Ruxolitinib Phosphate and Azacytidine in Treating Patients With Myelofibrosis or Myelodysplastic Syndrome/Myeloproliferative Neoplasm

PRIMARY OBJECTIVES:

I. To determine the efficacy of the combination of RUX (ruxolitinib phosphate) with AZA
(azacytidine) in patients with myelofibrosis (MF) (primary myelofibrosis, post polycythemia
vera myelofibrosis, or post essential thrombocythemia myelofibrosis [PMF, post- PV MF, or
post - ET MF]) in achieving objective improvements in disease status.

II. To determine the efficacy of the combination of RUX + AZA in patients with
myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) including chronic
myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (breakpoint cluster region
[BCR]-c-abl oncogene 1, non-receptor tyrosine kinase [ABL1] negative: aCML), and
myelodysplastic syndromes/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), in
achieving objective improvements in disease status.

SECONDARY OBJECTIVES:

I. To determine the safety of the RUX + AZA combination in patients with MF and MDS/MPN.

TERTIARY OBJECTIVES:

I. To explore time to response (TTR) and duration of response (DOR). II. To explore the
effect of the combination on anemia and transfusion dependence in patients with MF and
MDS/MPN.

III. To explore the impact of baseline mutational profile on International Working Group
(IWG)-Myeloproliferative Neoplasms Research and Treatment (MRT) response and overall survival
in patients with MF and MDS/MPN.

IV. To explore the impact of baseline anemia on overall survival in patients with MF and
MDS/MPN.

OUTLINE: Patients are assigned to 1 of 2 treatment arms.

ARM I (MF): Patients with MF receive ruxolitinib phosphate orally (PO) twice daily (BID) on
days 1-28. Beginning course 4, patients also receive azacytidine subcutaneously (SC) or
intravenously (IV) for 5 days. Treatment repeats every 28 days for 15 courses in the absence
of disease progression or unacceptable toxicity.

ARM II (MDS/MPN): Patients with MDS/MPN receive ruxolitinib phosphate and azacytidine as in
Arm I.

After completion of study treatment, patients are followed up for 30 days and up to 5 years.

Inclusion Criteria:

- Patients with a diagnosis of primary myelofibrosis (PM), post polycythemia vera
myelofibrosis (PPV MF), or post essential thrombocythemia myelofibrosis (PET MF)
requiring therapy, including those previously treated and relapsed or refractory, or
if newly diagnosed, with intermediate or high risk according to International Working
Group (IWG-MRT) criteria

- Patients with a diagnosis of myelodysplastic syndrome/myeloproliferative neoplasm,
unclassifiable (MDS/MPN-U) that require therapy

- Understanding and voluntarily signing an Institutional Review Board (IRB)-approved
informed consent form

- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

- Direct bilirubin of =< 2 mg/dL

- Serum glutamate pyruvate transaminase (SGPT) =< 2.5 x upper limit of normal (ULN) or 5
x ULN if related to MF or MDS/MPN associated liver infiltration

- If total bilirubin is =< 2, fractionation is not required for eligibility
determination

- Creatinine =< 2.5 mg/dL

- Platelets >= 50 x 10^9/L

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

Exclusion Criteria:

- For the MF and MDS/MPN-U arms (arms 1 & 2), use of any other standard drug (except
hydroxyurea, anagrelide, growth factors, Revlimid, clofarabine, etc) or experimental
drug or therapy within 14 days of starting study therapy

- Patients previously treated with RUX or AZA (only applicable for the MF and MDS/MPN
arms)

- Any serious psychological condition or psychiatric illness that would prevent the
subject from signing the informed consent document, in the investigator opinion

- Pregnant or lactating females

- Subjects of childbearing potential who are unwilling to take appropriate precautions
(from screening through follow-up) to avoid becoming pregnant or fathering a child;
females of non-childbearing potential are defined as women who a) are 55 years of age
with history of amenorrhea for 1 year OR b) are surgically sterile for at least 3
months; for females of childbearing potential, or for males, pregnancy must be avoided
by taking appropriate precautions; these precautions and the methods of contraception
should be communicated to the subjects and their understanding confirmed

- Any condition which places the subject at unacceptable risk if he/she were to
participate in the study or confounds the ability to interpret data from the study

- Known positive for human immunodeficiency virus (HIV) or with known active infectious
hepatitis, type A, B or C

- Patients with active malignancy of other type than required for this study, are not
eligible with the exception of currently treated basal cell, squamous cell carcinoma
of the skin, or carcinoma "in situ" of the cervix or breast; patients with
malignancies with indolent behavior such as prostate cancer treated with radiation or
surgery can be enrolled in the study as long as they have a reasonable expectation to
have been cured with the treatment modality received