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

• Sponsor: Jonathan Brammer (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT05141682
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 21
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 44
• Patients Per Site Per Month: 0.5

Study Details

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.

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

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. 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.

Study Design

• Study Type: Interventional
• Anticipated 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)
• Anticipated Study Start Date: May 1, 2022
• Anticipated Primary Completion Date: Dec 31, 2024
• Anticipated Study Completion Date: Dec 31, 2025

Arms and Interventions

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 Names: CC-486

Outcome Measures

Primary Outcome Measures

1. Maximum tolerated dose of oral azacitidine (CC-486) (Phase I) [Up to 4 cycles (1 cycle = 28 days)]

2. Overall response rate (complete response [CR] + partial response [PR]) (Phase II) [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 [Up to 3 years]

2. Progression-free survival (PFS [Up to 3 years]

3. Rate of conversion from PR at 4 months to CR at 8 months [From 4 months to 8 months]

4. Rate of conversion from PR at 4 months to CR at 12 months [From 4 months to 12 months]

5. Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance) [At 4 months]

6. Rate of molecular remission (TCR clearance, STAT3 mutation clearance) [At 8 months]

7. Rate of molecular remission (TCR clearance, STAT3 mutation clearance) [At 12 months]

8. Rate of treatment-emergent adverse events [Up to 12 months]

9. Degree of IL-15 promoter demethylation in responders versus non-responders [Up to 3 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Jonathan Brammer
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Jonathan E Brammer, MD, Ohio State University Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The Jamesline

Publications

None provided.

• 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
• First Posted: Dec 2, 2021
• Last Update Posted: Apr 25, 2022
• Last Verified: Apr 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
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Large Granular Lymphocytic; Azacitidine

Study Results

No Results Posted as of Apr 25, 2022