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

Primary Purpose

T-Cell Large Granular Lymphocyte Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Oral Azacitidine
Sponsored by
Jonathan Brammer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for T-Cell Large Granular Lymphocyte Leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Ohio State University Comprehensive Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (Oral Azacitidne)

Arm Description

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.

Outcomes

Primary Outcome Measures

Maximum tolerated dose of oral azacitidine (CC-486) (Phase I)
Overall response rate (complete response [CR] + partial response [PR]) (Phase II)
Assessed by the investigator based upon criteria derived from the ECOG 5998 and BNZ-1 clinical trials.

Secondary Outcome Measures

Duration of response to CC-486
Progression-free survival (PFS
Rate of conversion from PR at 4 months to CR at 8 months
Rate of conversion from PR at 4 months to CR at 12 months
Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance)
Rate of molecular remission (TCR clearance, STAT3 mutation clearance)
Rate of molecular remission (TCR clearance, STAT3 mutation clearance)
Rate of treatment-emergent adverse events
Degree of IL-15 promoter demethylation in responders versus non-responders

Full Information

First Posted
November 19, 2021
Last Updated
April 18, 2022
Sponsor
Jonathan Brammer
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT05141682
Brief Title
Oral Azacitidine for the Treatment of Relapsed or Refractory T-cell Large Granular Lymphocytic Leukemia
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)
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2022 (Anticipated)
Primary Completion Date
December 31, 2024 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jonathan Brammer
Collaborators
Bristol-Myers Squibb

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
T-Cell Large Granular Lymphocyte Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
21 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (Oral Azacitidne)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Oral Azacitidine
Other Intervention Name(s)
CC-486
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Maximum tolerated dose of oral azacitidine (CC-486) (Phase I)
Time Frame
Up to 4 cycles (1 cycle = 28 days)
Title
Overall response rate (complete response [CR] + partial response [PR]) (Phase II)
Description
Assessed by the investigator based upon criteria derived from the ECOG 5998 and BNZ-1 clinical trials.
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Duration of response to CC-486
Time Frame
Up to 3 years
Title
Progression-free survival (PFS
Time Frame
Up to 3 years
Title
Rate of conversion from PR at 4 months to CR at 8 months
Time Frame
From 4 months to 8 months
Title
Rate of conversion from PR at 4 months to CR at 12 months
Time Frame
From 4 months to 12 months
Title
Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance)
Time Frame
At 4 months
Title
Rate of molecular remission (TCR clearance, STAT3 mutation clearance)
Time Frame
At 8 months
Title
Rate of molecular remission (TCR clearance, STAT3 mutation clearance)
Time Frame
At 12 months
Title
Rate of treatment-emergent adverse events
Time Frame
Up to 12 months
Title
Degree of IL-15 promoter demethylation in responders versus non-responders
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
The Ohio State University Comprehensive Cancer Center
Phone
800-293-5066
Email
OSUCCCClinicaltrials@osumc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jonathan E Brammer, MD
Organizational Affiliation
Ohio State University Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ohio State University Comprehensive Cancer Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jonathan E. Brammer, MD
Phone
614-293-9563
Email
jonathan.brammer@osumc.edu
First Name & Middle Initial & Last Name & Degree
Jonathan E. Brammer, MD

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://cancer.osu.edu
Description
The Jamesline

Learn more about this trial

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

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