Ruxolitinib Phosphate and Dasatinib or Nilotinib in Treating Patients With Chronic Myeloid Leukemia

PRIMARY OBJECTIVES:

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)
(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.

TERTIARY OBJECTIVES:

I. To describe patterns of MR4.5 and molecular rate 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 dasatinib orally (PO) daily or nilotinib PO twice daily (BID) on days
1-90. Treatment repeats every 90 days for up to 4 courses in the absence of disease
progression or unacceptable toxicity.

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

After completion of study treatment, patients are followed up for up to 5 years.

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 baseline (at least 0.0032% IS)

- Patients must be receiving treatment with dasatinib (within the allowable dose range
of 70-100 mg daily) or nilotinib (within the allowable dose range of 200-400 mg BID)
as first or second line therapy for a minimum of 6 months prior to registration

- Patients must not have received > 2 TKIs for treatment of CML (hydroxyurea prior to
initiation of TKI is allowed)

- Patients must have been on their current TKI for a minimum of 6 months prior to
randomization

- If dasatinib or nilotinib is second-line therapy, the reason for stopping
first-line treatment must not have been resistance to prior treatment or failure
to achieve an adequate response on their first-line TKI (e.g., the patient could
have stopped due to intolerance to prior TKI)

- Patients must have been receiving TKI treatment for CML for at least one year and no
more than 10 years prior to randomization

- Patients must be expected to remain on the same TKI for the next 12 months

- Patients must not be receiving any other investigational agents

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

- 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

- 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; 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

- 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 baseline (at least 0.0032% IS)

- Patients must be offered participation in submission of specimens for central BCR-ABL
quantification; 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 offered participation in specimen banking for future research; with
patient?s consent, specimens must be submitted

- 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