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Oral Azacitidine for the Treatment of Relapsed or Refractory T-cell Large Granular Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05141682
Recruitment Status : Recruiting
First Posted : December 2, 2021
Last Update Posted : April 25, 2022
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Jonathan Brammer, Ohio State University Comprehensive Cancer Center

Brief Summary:
This phase I/II trial studies the best dose, possible benefits and/or side effects of oral azacitidine in treating patients with T-cell large granular lymphocytic leukemia that has come back (relapsed) or has not responded to previous treatment (refractory). Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Condition or disease Intervention/treatment Phase
T-Cell Large Granular Lymphocyte Leukemia Drug: Oral Azacitidine Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and maximum tolerated dose (MTD) of oral azacitidine (CC-486) in patients with symptomatic T-cell large granular lymphocytic leukemia (T-LGLL). (Phase I) II. To determine the overall response rate (complete response [CR] and partial response [PR]) of CC-486 in patients with T-LGLL. (Phase II)

SECONDARY OBJECTIVES:

I. Duration of response to CC-486. II. Progression-free survival. III. Rate of conversion from PR at 4 months to CR at 8 and 12 months. IV. Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance) at 4, 8, 12 months.

V. Effect of treatment on IL-15 promoter demethylation. VI. Effect of CC-486 on IL-15 promoter demethylation. VII. Safety of CC-486 in T-LGLL patients.

OUTLINE: This is a dose-escalation study.

Patients receive azacitidine orally (PO) on days 1-14. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients with PR or CR continue treatment for up to 8 additional cycles in the absence of disease progression or unacceptable toxicity.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose-Finding Clinical Trial With Expansion Cohort Evaluating CC-486 in Patients With Relapsed/Refractory T-Cell Large Granular Lymphocytic Leukemia (T-LGLL)
Estimated Study Start Date : May 1, 2022
Estimated Primary Completion Date : December 31, 2024
Estimated Study Completion Date : December 31, 2025


Arm Intervention/treatment
Experimental: Treatment (Oral Azacitidne)
Patients will receive CC-486 orally (PO) D1-14 of a 28-day cycle, in a similar fashion to the QUAZAR study for a minimum of 4 cycles. Patients that achieve a response (CR or PR) will remain on study for a maximum of 12 months. Patients without a response at 4 months will come off the study.
Drug: Oral Azacitidine
Given PO
Other Name: CC-486




Primary Outcome Measures :
  1. Maximum tolerated dose of oral azacitidine (CC-486) (Phase I) [ Time Frame: Up to 4 cycles (1 cycle = 28 days) ]
  2. Overall response rate (complete response [CR] + partial response [PR]) (Phase II) [ Time Frame: Up to 3 years ]
    Assessed by the investigator based upon criteria derived from the ECOG 5998 and BNZ-1 clinical trials.


Secondary Outcome Measures :
  1. Duration of response to CC-486 [ Time Frame: Up to 3 years ]
  2. Progression-free survival (PFS [ Time Frame: Up to 3 years ]
  3. Rate of conversion from PR at 4 months to CR at 8 months [ Time Frame: From 4 months to 8 months ]
  4. Rate of conversion from PR at 4 months to CR at 12 months [ Time Frame: From 4 months to 12 months ]
  5. Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance) [ Time Frame: At 4 months ]
  6. Rate of molecular remission (TCR clearance, STAT3 mutation clearance) [ Time Frame: At 8 months ]
  7. Rate of molecular remission (TCR clearance, STAT3 mutation clearance) [ Time Frame: At 12 months ]
  8. Rate of treatment-emergent adverse events [ Time Frame: Up to 12 months ]
  9. Degree of IL-15 promoter demethylation in responders versus non-responders [ Time Frame: Up to 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18 or older
  • Diagnosis of T-LGLL defined as: CD3+CD8+ cell population > 650/mm^3 and the presence of a clonal T-cell receptor (within 1 month of diagnosis). Note: patients with myelodysplastic syndrome (MDS)-like T-LGLL may be included with principal investigator (PI) approval even if CD3+CD8+ cell population is < 650/mm^3, though +TCR is required. Natural-killer (NK) large granular lymphocytic leukemia (LGL) is also permitted, provided there is a clonal NK-cell population noted with > 500 cells/mm^3
  • Failed at least one line of frontline therapy; off treatment for at least 14 days or 5 half-lives, whichever is longer
  • Require Treatment for T-LGLL (One or more required)

    • Symptomatic anemia with hemoglobin < 10 g/dL
    • Transfusion-dependent anemia
    • Neutropenia with absolute neutrophil count (ANC) < 500/mm^3
    • Neutropenia with ANC < 1500/mm^3 with recurrent infections
  • Platelet count >= 50 x 10^9/L
  • Serum creatinine =< 2 x the upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome with a bilirubin > 1.5 x ULN permitted)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x ULN
  • Eastern cooperative oncology group (ECOG) performance status =< 2
  • Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study
  • Able to sign informed consent

Exclusion Criteria:

  • Absolute neutrophil count (ANC) less than 200/m
  • Active Infection requiring ongoing anti-microbial treatment. Patients with human immunodeficiency virus (HIV), positive hepatitis B surface antigen or hepatitis C antibody will be excluded
  • Concurrent immune-suppressive therapy (prednisone or equivalent up to 20 mg permitted to treat T-LGL symptoms, but must be weaned within one month of initiation of trial drug). Patients on stable, chronic prednisone =< 10 mg for rheumatologic/autoimmune conditions are exempted from this requirement. They may enroll on the study
  • Active, concurrent malignancy unless deemed related to T-LGLL by PI
  • Prior use of 5-azacytidine or decitabine
  • Positive pregnancy test

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05141682


Contacts
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Contact: The Ohio State University Comprehensive Cancer Center 800-293-5066 OSUCCCClinicaltrials@osumc.edu

Locations
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United States, Ohio
Ohio State University Comprehensive Cancer Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Jonathan E. Brammer, MD    614-293-9563    jonathan.brammer@osumc.edu   
Principal Investigator: Jonathan E. Brammer, MD         
Sponsors and Collaborators
Jonathan Brammer
Bristol-Myers Squibb
Investigators
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Principal Investigator: Jonathan E Brammer, MD Ohio State University Comprehensive Cancer Center
Additional Information:
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Responsible Party: Jonathan Brammer, Principal Investigator, Ohio State University Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT05141682    
Other Study ID Numbers: OSU-21018
NCI-2021-08491 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
First Posted: December 2, 2021    Key Record Dates
Last Update Posted: April 25, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Large Granular Lymphocytic
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, T-Cell
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors