13, 2017

Study First Submitted Qc

September 13, 2017

Study First Posted

September 14, 2017

Last Update Submitted

October 19, 2017

Last Update Submitted Qc

October 19, 2017

Last Update Posted

October 23, 2017


ClinicalTrials.gov processed this data on October 23, 2017

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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