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.
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
Drug | Synonyms | Arms |
---|
Bosutinib | Bosulif, SKI 606, SKI-606 | Arm I (dasatinib, nilotinib) |
Dasatinib | BMS-354825, Dasatinib Hydrate, Dasatinib Monohydrate, Sprycel | Arm I (dasatinib, nilotinib) |
Nilotinib | AMN 107 Base Form | Arm I (dasatinib, nilotinib) |
Nilotinib Hydrochloride Monohydrate | AMN107, Nilotinib Monohydrochloride Monohydrate, Tasigna | Arm I (dasatinib, nilotinib) |
Ruxolitinib | INCB-18424, INCB18424, Jakafi, Oral JAK Inhibitor INCB18424 | Arm II (ruxolitinib phosphate, dasatinib, nilotinib) |
Ruxolitinib Phosphate | INCB-18424 Phosphate, Jakafi | Arm 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
Name | Type | Description | Interventions |
---|
Arm I (dasatinib, nilotinib) | Active Comparator | Patients 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) | Experimental | 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. | - 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
April 30, 2021