Azacitidine in Treating Patients With Myelofibrosis

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00381693
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 10
• Locations: 2
• Duration (Months): 32
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase II trial is studying how well azacitidine works in treating patients with myelofibrosis.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloproliferative Disorders; Secondary Myelofibrosis	Drug: azacitidine	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of azacitidine in patients with myelofibrosis (MF) with myeloid metaplasia.

• Evaluate the safety of azacitidine in these patients. Secondary

• Evaluate pertinent biologic characteristics of MF before and during therapy with azacitidine.

• Assess the effects of study treatment on constitutional symptoms in these patients.

• Estimate time to event distributions for overall survival and progression. OUTLINE: Patients receive azacitidine subcutaneously once daily on days 1-5. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 3 years.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Azacitidine in Myelofibrosis
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Apr 1, 2009

Outcome Measures

Primary Outcome Measures

1. Patients With Confirmed Response (Complete Remission or Partial Remission on 2 Consecutive Evaluation at Least 4 Weeks Apart) During the First 4 Months of Treatment [4 months]

   Response Definitions: Completion Remission (CR):complete resolution of disease-related symptoms, ultrasound-documented resolution of hepastosplenomegaly, normalization of the peripheral blood count, white cell differential, and smear, normalization of bone marrow histology including disappearance of fibrosis and osteosclerosis. Residual cytogenetic abnormalities are allowed. Partial Remission (PR): a major response in any baseline applicable criteria (except constitutional symptoms) without progression in any other category.

Secondary Outcome Measures

1. Overall Survival (OS) [From date of registration until death or 3 years after registration if patient is still alive]

   OS was defined as the time from registration to death due to any cause or time from registration to 3 years after registration if patient is still alive.

2. Time to Progression [up to 3 years]

   Time to progression was defined as the time from registration to progression of disease. Those who die without documentation of disease progression will be considered to have had disease progression at the time of their death unless documented evidence clearly indicates no progression has occured.

3. Number of Participants With Treatment Related Adverse Events [Every 4 weeks during treatment]

   Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE. Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed myelofibrosis with myeloid metaplasia (MMM), including any of the following subtypes:

• Agnogenic myeloid metaplasia

• Post-polycythemic myeloid metaplasia

• Post-thrombocythemic myeloid metaplasia

• Evaluable and symptomatic disease, defined as 1 of the following:

• Anemia (hemoglobin < 10 g/dL or erythrocyte transfusion-dependent, requiring 1 transfusion ≤ 8 weeks)

• Treatment required* for symptomatic palpable splenomegaly (palpable hepatomegaly is acceptable if previously splenectomized) NOTE: *Subjective but painful enough to mandate intervention

• Absence of t(9;22) by fluorescent in situ hybridization (FISH) or standard cytogenetics (by peripheral blood or marrow)

• Previous demonstration of a lack of this translocation (at any point) is sufficient

• No advanced malignant hepatic tumors

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Absolute neutrophil count ≥ 1,000/mm³

• Platelet count ≥ 50,000/mm³

• Creatinine ≤ 2.0 mg/dL

• Total bilirubin ≤ 2.0 mg/dL OR direct bilirubin ≤ 2.0 mg/dL if total bilirubin elevated (unless attributed to underlying disease)

• AST and ALT ≤ 2 times upper limit of normal (unless clinically attributed to hepatic extramedullary hematopoiesis)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No baseline peripheral or autonomic neuropathy ≥ grade 2

• No condition, including the presence of laboratory abnormalities, that would preclude study compliance

• No hypersensitivity to mannitol or azacitidine

• Not incarcerated in a municipality (i.e., county, state, or federal prison)

PRIOR CONCURRENT THERAPY:

• At least 14 days since prior chemotherapy, including interferon alfa, anagrelide, or other myelosuppressive agents

• At least 14 days since prior systemic corticosteroids

• At least 14 days since prior investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Ruben A. Mesa, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00381693
• Other Study ID Numbers: CDR0000503972; P30CA015083; MC058D; 05-004297
• First Posted: Sep 28, 2006
• Last Update Posted: Apr 21, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: primary myelofibrosis; polycythemia vera; essential thrombocythemia; secondary myelofibrosis
• Additional relevant MeSH terms: Primary Myelofibrosis; Myeloproliferative Disorders; Azacitidine

Study Results

Participant Flow

Recruitment Details	Ten patients were recruited from August 2006 to December 2007 at Mayo Clinic. This trial was permanently closed in December 2007 due to lack of accrual and it demonstrated too little clinical benefit.

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
Period Title: Overall Study
STARTED	10
COMPLETED	2
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
Overall Participants	10
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	72
Sex: Female, Male (Count of Participants)
Female	2 20%
Male	8 80%
Region of Enrollment (participants) [Number]
United States	10 100%
Disease (participants) [Number]
Primary Myelofibrosis	8 80%
Post-polycythemia Vera Myelofibrosis	1 10%
Post-essential Thrombocythemia Myelofibrosis	1 10%
Lilie Score at Diagnosis (Myelofibrosis only) (participants) [Number]
0 (Low Risk)	2 20%
1 (Intermediate Risk)	5 50%
2 (High Risk)	3 30%
Red Cell Transfusion-dependent (participants) [Number]
Yes	7 70%
No	3 30%
Prior Thrombosis or Hemorrhage (participants) [Number]
Yes	0 0%
No	10 100%
Prior Therapy for Myelofibrosis (participants) [Number]
Yes	7 70%
No	3 30%

Outcome Measures

1. Primary Outcome

Title	Patients With Confirmed Response (Complete Remission or Partial Remission on 2 Consecutive Evaluation at Least 4 Weeks Apart) During the First 4 Months of Treatment
Description	Response Definitions: Completion Remission (CR):complete resolution of disease-related symptoms, ultrasound-documented resolution of hepastosplenomegaly, normalization of the peripheral blood count, white cell differential, and smear, normalization of bone marrow histology including disappearance of fibrosis and osteosclerosis. Residual cytogenetic abnormalities are allowed. Partial Remission (PR): a major response in any baseline applicable criteria (except constitutional symptoms) without progression in any other category.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
Measure Participants	10
Number [participants]	0 0%

2. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time from registration to death due to any cause or time from registration to 3 years after registration if patient is still alive.
Time Frame	From date of registration until death or 3 years after registration if patient is still alive

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
Measure Participants	10
Median (95% Confidence Interval) [months]	16.9

3. Secondary Outcome

Title	Time to Progression
Description	Time to progression was defined as the time from registration to progression of disease. Those who die without documentation of disease progression will be considered to have had disease progression at the time of their death unless documented evidence clearly indicates no progression has occured.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

Only 2 out of 10 patients had disease progression. One patient progressed at 0.5 months after registration and one patient progressed at 2.8 months after registration. Thus, median of time to progression and upper limit of 95% confidence interval are not attainable.

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
Measure Participants	0

4. Secondary Outcome

Title	Number of Participants With Treatment Related Adverse Events
Description	Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE. Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE
Time Frame	Every 4 weeks during treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
Measure Participants	10
Grade 1-2 Hematologic	1 10%
Grade 3-4 Hematologic	8 80%
Grade 1-2 Non-hematologic	23 230%
Grade 3-4 Non-hematologic	0 0%

Adverse Events

Arm/Group Title	Azacitidine
Arm/Group Description	Azacitidine 75 mg/m^2 subcutaneously
All Cause Mortality
	Azacitidine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Azacitidine
	Affected / at Risk (%)	# Events
Total	4/10 (40%)
Blood and lymphatic system disorders
Anemia	1/10 (10%)	1
Investigations
Neutrophil count decreased	1/10 (10%)	2
Platelet count decreased	2/10 (20%)	3
Vascular disorders
Hematoma	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Azacitidine
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Anemia	5/10 (50%)	8
Gastrointestinal disorders
Diarrhea	2/10 (20%)	4
Nausea	6/10 (60%)	8
Vomiting	5/10 (50%)	6
General disorders
Edema Limbs	1/10 (10%)	1
Fatigue	9/10 (90%)	24
Investigations
Leukopenia	2/10 (20%)	4
Neutrophil count decreased	5/10 (50%)	18
Platelet count decreased	7/10 (70%)	24
Nervous system disorders
Peripheral sensory neuropathy	2/10 (20%)	2
Respiratory, thoracic and mediastinal disorders
Cough	1/10 (10%)	1
Dyspnea	1/10 (10%)	1
Pneumonitis	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Pruritus	6/10 (60%)	10

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.