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Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis

Primary Purpose

Anemia, Primary Myelofibrosis, Secondary Myelofibrosis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ruxolitinib phosphate
danazol
quality-of-life assessment
questionnaire administration
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Anemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Mayo Clinic in Arizona
  • Tisch Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Supportive care (ruxolitinib phosphate and danazol)

Arm Description

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.

Outcomes

Primary Outcome Measures

Best Overall Response Rate as Determined by International Working Group Criteria
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

Survival Time
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)
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.

Full Information

First Posted
November 19, 2012
Last Updated
September 15, 2017
Sponsor
Mayo Clinic
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01732445
Brief Title
Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
April 2013 (Actual)
Primary Completion Date
July 14, 2016 (Actual)
Study Completion Date
August 10, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mayo Clinic
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anemia, Primary Myelofibrosis, Secondary Myelofibrosis

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Supportive care (ruxolitinib phosphate and danazol)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ruxolitinib phosphate
Other Intervention Name(s)
INCB18424, Jakafi, oral JAK inhibitor INCB18424, oral Janus-associated kinase inhibitor INCB18424
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
danazol
Other Intervention Name(s)
Chronogyn, DAN, Danocrine
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
quality-of-life assessment
Other Intervention Name(s)
quality of life assessment
Intervention Description
Ancillary studies
Intervention Type
Other
Intervention Name(s)
questionnaire administration
Intervention Description
Ancillary studies
Primary Outcome Measure Information:
Title
Best Overall Response Rate as Determined by International Working Group Criteria
Description
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.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Survival Time
Description
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.
Time Frame
From registration to death due to any cause, assessed up to 2 years
Title
Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4)
Description
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.
Time Frame
Up to 2 years
Other Pre-specified Outcome Measures:
Title
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
Description
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.
Time Frame
Baseline to up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ruben Mesa
Organizational Affiliation
Mayo Clinic
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mayo Clinic in Arizona
City
Scottsdale
State/Province
Arizona
ZIP/Postal Code
85259
Country
United States
Facility Name
Tisch Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis

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