Ruxolitinib for Adult T-Cell Leukemia

Study Overview
=================
Brief Summary
-----------------
Background: The human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL). Infection does not immediately cause ATL, but it can develop over time. ATL is a rare and aggressive type of cancer that disrupts the body's ability to control the HTLV-1 virus. Infected T lymphocytes that are transformed by HTLV-1 into malignant ATL cell have constitutively activated Interleukin-2 (IL-2), IL-9 and IL-15 production pathways that function as autocrine and paracrine stimulators of these cells by stimulating these cells through the Janus Kinase (JAK) 1 and 3/Signal transducer and activator of transcription 5 (STAT5) pathways. Ruxolitinib is a drug that has been approved to treat bone marrow disorders. Ruxolitinib is a tyrosine kinase inhibitor that disrupts signaling through the JAK 1 and 2/STAT3 and 5 pathways and have potential as a treatment for ATL. Researchers want to see if ruxolitinib can be a safe and effective treatment for ATL. Initially this trial was designed as a single dose level phase II trial with ruxolitinib given at the dose approved for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Clinical and correlative laboratory data demonstrated limited inhibition and impact on the subject's disease with the standard 20 mg twice daily dose. Given that the manufacturers of ruxolitinib had safety data for administering ruxolitinib to normal healthy volunteers at doses up to 50 mg twice or 100 mg once daily, the trial was reconfigured as a phase I dose escalation trial giving these higher doses on the twice daily schedule Objectives: Initial Phase II design: Define clinical or objective response rate for the 20 mg twice daily dose of Ruxolitinib. Define safety profile, Time to progression and survival time. Subsequent Phase I dose escalation with expansion cohort treated at the MTD or MAD: Determine the maximum tolerated dose (MTD) and clinical response rate for ruxolitinib administered at the higher dose levels. Determine safety profile, time to progression To test the safety and effectiveness of ruxolitinib for adult T-cell leukemia. Eligibility: - Individuals at least 18 years of age who have ATL caused by HTLV-1. Design: Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will also be performed. Participants will take ruxolitinib twice a day for 28 days. They will have blood tests on days 1, 14, and 28. These tests will look at the levels of HTLV-1 in the blood. Participants will have a final blood test about 2 weeks later. Treatment will also be monitored with imaging studies. Participants who have a partial response during treatment may be able to start taking ruxolitinib again after the final blood test. They will continue to take ruxolitinib for as long as it is effective and the side effects are not severe. Participants who have a full response during treatment will take ruxolitinib for 56 more days, and then stop treatment. If ATL returns, they may restart treatment and continue it for as long as it is effective.

Detailed Description
-----------------
Background: Adult T-cell leukemia is a lymphoproliferative disorder characterized by the presence of cluster of differentiation 4 (CD4)/cluster of differentiation 25 (CD25) expressing T cells (interleukin-2 receptor (IL-2R) alpha expressing) in the peripheral blood, in lymphoid and other tissues. In smoldering and chronic adult T-cell leukemia (ATL) the human T-cell leukemia virus 1 (HTLV-1) encoded protein, Tax constitutively activates interleukin-2 (IL-2), IL-9 and IL-15 autocrine/paracrine systems that in turn activate the Janus kinase (JAK)-1/3/signal transducer and activator of transcription 5 (STAT5) pathways. Ruxolitinib a therapeutic agent inhibits cytokine mediated Janus kinase (JAK)-1/2 activation and ex vivo proliferation of malignant T cells from subjects with ATL. Ruxolitinib is a potent orally bioavailable JAK1/2 inhibitor not licensed for the treatment of ATL. Primary Objective: Objective Initial Phase II: To determine clinical or objective response rate for ruxolitinib given at 20 mg twice daily Primary Objective Dose Escalation Phase I: To determine the maximum tolerated dose and clinical response rate for ruxolitinib given at doses of 30, 40 or 50 mg orally twice daily in subjects with smoldering, chronic and biologically indolent acute or lymphomatous subtype of ATL Eligibility Subjects greater than or equal to 18 years old with pathologically confirmed adult T-cell leukemia: smoldering or chronic or previously treated lymphomatous or acute subtypes with clinically indolent behavior indicated by lack of significant symptoms and treatment free interval of greater than 6 months. Subjects must have measurable or evaluable disease. Subjects with > 10% of their PBMCs having the characteristic abnormal (i.e., CD3dim, CD4 plus CD25 plus expressing) fluorescence activated cell sorting (FACS) profile for circulating ATL cells will be considered to have measurable disease. Subjects with symptomatic leukemic meningitis, bony or gastrointestinal (GI) tract involvement, serum calcium or Lactate dehydrogenase (LDH) > 1.5 times the upper limit of normal will be excluded. However, subjects that have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis (human T-cell leukemia virus 1 (HTLV-1) Associated Myelopathy (HAM)/tropical spastic paraparesis (TSP)) will be included. No prior treatment with another JAK inhibitor; subjects previously treated in this protocol at the lower dose are eligible to restart treatment at the higher dose levels. Design - This is a pilot open-label, trial with off label-use of oral ruxolitinib that will treat 27 to 33 Subjects with smoldering or chronic or clinically indolent ATL. Groups of 3 to 6 newly enrolled or reenrolled Subjects will begin treatment at an elevated dose of 30 mg orally given twice daily. If this dose is tolerated without exceeding the criteria for dose limiting toxicity (DLT) during the first cycle of treatment, the tolerability of treatment at 40 mg and then 50 mg twice daily will be evaluated.

Official Title
-----------------
Phase I/II Trial Evaluating the Safety and Efficacy of Ruxolitinib in Subjects With Smoldering and Chronic Adult T-cell Leukemia (ATL)

Conditions
-----------------
T Cell Leukemia, Adult, Leukemia, Adult T-Cell, T Cell Leukemia, HTLV I Associated

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Drug: Ruxolitinib
* Drug: Ruxolitinib
* Drug: Ruxolitinib


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA: NOTE: After approval and activation of Amendment D, subjects who have failed this protocol treatment previously at the initial dose level may be eligible for re-enrollment and retreatment if they otherwise meet eligibility criteria. Subjects greater than or equal to 18 years old with pathologically confirmed adult T- cell leukemia: smoldering or chronic, or previously treated lymphomatous or acute subtypes with clinically indolent behavior indicated by lack of significant symptoms and treatment free interval of greater than 6 months are eligible for treatment in the dose escalation and expansion cohorts. Subjects must have serum antibodies directed to human T-cell lymphotropic virus type 1 (HTLV-1). Subjects must have measurable or evaluable disease. Subjects with > 10% of the peripheral blood mononuclear cells (PBMCs) having the characteristic abnormal (i.e., CD3dim, cluster of differentiation 4 (CD4) plus cluster of differentiation 25 (CD25) plus expressing) fluorescence-activated cell sorting (FACS) profile for circulating adult T-cell leukemia (ATL) cells will be considered to have evaluable disease. Subjects must have adequate physiologic parameters: Absolute granulocyte count greater than or equal to 500 K/microL, platelet count greater than or equal to 75,000 K/microL and hemoglobin greater than or equal to 10 g/dL. Bilirubin and creatinine less than or equal to 1.5 times institutional upper limit of normal (ULN). Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) less than or equal to 3.0 times institutional ULN. Karnofsky Performance Score greater than or equal to 70% or Eastern Cooperative Oncology Group (ECOG) less than or equal 1. Subjects must be able to understand and sign Informed Consent Form. EXCLUSION CRITERIA: Subjects with symptomatic leukemic meningitis, bony or gastrointestinal (GI) tract involvement, serum calcium or lactate dehydrogenase (LDH) > 1.5 times the upper limit of normal will be excluded. However, subjects that have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis (human T-cell lymphotropic virus type 1 (HTLV-1) Associated Myelopathy (HAM)/tropical spastic paraparesis (TSP) will be included. Subjects with symptomatic leukemic meningitis, bony or GI tract involvement, serum calcium or LDH > 1.5 X the upper limit of normal will be excluded. However, subjects that have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis (HAM/TSP) will be included. Subjects who have received high doses of systemic corticosteroids for the treatment of their ATL within 4 weeks prior to the start of therapy. Subjects who have received any cytotoxic therapy, immunotherapy, antitumor vaccines or monoclonal antibodies in the 4 weeks prior to the start of the study. Life expectancy of less than 3 months. Documented active bacterial infections, HTLV-II infection, or hepatitis B or C as follows: A positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antigen (HBsAb) positive and hepatitis B core antibody (HBcAb) negative), or a fully resolved acute hepatitis B infection is not an exclusion criterion. Subjects with an indolent chronic hepatitis B infection (normal ALT, AST, albumin and no radiographic or biopsy evidence of cirrhosis) may be eligible. Subjects with active hepatitis C are excluded. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA). Subjects who have untreated human immunodeficiency virus (HIV) are not eligible for this study because by definition they have a defective immune response and are at much higher risk for opportunistic infections due to immune disregulation by both HTLV-1 and HTLVIII (HIV) viruses. Subjects on HIV therapy with undetectable viral loads as measured by HIV RNA quantitative real time PCR may be eligible. Inability or refusal to practice effective contraception during therapy. Men and women of childbearing potential must use an effective method of birth control or abstinence during treatment and for 1 week after completion of the treatment. Subject has significant and/or uncontrolled cardiac, renal, hepatic or other systemic disorders or significant psychological conditions at baseline visit that in the investigators judgment would jeopardize subject enrollment or compliance with the study procedures. Subjects with an absolute requirement for a medication that is a strong inhibitor of Cytochrome P450 3A4 (P450 CYP3A4) are not eligible.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Original Phase II Standard Ruxolitinib dose cohort<br>Ruxolitinib 20 mg orally twice daily for 28 days. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity. | Drug: Ruxolitinib<br>* Ruxolitinib 20 mg orally twice daily for 28 days. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity.<br>* Other names: Jakafi;|
| Experimental: 2- Phase 1 Dose Escalation cohorts<br>Dose level 1: Ruxolitinib 30 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity. Dose level 2: Ruxolitinib: Ruxolitinib 40 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity. Dose level 3: Ruxolitinib: Ruxolitinib 50 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity. | Drug: Ruxolitinib<br>* Ruxolitinib 30 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity.<br>* Other names: Jakafi;Drug: Ruxolitinib<br>* Ruxolitinib: Ruxolitinib 40 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity.<br>* Other names: Jakafi;Drug: Ruxolitinib<br>* Ruxolitinib 50 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity.<br>* Other names: Jakafi;|
| Experimental: 3- Phase 1 Dose Expansion Cohort<br>Ruxolitinib at the maximum tolerated dose (MTD) or the maximum administered dose (MAD) defined in the phase 1 dose escalation cohorts. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity. | Drug: Ruxolitinib<br>* Ruxolitinib 20 mg orally twice daily for 28 days. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity.<br>* Other names: Jakafi;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Best Response | Best response is complete response (CR) plus partial response (PR). Response was measured by the Revised Response Criteria for Lymphoma by Cheson, et al, and the International Consensus Meeting Criteria for Adult T-Cell Lymphoma (ATL). Complete response is disappearance of all clinical, microscopic, and radiographic evidence of disease. Partial response is a ≥50% reduction in the sum of the products of the greatest diameters of measurable disease without the appearance of new lesion. Stable disease is failure to attain complete response, partial response, or progressive disease. Progressive disease in peripheral blood is defined by a 50% increase from nadir in the count of flower cells and an absolute lymphocyte count, including flower cells, of 4x10^9/L; or the appearance of new lesions excluding skin. | From the time of the start of treatment to approximately 3 years of 5 | 
| Phase I: Maximum Tolerated Dose (MTD) | MTD is defined as the dose level at which no more than 1 of up to 6 participants experience dose-limiting toxicity (DLT) during the first cycle (28 days) treatment, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. A DLT is any grade 3 or 4 toxicity, if deemed possibly, probably, or definitely related to the study drug by the principal investigator during the first cycle of treatment with some exceptions such as Grade 3 anemia without hemolysis. Grade 3 or 4 granulocytopenia or leukopenia without infection, Grade 3 thrombocytopenia without bleeding, and Grade 3 or 4 lymphopenia. Grade 3 is severe or medically significant. Grade 4 is life-threatening, urgent intervention indicated. | From the time of the start of treatment to approximately 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II: Time to Progression (TTP) | TTP is defined as the date of protocol consent until date of progressive disease is documented. Progressive disease was assessed by the Revised Response Criteria for Lymphoma by Cheson, et al, and the International Consensus Meeting Criteria for Adult T-Cell Lymphoma (guideline (version 1.1). Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and the appearance of one or more new lesions. | From the time of the start of treatment to approximately 3 years | 
| Phase II: Survival Time | Survival time is defined as the date of protocol consent until the date of the subject's death for any cause. | From the time of the start of treatment to approximately 3 years | 
| Phase I: Grade of Serious and/or Non-serious Adverse Events (SAEs) Related to the Experimental Treatment by Grade | Grade of serious adverse events (SAEs) related to the experimental treatment. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, and Grade 4 is life-threatening. | From the time of the start of treatment to approximately 1 year | 
| Phase I: Time to Progression When Ruxolitinib is Administered at Doses of 30, 40 or 50 mg Orally Twice Daily | TTP is defined as the date of protocol consent until date of progressive disease is documented. Progressive disease was assessed by the Revised Response Criteria for Lymphoma by Cheson, et al, and the International Consensus Meeting Criteria for Adult T-Cell Lymphoma guidelines (version 1.1). Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, and the appearance of one or more new lesions. | From the time of the start of treatment to approximately 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
JAK 1/2, Human T-Cell Lymphotropic Virus 1, HTLV-1, Janus Kinase Inhibitor