Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis

• ClinicalTrials.gov Identifier: NCT01732445
• Recruitment Status: Completed
• First Posted: November 22, 2012
• Results First Posted: October 18, 2017
• Last Update Posted: October 18, 2017
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Mayo Clinic

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Anemia; Primary Myelofibrosis; Secondary Myelofibrosis	Drug: ruxolitinib phosphate; Drug: danazol; Other: quality-of-life assessment; Other: questionnaire administration	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: A Phase 2 Pilot Trial of Ruxolitinib Combined With Danazol for Patients With Primary Myelofibrosis (MF), Post Essential Thrombocythemia-Myelofibrosis (Post ET) and Post Polycythemia Vera Myelofibrosis (PV MF) Suffering From Anemia
• Actual Study Start Date: April 2013
• Actual Primary Completion Date: July 14, 2016
• Actual Study Completion Date: August 10, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Supportive care (ruxolitinib phosphate and 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.	Drug: ruxolitinib phosphate; Given PO; Other Names: INCB18424; Jakafi; oral JAK inhibitor INCB18424; oral Janus-associated kinase inhibitor INCB18424; Drug: danazol; Given PO; Other Names: Chronogyn; DAN; Danocrine; Other: quality-of-life assessment; Ancillary studies; Other Name: quality of life assessment; Other: questionnaire administration; Ancillary studies

Outcome Measures

Primary Outcome Measures :

1. Best Overall Response Rate as Determined by International Working Group Criteria [ Time Frame: 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 :

1. Survival Time [ Time Frame: 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.
2. Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4) [ Time Frame: 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.

Other Outcome Measures:

1. Patient-reported Symptoms Assessed Using the MPN-SAF, as Measured by the Percentage of Patients With a Decrease in MPN-SAF TSS Greater Than 50% From Baseline [ Time Frame: Baseline to up to 2 years ]
   Patient-reported symptoms will be described at each time point using the mean, confidence interval, median, and range. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) will be analyzed using published scoring algorithms. MPN-SAF includes 27 items scored on a scale of 0 to 10. The MPN-SAF Total Symptom Score (TSS) (range 0-100) was computed according to the published scoring algorithm. Higher scores represent worse symptom burden. The percentage of patients with a decrease in MPN-SAF TSS greater than 50% from baseline and 95% confidence interval are reported below.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic in Arizona

Scottsdale, Arizona, United States, 85259

United States, New York

Tisch Cancer Center

New York, New York, United States, 10029

Sponsors and Collaborators

Mayo Clinic

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ruben Mesa; Mayo Clinic

More Information

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01732445
• Other Study ID Numbers: MC1283; NCI-2012-02201 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); MC1283 ( Other Identifier: Mayo Clinic in Arizona ); P30CA015083 ( U.S. NIH Grant/Contract )
• First Posted: November 22, 2012
• Results First Posted: October 18, 2017
• Last Update Posted: October 18, 2017
• Last Verified: May 2017

Additional relevant MeSH terms:

Anemia; Primary Myelofibrosis; Hematologic Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Danazol; Janus Kinase Inhibitors; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action