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

Study Overview
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Brief Summary
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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.

Detailed Description
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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. To determine the overall response rate (complete response [CR] and partial response [PR]) of ruxolitinib in patients with T-LGLL. II. Duration of response to ruxolitinib. III. Leukemia-free survival. IV. Rate of conversion from PR at 4 months to CR at 8 and 12 months (at full ruxolitinib dosage). V. Rate of molecular remission (T-cell receptor [TCR] clearance, STAT3 mutation clearance) at 4, 8, 12 months. VI. Incidence of grade III/IV toxicities (at full ruxolitinib dosage). VII. 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. 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.

Official Title
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A Phase II Study Evaluating the Efficacy of Ruxolitinib in Patients With T-Cell Large Granular Lymphocytic Leukemia (T-LGLL)

Conditions
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T-Cell Large Granular Lymphocyte Leukemia

Intervention / Treatment
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* Drug: Ruxolitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older 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 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 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 Positive pregnancy test Platelet count < 50,000/uL Unstable angina or myocardial infarction within the past 2 months Chronic obstructive pulmonary disease or other interstitial lung disease in active exacerbation Serum alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin, or alkaline phosphatase > 1.5 x upper limit of normal (ULN) (unless document Gilbert's) Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 using the Modification of Diet in Renal Disease (MDRD) equation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ruxolitinib)<br>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. | Drug: Ruxolitinib<br>* Given PO<br>* Other names: Oral JAK Inhibitor INCB18424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The ORR will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least four months of therapy with ruxolitinib. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed). Additional outcomes including rates of conversion from PR at 4 months to CR at 8 and 12 months on full dose ruxolitinib, and rate of molecular remission (TCR clearance, STAT3 mutation clearance) at 4, 8, 12 months on full dose ruxolitinib will also be reported as proportions with 95% binomial CIs. | Up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events | Treatment-emergent adverse events will be reported overall and by toxicity grade. | Up to 12 months | 
| Leukemia-free survival (LFS) | Kaplan Meier curves will be generated and the median LFS and 95% CIs will be reported. | From first response until disease progression, death, or censoring (if alive and disease-free at the end of follow-up), assessed up to 12 months | 
| Patient quality-of-life (QOL) EORTC | Will be assessed via responses to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire at baseline, 5 months, and 1 year on study. Changes in QOL will be calculated from the differences in scores between baseline and 5 months, baseline and 1 year, and 5 months and 1 year, for each patient. The proportions of patients who had improvement in QOL scores between time points will be compared between responding patients and non-responding patients, patients with and without rheumatologic disease, and between patients classified as having an objective benefit and patients who did not have an objective benefit. Mean changes in patient QOL between time points will also be reported. | Up to 12 months | 
| Patient quality-of-life (QOL) QLQ-C30 | Will be assessed via responses to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 given at baseline, 5 months, and 1 year on study. Changes in QOL will be calculated from the differences in scores between baseline and 5 months, baseline and 1 year, and 5 months and 1 year, for each patient. The proportions of patients who had improvement in QOL scores between time points will be compared between responding patients and non-responding patients, patients with and without rheumatologic disease, and between patients classified as having an objective benefit and patients who did not have an objective benefit. Mean changes in patient QOL between time points will also be reported. | Up to 12 months | 
| Patient quality-of-life (QOL) HAQDi | Will be assessed via responses to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Health Assessment Questionnaire-Disability Index questionnaires given at baseline, 5 months, and 1 year on study. Changes in QOL will be calculated from the differences in scores between baseline and 5 months, baseline and 1 year, and 5 months and 1 year, for each patient. The proportions of patients who had improvement in QOL scores between time points will be compared between responding patients and non-responding patients, patients with and without rheumatologic disease, and between patients classified as having an objective benefit and patients who did not have an objective benefit. Mean changes in patient QOL between time points will also be reported. | Up to 12 months | 
| Patient quality-of-life (QOL) SF-36 | Will be assessed via responses to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Short Form-36 given at baseline, 5 months, and 1 year on study. Changes in QOL will be calculated from the differences in scores between baseline and 5 months, baseline and 1 year, and 5 months and 1 year, for each patient. The proportions of patients who had improvement in QOL scores between time points will be compared between responding patients and non-responding patients, patients with and without rheumatologic disease, and between patients classified as having an objective benefit and patients who did not have an objective benefit. Mean changes in patient QOL between time points will also be reported. | Up to 12 months |