Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis

PRIMARY OBJECTIVES:

I. To evaluate the efficacy (best overall response) of ruxolitinib (ruxolitinib phosphate)
and danazol in patients with myelofibrosis suffering from anemia.

SECONDARY OBJECTIVES:

I. To evaluate the overall survival of patients with myelofibrosis suffering from anemia
initiating ruxolitinib and danazol.

II. To evaluate the adverse event profile of ruxolitinib and danazol in patients with
myelofibrosis suffering from anemia.

TERTIARY OBJECTIVES:

I. To evaluate quality of life (QOL) and patient-reported symptoms using the
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and European Organization for
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) with
ruxolitinib and danazol for patients with myelofibrosis suffering from anemia.

OUTLINE:

Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) and danazol PO thrice
daily (TID) on days 1-56. Treatment repeats every 56 days for 6 courses in the absence of
disease progression or unacceptable toxicity. At the treating physician's discretion,
patients may continue treatment past 6 courses if they are without disease progression.

After completion of study treatment, patients are followed up every 6 months for 2 years.

Inclusion Criteria:

- Histological confirmation of primary myelofibrosis (MF), post polycythemia vera (PV)
or post essential thrombocythemia (ET) myelofibrosis (intermediate 1, intermediate II
or high risk) requiring medical therapy

- Anemia is required for trial entry (defined as hemoglobin < 10g/dL or transfusion
dependent [having needed a transfusion anytime in the past 6 months])

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 at study
entry

- Absolute neutrophil count (ANC) >= 1000/uL

- Platelet count >= 50,000/uL

- Serum creatinine =< 1.5 x the upper limit of normal (ULN)

- Total bilirubin =< 1.5 x ULN; if total bilirubin is > 1.5 x ULN, a direct bilirubin
should be performed and must be < 1.5mg/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN; higher
values (i.e., =< 5 x ULN) are allowed if clinically compatible with hepatic
extramedullary hematopoiesis

- Life expectancy of >= 6 months

- Patient able to provide voluntary written informed consent to participate

- Willing to comply with scheduled visits, treatment plans, laboratory assessments, and
other study-related procedures

- Negative pregnancy test done =< 7 days prior to registration, for women of
childbearing potential only

Exclusion Criteria:

- Any chemotherapy (e.g., hydroxyurea), immunomodulatory drug therapy (e.g.,
thalidomide, interferon-alpha), immunosuppressive therapy, corticosteroids > 10 mg/day
prednisone or equivalent, or growth factor treatment (e.g., erythropoietin), hormones
(e.g., androgens, danazol) =< 14 days prior to registration; note: patients who are on
ruxolitinib may continue on without a 14 day wash out at the treating physician's
discretion

- Major surgery =< 28 days or radiation =< 6 months prior to registration

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- Active acute infection requiring antibiotics

- Uncontrolled congestive heart failure (New York Heart Association classification 3 or
4), angina, myocardial infarction, cerebrovascular accident, coronary/peripheral
artery bypass, graft surgery, transient ischemic attack, or pulmonary embolism within
3 months prior to registration

- Participation in any study of an investigational agent (drug, biologic, device) =< 30
days, unless during non-treatment phase

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Known human immunodeficiency virus or acquired immunodeficiency syndrome-related
illness

- Clinically active hepatitis B or C

- Active malignancy other than MF, except adequately treated basal cell carcinoma and
squamous cell carcinoma of the skin, cervical carcinoma in situ or other malignancies
that have been stable and off therapy for 5 years

- Patient currently taking simvastatin, or lovastatin at a dose greater than 10 mg/day

- Men with prostate specific antigen (PSA) > 4 ng/ml or with uncontrolled benign
prostatic hypertrophy

- Patient received prior combination treatment with ruxolitinib and danazol together;
note: previous treatment with ruxolitinib and/or danazol as single agent therapy is
allowed

- Receiving any medications or substances that are strong or moderate inhibitors of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); use of the following
strong or moderate inhibitors are prohibited =< 7 days prior to registration

- Strong inhibitors of CYP3A4:

- Indinavir (Crixivan)

- Nelfinavir (Viracept)

- Atazanavir (Reyataz)

- Clarithromycin (Biaxin, Biaxin XL)

- Itraconazole (Sporanox)

- Ketoconazole (Nizoral)

- Nefazodone (Serzone)

- Saquinavir (Fortovase, Invirase)

- Telithromycin (Ketek)

- Moderate inhibitors of CYP3A4

- Erythromycin (Erythrocin, E.E.S., Ery-Tab, Eryc, EryPed, PCE)

- Fluconazole (Diflucan)

- Grapefruit juice

- Verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan)

- Verelan PM

- Diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT,
Dilacor XR, Diltia XT, Taztia XT, Tiazac)