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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: T-Cell Large Granular Lymphocyte Leukemia
• Intervention / Treatment: Drug: Oral Azacitidine

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.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: The Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Principal Investigator: John Reneau, MD
      • Contact: John Reneau, MD; Phone Number: 614-293-3196; Email: John.Reneau@osumc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of oral azacitidine (CC-486) (Phase I)		Up to 4 cycles (1 cycle = 28 days)
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 Outcome Measures

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

Collaborators and Investigators

• Sponsor: John Reneau
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: John Reneau, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: November 19, 2021
• First Submitted That Met QC Criteria: November 19, 2021
• First Posted (Actual): December 2, 2021

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, T-Cell; Leukemia; Leukemia, Lymphoid; Leukemia, Large Granular Lymphocytic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: OSU-21018; NCI-2021-08491 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No