Ruxolitinib Phosphate and Danazol in Treating Anemia in Patients With Myelofibrosis

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01732445
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 14
• Locations: 2
• Arm: 1
• Actual Duration (Months): 52.3
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

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:

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

SECONDARY OBJECTIVES:

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

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

TERTIARY OBJECTIVES:

1. 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
• 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: Apr 1, 2013
• Actual Primary Completion Date: Jul 14, 2016
• Actual Study Completion Date: Aug 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 Names: 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 [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 [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) [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 [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

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01732445
• Other Study ID Numbers: MC1283; NCI-2012-02201; MC1283; P30CA015083
• First Posted: Nov 22, 2012
• Last Update Posted: Oct 18, 2017
• Last Verified: May 1, 2017

• Additional relevant MeSH terms: Anemia; Primary Myelofibrosis; Danazol; Janus Kinase Inhibitors

Study Results

Participant Flow

Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
Period Title: Overall Study
STARTED	14
COMPLETED	14
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	70.5
Sex: Female, Male (Count of Participants)
Female	5 35.7%
Male	9 64.3%
Region of Enrollment (Count of Participants)
United States	14 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
Measure Participants	14
Number (95% Confidence Interval) [percentage of patients with CR, PR or CI]	28.6

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
Measure Participants	14
Median (95% Confidence Interval) [months]	19.2

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
Measure Participants	14
Platelet count decreased	7.1
Anemia	64.3
White blood cell decreased	7.1
Neutrophil count decreased	14.3
Hypertension	7.1
Premature menopause	7.1

4. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
Measure Participants	14
Number (95% Confidence Interval) [percentage of patients]	28.6

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT).
Arm/Group Title	Supportive Care (Ruxolitinib Phosphate and Danazol)
Arm/Group Description	Patients receive ruxolitinib phosphate PO 10 mg BID and danazol PO 200 mg 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.
All Cause Mortality
	Supportive Care (Ruxolitinib Phosphate and Danazol)
	Affected / at Risk (%)	# Events
Total	2/14 (14.3%)
Serious Adverse Events
	Supportive Care (Ruxolitinib Phosphate and Danazol)
	Affected / at Risk (%)	# Events
Total	7/14 (50%)
Blood and lymphatic system disorders
Anemia	1/14 (7.1%)	1
Cardiac disorders
Myocardial infarction	1/14 (7.1%)	1
General disorders
General disorders and administration site conditions - Other, specify	1/14 (7.1%)	1
Sudden death NOS	1/14 (7.1%)	1
Infections and infestations
Lung infection	1/14 (7.1%)	1
Investigations
Platelet count decreased	1/14 (7.1%)	1
Metabolism and nutrition disorders
Hyperkalemia	2/14 (14.3%)	2
Hyponatremia	2/14 (14.3%)	2
Nervous system disorders
Intracranial hemorrhage	1/14 (7.1%)	1
Transient ischemic attacks	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	Supportive Care (Ruxolitinib Phosphate and Danazol)
	Affected / at Risk (%)	# Events
Total	14/14 (100%)
Blood and lymphatic system disorders
Anemia	9/14 (64.3%)	24
Gastrointestinal disorders
Diarrhea	3/14 (21.4%)	6
Nausea	3/14 (21.4%)	6
General disorders
Edema limbs	2/14 (14.3%)	2
Infections and infestations
Upper respiratory infection	1/14 (7.1%)	1
Urinary tract infection	1/14 (7.1%)	1
Investigations
Alanine aminotransferase increased	2/14 (14.3%)	2
Neutrophil count decreased	4/14 (28.6%)	5
Platelet count decreased	12/14 (85.7%)	29
White blood cell decreased	5/14 (35.7%)	9
Metabolism and nutrition disorders
Anorexia	1/14 (7.1%)	1
Hyperkalemia	1/14 (7.1%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	2/14 (14.3%)	2
Reproductive system and breast disorders
Irregular menstruation	1/14 (7.1%)	1
Premature menopause	1/14 (7.1%)	1
Skin and subcutaneous tissue disorders
Periorbital edema	1/14 (7.1%)	1
Photosensitivity	1/14 (7.1%)	1
Vascular disorders
Hypertension	1/14 (7.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.