Clinical Trials /

Testing the Addition of Ruxolitinib to the Usual Treatment (Tyrosine Kinase Inhibitors) for Chronic Myeloid Leukemia

NCT03654768

Description:

This randomized phase II trial studies how well ruxolitinib phosphate, and bosutnib, dasatinib, or nilotinib, work in treating patients with chronic myeloid leukemia. Chronic myeloid leukemia cells produce a protein called BCR-ABL. The BCR-ABL protein helps chronic myeloid leukemia cells to grow and divide. Tyrosine kinase inhibitors, such as bosutinib, dasatinib, and nilotinib, stop the BCR-ABL protein from working, which helps to reduce the amount of chronic myeloid leukemia cells in the body. Ruxolitinib is a different type of drug that helps to stop the body from making substances called growth factors. Chronic myeloid leukemia cells need growth factors to grow and divide. The addition of ruxolitinib to the tyrosine kinase inhibitor may or may not help reduce the amount of chronic myeloid leukemia cells in the body.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Ruxolitinib to the Usual Treatment (Tyrosine Kinase Inhibitors) for Chronic Myeloid Leukemia
  • Official Title: A Randomized Phase II Study of Ruxolitinib (NSC-752295) in Combination With BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia (CML) Patients With Molecular Evidence of Disease

Clinical Trial IDs

  • ORG STUDY ID: S1712
  • SECONDARY ID: NCI-2017-02066
  • SECONDARY ID: S1712
  • SECONDARY ID: S1712
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03654768

Conditions

  • Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Interventions

DrugSynonymsArms
BosutinibBosulif, SKI 606, SKI-606Arm I (dasatinib, nilotinib)
DasatinibBMS-354825, Dasatinib Hydrate, Dasatinib Monohydrate, SprycelArm I (dasatinib, nilotinib)
NilotinibAMN 107 Base FormArm I (dasatinib, nilotinib)
Nilotinib Hydrochloride MonohydrateAMN107, Nilotinib Monohydrochloride Monohydrate, TasignaArm I (dasatinib, nilotinib)
RuxolitinibINCB-18424, INCB18424, Jakafi, Oral JAK Inhibitor INCB18424Arm II (ruxolitinib phosphate, dasatinib, nilotinib)
Ruxolitinib PhosphateINCB-18424 Phosphate, JakafiArm II (ruxolitinib phosphate, dasatinib, nilotinib)

Purpose

This randomized phase II trial studies how well ruxolitinib phosphate, and bosutnib, dasatinib, or nilotinib, work in treating patients with chronic myeloid leukemia. Chronic myeloid leukemia cells produce a protein called BCR-ABL. The BCR-ABL protein helps chronic myeloid leukemia cells to grow and divide. Tyrosine kinase inhibitors, such as bosutinib, dasatinib, and nilotinib, stop the BCR-ABL protein from working, which helps to reduce the amount of chronic myeloid leukemia cells in the body. Ruxolitinib is a different type of drug that helps to stop the body from making substances called growth factors. Chronic myeloid leukemia cells need growth factors to grow and divide. The addition of ruxolitinib to the tyrosine kinase inhibitor may or may not help reduce the amount of chronic myeloid leukemia cells in the body.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To compare the rate of molecular response 4.5 (MR4.5) after 12 months of combination
      therapy with ruxolitinib phosphate (ruxolitinib) plus a tyrosine-kinase inhibitor (TKI)
      (bosutinib, dasatinib, or nilotinib) versus a TKI alone, based on local polymerase chain
      reaction (PCR) testing to measure BCR-ABL transcripts in chronic phase chronic myelogenous
      leukemia (CML) patients with molecular evidence of disease.

      SECONDARY OBJECTIVES:

      I. To estimate the frequency and severity of toxicities of each regimen in this patient
      population.

      II. To estimate progression free survival and overall survival of each regimen in this
      patient population.

      ADDITIONAL OBJECTIVES:

      I. To describe patterns of MR4.5 and molecular response 4.0 (MR4.0) attainment and failure
      over the 3, 6, 9, and 12-month time points of each regimen in this patient population.

      II. To evaluate drug compliance based on patient reported drug intake calendars in this
      patient population.

      III. To describe the kinetics of response in this patient population (as measured by
      quantitative BCR-ABL/BCR ratio) in both arms over the 3, 6, 9, and 12-month time points.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive bosutinib orally (PO) daily or dasatinib PO daily or nilotinib PO
      twice daily (BID) on days 1-90. Treatment repeats every 90 days for up to 4 cycles in the
      absence of disease progression or unacceptable toxicity.

      ARM II: Patients receive ruxolitinib phosphate PO BID on days 1-90, and bosutinib PO daily or
      dasatinib PO daily or nilotinib PO BID on days 1-90. Treatment repeats every 90 days for up
      to 4 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for 2 years, and
      then annually up to 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (dasatinib, nilotinib)Active ComparatorPatients receive bosutinib PO daily or dasatinib PO daily or nilotinib PO BID on days 1-90. Treatment repeats every 90 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Bosutinib
  • Dasatinib
  • Nilotinib
  • Nilotinib Hydrochloride Monohydrate
Arm II (ruxolitinib phosphate, dasatinib, nilotinib)ExperimentalPatients receive ruxolitinib phosphate PO BID on days 1-90, and bosutinib PO daily or dasatinib PO daily or nilotinib PO BID on days 1-90. Treatment repeats every 90 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Bosutinib
  • Dasatinib
  • Nilotinib
  • Nilotinib Hydrochloride Monohydrate
  • Ruxolitinib
  • Ruxolitinib Phosphate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a diagnosis of chronic phase chronic myeloid leukemia without any
             history of progression to accelerated or blast phase CML; no new bone marrow
             aspiration and biopsy is needed to prove diagnosis prior to randomization; however,
             documentation stating the patient is in chronic phase is required

          -  Patients must have detectable BCR-ABL transcripts measured by reverse transcriptase
             (RT)-PCR at a clinical laboratory improvement act (CLIA)-approved laboratory and
             reported on the international scale (IS) with a value of > 0.0032% IS and =< 1.0% IS
             within 21 days prior to randomization; the RT-PCR assay must have the sensitivity to
             detect a 4.5 log reduction in BCR-ABL transcripts from 100% IS (0.0032% IS or lower)

          -  Patients must have been receiving TKI treatment for CML for at least 12 months prior
             to randomization

          -  Patients must be currently receiving treatment with bosutinib (within the allowable
             dose range of 200-500 mg daily), nilotinib (within the allowable dose range of 150-400
             mg BID or a cumulative daily dose of 300-800 mg), or dasatinib (within the allowable
             dose range of 40-140 mg daily); they must have received their current TKI for a
             minimum of 6 months prior to randomization and must be expected to remain on the same
             TKI for the next 12 months

          -  Patient must not have a history of resistance to any prior TKI drug; if patient has
             received more than one TKI, the reason for changing treatment must have been
             intolerance to the prior TKI and the treatment change must have occurred >= 6 months
             prior to randomization

          -  Patients must not be receiving any other investigational agents

          -  Patients must have complete history and physical examination within 28 days prior to
             randomization

          -  If clinically indicated, patients must have corrected Fridericia's correction formula
             (QTcF) interval < 500 ms (by Fridericia calculation) on a 12-lead electrocardiography
             (EKG) within 7 days prior to randomization

          -  Platelets >= 100,000/mm^3 (100.0 x 10^9/L) within 7 days prior to randomization

          -  Absolute neutrophil count (ANC) > 1,000/mm^3 (1.0 x 10^9/L) within 7 days prior to
             randomization

          -  Hemoglobin >= 8 g/dL within 7 days prior to randomization

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x
             institutional upper limit of normal (IULN) within 7 days prior to randomization

          -  Total bilirubin =< 1.5 x IULN within 7 days prior to randomization (unless the patient
             has a known diagnosis of Gilbert's syndrome)

          -  Serum creatinine =< 1.5 x IULN within 7 days prior to randomization

          -  Prior malignancy is allowed providing it does not require concurrent therapy;
             exception: active hormonal therapy is allowed

          -  Patients must not be pregnant or nursing due to the teratogenic potential of the drugs
             used on this study; women of child-bearing potential must have a negative serum
             pregnancy test within 7 days prior to randomization; women/men of reproductive
             potential must have agreed to use an effective contraceptive method during treatment
             and for 30 days after discontinuation of study drug; a woman is considered to be of
             "reproductive potential" if she has had menses at any time in the preceding 12
             consecutive months; in addition to routine contraceptive methods, "effective
             contraception" also includes heterosexual celibacy and surgery intended to prevent
             pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
             bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
             previously celibate patient chooses to become heterosexually active during the time
             period for use of contraceptive measures outlined in the protocol, he/she is
             responsible for beginning contraceptive measures

          -  Patients known to be human immunodeficiency virus positive (HIV+) are eligible
             provided they meet all other eligibility criteria and have undetectable HIV viral
             loads on their most recent viral load test which must have been performed in the last
             6 months

          -  Specimens (peripheral blood) must be collected and submitted to a CLIA-approved
             laboratory, within 21 days prior to randomization; BCR-ABL transcripts must be
             measured using RT-PCR and results must be reported using the international scale; the
             RT-PCR assay must have the sensitivity to detect a 4.5 log reduction in BCR-ABL
             transcripts from 100% IS (must be able to detect 0.0032% IS or lower)

          -  Patients must be offered participation in submission of specimens for central BCR-ABL
             quantification and banking for future specimens; this submission is highly encouraged
             as an important protocol endpoint; with patient's consent, specimens must be collected
             and submitted, within 21 days prior to randomization

          -  Patients must be informed of the investigational nature of this study and must sign
             and give written informed consent in accordance with institutional and federal
             guidelines

          -  As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
             treating institution's identity is provided in order to ensure that the current
             (within 365 days) date of institutional review board approval for this study has been
             entered in the system
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of molecular response 4.5 (MR4.5)
Time Frame:At 12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From the date of randomization until death from any cause with observations censored at the date of last contact for patients last known to be alive, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.
Measure:Progression-free survival
Time Frame:From the date of randomization on study until the first of treatment failure/loss of response, progression, or death from any cause, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. CTCAE version 5.0 will be utilized for serious adverse events reporting only.
Measure:MR4.5 attainment and failure
Time Frame:Up to 12 months
Safety Issue:
Description:Will be summarized descriptively
Measure:Molecular rate 4.0 (MR 4.0) attainment and failure
Time Frame:Up to 12 months
Safety Issue:
Description:Will be summarized descriptively
Measure:Drug compliance
Time Frame:Up to 5 years
Safety Issue:
Description:Will be summarized descriptively
Measure:BCR-ABL/BCR analysis
Time Frame:Up to 5 years
Safety Issue:
Description:Linear regression models will be used to assess associations between treatment arm and the quantitative endpoint.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Southwest Oncology Group

Last Updated

September 15, 2020