Ruxolitinib in Treating Participants With Chronic Myeloid Leukemia With Minimal Residual Disease While on Therapy With Tyrosine Kinase Inhibitors

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the
combination of ruxolitinib and a tyrosine kinase inhibitor (TKI) in patients with chronic
myeloid leukemia (CML). (Phase I) 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). (Phase II)

SECONDARY OBJECTIVES:

I. To determine the clinical activity of the combination of ruxolitinib and a TKI in patients
with CML. (Phase I) II. To determine the safety of the combination of ruxolitinib and a TKI
in patients with CML in CCyR with minimal residual disease. (Phase II) III. Determine the
overall survival, event-free survival and survival free from transformation to accelerated
and blast phase. (Phase I and II) IV. Determine the effect of therapy on bone marrow
progenitors in clonogenic assays. (Phase I and II) V. Investigate the effect of therapy on
molecular responses as assessed by genomic deoxyribonucleic acid (DNA) polymerase chain
reaction (PCR). (Phase I and II) VI. Determine the effect of therapy on TKI-resistant
quiescent leukemic Philadelphia chromosome (Ph)+ stem cells (CFSEmax/CD34+) by flow
cytometric evaluation of activated Crkl and Jak2. (Phase I and II) VII. Assess the effect of
therapy on self-renewal and/or survival of leukemic stem cells by fluorescence in situ
hybridization (FISH) analysis on colonies. (Phase I and II) VIII. Assess ruxolitinib
pharmacokinetics (PK) in preselected time intervals during co-administration of this agent
with TKIs. (Phase I and II)

OUTLINE: This is a phase I, dose-escalation study of ruxolitinib followed by a phase II
study.

Participants receive commercially available TKIs (imatinib mesylate, nilotinib, or dasatinib)
as they had been receiving during the last 6 months and ruxolitinib orally (PO) twice daily
(BID). Courses repeat every 28 days for 2 years in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, participants are followed up for 30 days.

Inclusion Criteria:

- Patients with Philadelphia chromosome (Ph)-positive or BCR/ABL-positive CML (as
determined by cytogenetics, FISH, or PCR).

- 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.

- Patients must have received the current TKI for at least 18 months and not have
increased their dose in the last 6 months.

- 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 complete
hematologic response (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.

- 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 MD Anderson Cancer Center [MDACC] molecular diagnostic laboratory), and
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 and lacks a sustained complete
molecular response (CMR, defined as transcript levels still detectable in the MDACC
molecular diagnostic laboratory).

- 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.

- 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.

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2.

- Bilirubin < 2 x upper limit of normal (ULN) (unless associated with Gilbert's
syndrome).

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN.

- Absolute neutrophil count (ANC) >= 1 x 10(9)/L.

- Platelets >= 100 x 10(9)/L.

- Serum creatinine < 1.5 mg/dL or creatinine clearance greater or equal than 60 cc/min
as defined by the Cockcroft-Gault equation.

- 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.

Exclusion Criteria:

- 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.

- Patients receiving any other investigational agents.

- Patients who are pregnant or breast-feeding.

- Patients with clinically significant heart disease (New York Heart Association [NYHA]
class III or IV).

- Patients with corrected QT (QTc) > 480 msec.

- Patients taking a potent CYP3A4 inhibitor that cannot be changed to an alternate drug.

- Known or suspected hypersensitivity to ruxolitinib.

- Patients with advanced malignant hepatic tumors.

- Patients with known active hepatitis B or C, or human immunodeficiency virus (HIV)
infection.

- Patients with other medical conditions or concomitant medications that in the opinion
of the principal investigator may interfere with the therapeutic treatment.