Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis

Phase 2

Completed

Conditions: Anemia
Primary Myelofibrosis
Secondary Myelofibrosis

Interventions: Drug: ruxolitinib phosphate
Drug: danazol
Other: quality-of-life assessment
Other: questionnaire administration

Registration Number: NCT01732445

Lead Sponsor: Mayo Clinic

Brief Summary: This phase II pilot trial studies how well ruxolitinib phosphate and danazol work in treating anemia in patients with myelofibrosis. Ruxolitinib phosphate and danazol may cause the body to make more red blood cells. They are used to treat anemia in patients with myelofibrosis.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Supportive care (ruxolitinib phosphate and danazol)	ruxolitinib phosphate	Patients receive ruxolitinib phosphate PO BID and danazol PO 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.
Supportive care (ruxolitinib phosphate and danazol)	quality-of-life assessment	Patients receive ruxolitinib phosphate PO BID and danazol PO 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.
Supportive care (ruxolitinib phosphate and danazol)	danazol	Patients receive ruxolitinib phosphate PO BID and danazol PO 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.
Supportive care (ruxolitinib phosphate and danazol)	questionnaire administration	Patients receive ruxolitinib phosphate PO BID and danazol PO 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.

Primary Outcome Measures

Name	Time	Method
Best Overall Response Rate as Determined by International Working Group Criteria	Up to 2 years	Best overall response rate as determined by International Working Group criteria: An evaluable patient will be classified as a responder for the primary endpoint if the patient's best overall response is CR, PR or CI (Clinical Improvement) as determined by International Working Group Criteria over all cycles of study treatment. The percentage of successes will be estimated by the number of successes (defined as complete response, partial response, or clinical improvement) divided by the total number of evaluable patients times 100. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Name	Time	Method
Survival Time	From registration to death due to any cause, assessed up to 2 years	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. The median and 95% confidence interval are reported below.
Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)	Up to 2 years	The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns within patient groups. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing. The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.