Phase I-II Study of Ruxolitinib (INCB18424) for Patients with Chronic Myeloid Leukemia (CML) with Minimal Residual Disease While on Therapy with Tyrosine Kinase Inhibitors
This is a 2 part study. The goal of the first part of this clinical research study is to find the highest tolerable dose of ruxolitinib that can be given with a TKI that you are already taking (such as gleevec, sprycel, or nilotinib) as part of your standard of care treatment. The goal of the second part of this study is to learn if this drug combination can help to control CML. Although you have a good response to therapy, the disease is still detectable at low levels (this is called "minimal residual disease"). Researchers believe that eliminating all detectable evidence of disease may decrease the chances that the leukemia will ever come back. The safety of the drug combination will also be studied in both parts. Ruxolitinib is designed to block a protein called Jak2 that may help keep some leukemia cells alive even with TKI therapy. Blocking this protein may cause the cells to die.
Disease Group: Leukemia
Treatment Agent: Ruxolitinib
Treatment Location: Only at MD Anderson
Sponsor: Incyte Corporation
Primary Objective: Phase I: To determine the DLT and MTD of the combination of ruxolitinib and a tyrosine kinase inhibitor (TKI) in patients with chronic myeloid leukemia (CML). Phase II: To determine the clinical activity of the combination of ruxolitinib and a TKI in patients with CML in complete cytogenetic remission (CCyR) with minimal residual disease (MRD). Secondary Objectives: Phase I To determine the clinical activity of the combination of ruxolitinib and a TKI in patients with CML Phase II To determine the safety of the combination of ruxolitinib and a TKI in patients with CML in CCyR with minimal residual disease. Both phases Determine the overall survival, event-free survival and survival free from transformation to accelerated and blast phase. Determine the effect of therapy on bone marrow progenitors in clonogenic assays. Investigate the effect of therapy on molecular responses as assessed by genomic DNA PCR. Determine the effect of therapy on TKI-resistant quiescent leukemic Ph+ stem cells (CFSEmax/CD34+) by flow cytometric evaluation of activated Crkl and Jak2. Assess the effect of therapy on self-renewal and/or survival of leukemic stem cells by FISH Analysis on colonies. Assess Ruxolitinib pharmacokinetics (PK) in preselected time intervals during co-administration of this agent with TKIs.
IRB Review and Approval Date: 07/24/2013
Recruitment Status: Open
Projected Accrual: N/A
1) Patients 18 years or older with Philadelphia chromosome (Ph)-positive
or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR).
2) Patients must be on continuous TKI therapy for management of their CML. Any commercially available and FDA- approved TKI can be used, i.e., imatinib mesylate (IM), nilotinib (NIL) or dasatinib (DAS). Patients may be receiving TKI at entry in the frontline or salvage setting, including patients currently on imatinib after alpha-interferon failure or on dasatinib or nilotinib after failure to prior therapy including imatinib.
3) Patients must have received the current TKI for at least 18 months and not have increased their dose in the last 6 months.
4) For the phase I portion of the study, patients may be included without a CCyR provided they remain in chronic or accelerated phase CML and have at least a CHR. For the Phase II portion of the study patients must be in complete cytogenetic remission (CCyR), regardless of the stage of disease they had at the time they started therapy with TKI.
5) Patients must have detectable BCR-ABL transcript levels meeting at least 1 of the following criteria: Patient has never achieved a major molecular response (MMR, as defined by a BCR-ABL/ABL </=0.1% in the international scale (currently equivalent to 0.28 in the MDACC molecular diagnostic laboratory), & transcript levels have shown in at least 2 consecutive measures separated by at least 1 month to have increased by any value; or achieved a major molecular response which has been lost, with an interim increase in transcript levels by at least one-log, confirmed in two consecutive analyses separated by at least 1 month; or patient has received therapy for at least 2 years & lacks a sustained major molecular response; or patient has received therapy for at least 5 years & lacks a sustained complete molecular response (CMR, defined as transcript levels still detectable in the MDACC molecular diagnostic laboratory).
6) Patients must not have had a known interruption of TKI therapy of greater than 21 consecutive days or for a total of 6 weeks in the 6 months prior to enrollment.
7) Patients must be able to understand and sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the institutional policies.
8) ECOG performance status </=2.
9) Adequate organ function defined as: bilirubin <2x upper limit of normal (ULN) (unless associated with Gilbert’s syndrome), and ALT or AST <2.5x ULN.
10) ANC >/=1 x10(9)/L and platelets >/=100 x10(9)/L.
11) Serum creatinine < 1.5 mg/dL or creatinine clearance greater or equal than 60 cc/min as defined by the Cockcroft-Gault Equation: Males(mL/min):(140-age)*IBW(kg) / 72*(serum creatinine (mg/dl)); Females (mL/min):0.85*(140-age)*IBW(kg) / 72*(serum creatinine (mg/dl)).
12) Women of childbearing potential should be advised to avoid becoming pregnant while on therapy with Ruxolitinib and for 30 days after the last dose and practice effective methods of contraception. Men should be advised not to father a child while receiving treatment with Ruxolitinib and for 30 days after the last dose. Effective methods of contraception for this study include barrier methods (e.g., condoms, diaphragm); spermicidal jelly or foam; oral, depo provera, or injectable hormonal contraceptives; intrauterine devices; tubal ligation; and abstinence.
1) For the phase I portion of the study, patients in blast phase. For
the phase II portion of the study, patients in accelerated or blast phase.
2) Patients receiving any other investigational agents.
3) Patients who are pregnant or breast-feeding.
4) Patients with clinically significant heart disease (NYHA Class III or IV).
5) Patients with QTc > 480 msec.
6) Patients taking a potent CYP3A4 inhibitor that cannot be changed to an alternate drug.
7) Known or suspected hypersensitivity to ruxolitinib.
8) Patients with advanced malignant hepatic tumors.
9) Patients with known active hepatitis B or C, or HIV infection.
10) Patients with other medical conditions or concomitant medications that in the opinion of the principal investigator may interfere with the therapeutic treatment.
Information and next steps
Phase I/Phase II
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