Summary

This phase II trial studies how well ruxolitinib and tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, nilotinib or bosutinib, work in treating patients who are attempting to stop TKI medications for a second time for chronic phase-chronic myeloid leukemia that has come back (recurrent). Ruxolitinib and imatinib, dasatinib, nilotinib or bosutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The purpose of this trial is to see if adding ruxolitinib to imatinib, dasatinib, nilotinib or bosutinib works better in prolonging treatment-free remission in patients with chronic phase-chronic myeloid leukemia.

Objectives

PRIMARY OBJECTIVE:
I. To determine the 1-year treatment free remission rate after 12 cycles of combination therapy with TKIs plus ruxolitinib phosphate (ruxolitinib) in subjects who have experienced molecular relapse after prior TKI discontinuation.

SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of the treatment combinations.
II. To assess the impact on health-related quality of life in patients while on combination therapy and after TKI discontinuation.
III. To compare changes in phosphorylation of STAT3 (pSTAT3) in K562 and KU812 cell lines measured by the Phos-Flow (STAT3/5) platform, using plasma from chronic myeloid leukemia (CML) patients being treated with TKIs plus ruxolitinib using the plasma inhibitory assay technique.
IV. To describe multiparameter flow based assessment of the T-cell compartment (activity/polarization) as well as natural killer (NK) cells in CML patients at various time points when they are being treated with TKIs alone, TKIs plus ruxolitinib and at a time when they are off both TKIs and ruxolitinib.
V. To correlate changes in pSTAT3 and pSTAT5 with clinical response and rate of treatment free remission (TFR).

OUTLINE:

COMBINATION TREATMENT PHASE: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) and imatinib, dasatinib, nilotinib or bosutinib on day 1. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.

TREATMENT FREE REMISSION PHASE: Patients undergo collection of blood samples at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 58, 64, 70, 76, 82, 88, 94, and 100. Patients whose results show they are no longer in major molecular response (MMR) resume treatment with imatinib, dasatinib, nilotinib or bosutinib per physician discretion.

After completion of study treatment, patients are followed up every 6 months until 5 years from study entry.

Eligibility

1. Age >= 18 years
2. Willing and able to give informed consent
3. Diagnosed with CML in chronic phase and have either the b3a2 (e14a2) or b2a2 (e13a2) variants that give rise to the p210 BCR-ABL protein. Subtype classification whether b3a2 (e14a2) or b2a2 (e13a2) is not required for study eligibility
4. Must have a documented history of attempting only one prior TKI discontinuation under the guidance of a treating physician
5. Must have met ALL the following criteria prior to first attempt to discontinue their TKI: * Stable molecular response (MR4; =< 0.01% international reporting scale [IS]) for >= 2 years (allowance for a 2-week variance) , as documented on at least four tests, performed at least 3 months apart (e.g. If a patient has had > 4 polymerase chain reaction [PCR] tests performed during the two years leading up to their initial TKI discontinuation, any value between 0.01 and 0.05% IS is considered a stable result, however, at least 4 tests must be < 0.01% IS. If any results are >0.05% IS, tests must have been repeated within 1 month and be less than 0.01% IS and stable.) * Treatment with one of the following Food and Drug Administration (FDA) approved TKIs; imatinib, dasatinib, nilotinib or bosutinib, at any dose for a minimum of approximately 3 years (allowance of a 4-week variance) prior to discontinuing TKIs * Has been on any number of TKIs, but has not been resistant to any TKI (changes made for intolerance are allowed)
6. Must have relapsed (defined as loss of major molecular response [MMR]), real-time quantitative (RQ)-polymerase chain reaction (PCR) for BCR-ABL > 0.1% IS after first attempted discontinuation of TKI
7. After first failed TFR attempt, must have a minimum duration of 1 year on a TKI, and must plan to remain on this same TKI for a minimum of 12 months during the combination treatment phase
8. Current TKI must be the same as the TKI being taken prior to the initial TFR attempt (e.g. if patient is on imatinib prior to first TFR attempt, they should be on imatinib at time of enrollment on this study)
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-3
10. Must have a RQ-PCR for BCR-ABL =< 0.0032% IS (MR4.5) reported by the trial designated central lab at the time of study enrollment
11. Female patients must meet one of the following: * Postmenopausal for at least one year before the screening visit * Surgically sterile * If they are of childbearing potential, agree to practice two effective methods of contraception from the time of signing of the informed consent form through 90 days after the last dose of study drug * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable contraception methods.)
12. Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to one of the following: * Practice effective barrier contraception during the entire study treatment period and through 90 days after the last study drug dose * Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable * Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
13. TFR PHASE:
14. Stable molecular response (MR4.5; =< 0.0032% IS) documented on at least three tests, performed at least 3 months apart while on combination therapy
15. TFR phase screening PCR RQ-PCR for BCR-ABL =< 0.0032% IS (MR4.5)
16. ECOG 0-3
17. Completion of 12 cycles on the combination therapy phase