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

T-Cell Large Granular Lymphocyte Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05141682
• Other study ID #: OSU-21018
• Secondary ID: NCI-2021-08491
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 29, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Ohio State University Comprehensive Cancer Center
• Contact: The Ohio State University Comprehensive Cancer Center
• Phone: 800-293-5066
• Email: OSUCCCClinicaltrials[@]osumc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 27
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

• 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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• T-Cell Large Granular Lymphocyte Leukemia

Intervention

Drug:
• Oral Azacitidine
Given PO

Locations

Country	Name	City	State
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
John Reneau	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose of oral azacitidine (CC-486) (Phase I)		Up to 4 cycles (1 cycle = 28 days)
Primary	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.	Up to 3 years
Secondary	Duration of response to CC-486		Up to 3 years
Secondary	Progression-free survival (PFS		Up to 3 years
Secondary	Rate of conversion from PR at 4 months to CR at 8 months		From 4 months to 8 months
Secondary	Rate of conversion from PR at 4 months to CR at 12 months		From 4 months to 12 months
Secondary	Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance)		At 4 months
Secondary	Rate of molecular remission (TCR clearance, STAT3 mutation clearance)		At 8 months
Secondary	Rate of molecular remission (TCR clearance, STAT3 mutation clearance)		At 12 months
Secondary	Rate of treatment-emergent adverse events		Up to 12 months
Secondary	Degree of IL-15 promoter demethylation in responders versus non-responders		Up to 3 years

External Links

•   The Jamesline