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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 : March 16, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE October 20, 2012
First Posted Date  ICMJE October 23, 2012
Last Update Posted Date March 16, 2021
Actual Study Start Date  ICMJE October 26, 2012
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2018)
  • Response rate [ Time Frame: After treatment or at time of progressive disease ]
    Response rates will be assessed and tabulated
  • maximum tolerated dose [ Time Frame: 28 days ]
    type, frequency, and grade/severity of adverse events
Original Primary Outcome Measures  ICMJE
 (submitted: October 20, 2012)
Clinical Response Rate [ Time Frame: after treatment ends (could be 1 or many months) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2020)
Progression free survival [ Time Frame: C1-2 then every 2 cycles ]
date of registration until documented disease progression
Original Secondary Outcome Measures  ICMJE
 (submitted: October 20, 2012)
Safety profile, time to progression and survival time. [ Time Frame: after 28 days of treatment ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ruxolitinib for Adult T-Cell Leukemia
Official Title  ICMJE Phase II Trial Evaluating the Safety and Efficacy of Ruxolitinib in Patients With Smoldering and Chronic Adult T-cell Leukemia (ATL)
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.
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 not licensed for the treatment of ATL.

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 with off label-use 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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • T Cell Leukemia, Adult
  • Leukemia, Adult T-Cell
  • T Cell Leukemia, HTLV I Associated
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: 1- CLOSED
    Ruxolitinib 20mg orally twice daily for 28 days. Patient may continue to receive treatment until PD.
    Interventions:
    • Drug: Ruxolitinib
    • Drug: ruxolitinib
  • 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.
    Interventions:
    • Drug: Ruxolitinib
    • Drug: ruxolitinib
  • Experimental: 3- Dose Expansion
    Ruxolitinib at the MTD orally twice daily for 28 days. Patients may continue to receive treatment until PD or unacceptable toxicity.
    Interventions:
    • Drug: Ruxolitinib
    • Drug: ruxolitinib
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 30, 2018)
35
Original Estimated Enrollment  ICMJE
 (submitted: October 20, 2012)
20
Estimated Study Completion Date  ICMJE November 1, 2022
Estimated Primary Completion Date November 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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 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 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, 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, HTLV-II infection, or hepatitis B or C as follows:

    • 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.
    • Patients with active hepatitis C are excluded. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  • 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.
  • 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.
  • 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 are not eligible.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: NCI Medical Oncology Referral Office (240) 760-6050 NCIMO_Referrals@mail.nih.gov
Contact: Kevin C Conlon, M.D. (240) 760-6087 conlonkc@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01712659
Other Study ID Numbers  ICMJE 130006
13-C-0006
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Kevin C Conlon, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date March 11, 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP