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Ruxolitinib for Adult T-Cell Leukemia

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ClinicalTrials.gov Identifier: NCT01712659
Recruitment Status : Recruiting
First Posted : October 23, 2012
Last Update Posted : December 6, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( 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. It also affects the growth and reproduction of cells infected with the virus.
  • Ruxolitinib is a drug that has been approved to treat bone marrow disorders. It can interfere with the proteins that are important to the development and growth of ATL cells. Drugs like ruxolitinib may be able to interrupt important activity in ATL cells. Researchers want to see if ruxolitinib can be a safe and effective treatment for ATL.

Objectives:

- 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.

Condition or disease Intervention/treatment Phase
T Cell Leukemia, Adult Leukemia, Adult T-Cell T Cell Leukemia, HTLV I Associated Drug: Ruxolitinib Drug: ruxolitinib Phase 2

Detailed Description:

Background:

  • Adult T-cell leukemia is a lymphoproliferative disorder characterized by the presence of CD4/CD25 expressing T cells (IL-2R alpha expressing) in the peripheral blood, in lymphoid and other tissues.
  • In smoldering and chronic ATL the 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/STAT5 pathways.
  • Ruxolitinib a therapeutic agent inhibits cytokine mediated JAK1/2 activation and ex vivo proliferation of malignant T cells from patients with ATL.
  • Ruxolitinib is a potent orally bioavailable JAK1/2 inhibitor.

Primary Objective:

- 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 patients with smoldering, chronic and

biologically indolent acute or lymphomatous subtype of ATL

Eligibility

  • Patients 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.
  • Patients must have measurable or evaluable disease. Patients with > 10% of their PBMCs having the characteristic abnormal (i.e., CD3dim, CD4 plus CD25 plus expressing) FACS profile for circulating ATL cells will be considered to have measurable disease.
  • Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum calcium or LDH > 1.5 times the upper limit of normal will be excluded. However patients that have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis (HAM/TSP) will be included.
  • No prior treatment with another JAK inhibitor; patients 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 of oral ruxolitinib that will enroll 27 to 33 patients with

smoldering or chronic or clinically indolent ATL. Groups of 3 to 6 newly enrolled or

reenrolled patients will begin treatment at a 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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial Evaluating the Safety and Efficacy of Ruxolitinib in Patients With Smoldering and Chronic Adult T-cell Leukemia (ATL)
Study Start Date : October 20, 2012
Estimated Primary Completion Date : January 3, 2019
Estimated Study Completion Date : November 1, 2021


Arm Intervention/treatment
Experimental: 3- Dose Escalation
Ruxolitinib at the MTD orally twice daily for 28 days. Patients may continue to receive treatment until PD or unacceptable toxicity.
Drug: Ruxolitinib
Ruxolitinib 20 mg orally twice daily for 28 days. Patient may continue to receive treatment until PD.

Drug: ruxolitinib
ruxolitinib 30-50 mg orally twice daily for 28 days. Patients may continue to receive treatment until PD or unacceptable toxicity

Experimental: 1- CLOSED
Ruxolitinib 20mg orally twice daily for 28 days. Patients may continue to receive treatment until PD
Drug: Ruxolitinib
Ruxolitinib 20 mg orally twice daily for 28 days. Patient may continue to receive treatment until PD.

Drug: ruxolitinib
ruxolitinib 30-50 mg orally twice daily for 28 days. Patients may continue to receive treatment until PD or unacceptable toxicity

Experimental: 2- Dose Escalation
Ruxolitinib 30-50 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Patients may continue to receive treatment until PD or unacceptable toxicity
Drug: Ruxolitinib
Ruxolitinib 20 mg orally twice daily for 28 days. Patient may continue to receive treatment until PD.

Drug: ruxolitinib
ruxolitinib 30-50 mg orally twice daily for 28 days. Patients may continue to receive treatment until PD or unacceptable toxicity




Primary Outcome Measures :
  1. Response rate [ Time Frame: After treatment or at time of progressive disease ]
    Response rates will be assessed and tabulated

  2. maximum tolerated dose [ Time Frame: 28 days ]
    type, frequency, and grade/severity of adverse events



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

NOTE: After approval and activation of Amendment D, patients 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.

  • Patients 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 monthsare eligible for treatment in the dose escalation and expansion cohorts.
  • Patients must have serum antibodies directed to HTLV-1.
  • Patients must have measurable or evaluable disease. Patients with > 10% of the PBMCs having the characteristic abnormal (i.e., CD3dim, CD4 plus CD25 plus expressing) FACS profile for circulating ATL cells will be considered to have evaluable disease.
  • Patients 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 ULN.
  • AST, ALT less than or equal to 3.0 times institutional ULN.
  • Karnofsky Performance Score greater than or equal to 70% or ECOG less than or equal 1.
  • Patients must be able to understand and sign Informed Consent Form.

EXCLUSION CRITERIA:

  • Patients previously treated with a JAK inhibitor.
  • Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum calcium or LDH > 1.5 times the upper limit of normal will be excluded. However, patients that have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis (HAM/TSP) will be included.
  • Patients who have received high doses of systemic corticosteroids for the treatment of their ATL within 4 weeks prior to the start of therapy.
  • Patients 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, active or chronic hepatitis B with evidence of end organ damage or dysfunction, hepatitis C or HTLV-II infection.
  • - A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb positive and HBc Ab negative), or a fully resolved acute hepatitis B infection is not an exclusion criterion.
  • - Patients with an indolent chronic hepatitis B infection (normal ALT, AST, albumin and no radiographic or biopsy evidence of cirrhosis) may be eligible.
  • - A positive hepatitis C serology is an exclusion criterion.
  • Patients 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. Patients on HIV therapy with undetectable viral loads as measured by HIV RNA quantitative real time PCR may be eligible.
  • Pregnant and breast-feeding patients are not eligible for the study because the effects of ruxolitinib on the developing fetus are unknown.
  • 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 4 months after completion of the treatment.
  • Patient has significant and/or uncontrolled cardiac, renal, hepatic or other systemic disorders or significant psychological conditions at baseline visit that in the investigator s judgment would jeopardize subject enrollment or compliance with the study procedures.
  • Patients with an absolute requirement for a medication that is a strong inhibitor of P450 CYP3A4

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01712659


Contacts
Contact: Maureen E Edgerly, R.N. (240) 760-6013 NCIMO_Referrals@mail.nih.gov
Contact: Kevin C Conlon, M.D. (240) 760-6087 conlonkc@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Kevin C Conlon, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01712659     History of Changes
Other Study ID Numbers: 130006
13-C-0006
First Posted: October 23, 2012    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: November 29, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
JAK 1/2
Human T-Cell Lymphotropic Virus 1
HTLV-1
Janus Kinase Inhibitor

Additional relevant MeSH terms:
Leukemia
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases