Ruxolitinib for the Treatment of T-Cell Large Granular Lymphocytic Leukemia

Jonathan Brammer

Status and phase: Enrolling; Phase 2

Conditions: T-Cell Large Granular Lymphocyte Leukemia

Treatments: Drug: Ruxolitinib

Study type: Interventional

Funder types: Other

Identifiers

NCT05592015

OSU-21336

NCI-2022-02385 (Registry Identifier)

Details and patient eligibility

About

This phase II trial tests whether ruxolitinib works to shrink tumors in patients with T-cell large granular lymphocyte leukemia. Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Full description

PRIMARY OBJECTIVE:

I. Determine the overall response rate (ORR) of ruxolitinib in patients with T-cell large granular lymphocytic leukemia (T-LGLL) as compared to historical controls.

SECONDARY OBJECTIVES:

I. Rate of conversion from PR at 4 months to CR at 8 and 12 months (at full ruxolitinib dosage).

II. Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance) at 4, 8, 12 months.

III. Incidence of grade III/IV toxicities (at full ruxolitinib dosage). IV. Quality of life using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core 30 (C30), Health Assessment Questionnaire-Disability Index (HAQDi), Short Form (SF)-36 questionnaire at baseline, after 5 months, 1 year of treatment.

EXPLORATORY OBJECTIVE:

I. Objective benefit (OB) rate at 4 months defined as a patient that had improvement in their cytopenias, transfusion dependence but not attaining a PR.

II. Leukemia-free survival III. Progression-free survival

OUTLINE:

Patients receive ruxolitinib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity. Patients who achieve a response (CR or PR) may receive an additional 12 months of ruxolitinib, for a maximum of 24 months.

Enrollment: 28 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Age 18 or older and able to swallow pills

• Diagnosis of T-LGLL defined as: CD3+CD8+ cell population > 650/mm^3 or CD3+CD8+CD57+ population > 500/mm^3 and the presence of a clonal T-cell receptor (within 1 month of diagnosis). Note: patients with MDS-like T-LGLL may be included with PI approval even if CD3+CD8+ cell population is < 650/mm^3, though +TCR is required. Natural-Killer (NK) LGL is also permitted, provided there is a clonal NK-cell population noted with > 500 cells/mm^3

• Untreated T-LGLL or failed at least one line of frontline therapy;

• Patients must be 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. Platelet transfusion may be utilized to meet inclusion criteria, as long as the platelet count remains >50,000/uL within 5 days of last transfusion. Note: Patients with platelets <100 x 109/L and renal impairment are not permitted to enroll to the study. Renal impairment is defined as creatinine clearance (CrCl) < 90 mL/min.

• Serum creatinine =< 2 x the upper limit of normal (ULN)

• • Estimated glomerular filtration rate (eGFR) => 30 mL/min using the Modification of Diet in Renal Disease (MDRD) equation (multiplying eGFR by each subjects Body Surface Area [BSA])

• 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) =< 2.5 x ULN

• Alkaline phosphatase (ALP) =< 2.5 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 treatment until 5 half-lives have passed. Male subject agrees to use an acceptable method for contraception for the duration of the study treatment until 5 half-lives have passed.

• Able to sign informed consent

Exclusion criteria

• Absolute neutrophil count (ANC) less than 100/mm^3
• 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 principal investigator (PI). Early stage skin cancers, prostate cancer, permitted if under no active therapy
• For females of childbearing potential: Positive pregnancy test or lactating
• Unstable angina or myocardial infarction within the past 2 months
• Chronic obstructive pulmonary disease or other interstitial lung disease in active exacerbation
• Cirrhosis

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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28 participants in 1 patient group

Treatment (ruxolitinib)

Experimental group

Description:

Patients receive ruxolitinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity. Patients who achieve a response (CR or PR) may receive an additional 12 months of ruxolitinib, for a maximum of 24 months.

Treatment:

Drug: Ruxolitinib