Ruxolitinib for Adult T-Cell Leukemia

Phase 1

Terminated

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

Interventions: Drug: Ruxolitinib

Registration Number: NCT01712659

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 19

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
3- Phase 1 Dose Expansion Cohort	Ruxolitinib	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.
Original Phase II Standard Ruxolitinib dose cohort	Ruxolitinib	Ruxolitinib 20 mg orally twice daily for 28 days. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity.
2- Phase 1 Dose Escalation cohorts	Ruxolitinib	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.

Primary Outcome Measures

Name	Time	Method
Phase II: Best Response	From the time of the start of treatment to approximately 3 years of 5	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.
Phase I: Maximum Tolerated Dose (MTD)	From the time of the start of treatment to approximately 1 year	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.

Secondary Outcome Measures

Name	Time	Method
Phase I: Grade of Serious and/or Non-serious Adverse Events (SAEs) Related to the Experimental Treatment by Grade	From the time of the start of treatment to approximately 1 year	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.
Phase II: Survival Time	From the time of the start of treatment to approximately 3 years	Survival time is defined as the date of protocol consent until the date of the subject's death for any cause.
Phase II: Time to Progression (TTP)	From the time of the start of treatment to approximately 3 years	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.
Phase I: Time to Progression When Ruxolitinib is Administered at Doses of 30, 40 or 50 mg Orally Twice Daily	From the time of the start of treatment to approximately 1 year	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.