Azacitidine and Erythropoietin Versus Azacitidine Alone for Patients With Low-Risk Myelodysplastic Syndromes

Phase II Randomized Trial With A Modified Dose & Schedule of Subcutaneously Administered Azacitidine & Erythropoietin v Azacitidine Alone in Patients With Low-Risk Myelodysplastic Syndromes (Less Than 11% Marrow & Peripheral Blood Blasts)

This trial is designed to explore a modified dose and schedule of azacitidine in order to more effectively address the needs of patients with low-risk myelodysplastic syndromes (MDS), i.e., to alter the natural history of the disease without excessive toxicity or burden. The administration of erythropoietin is designed to influence the differentiation of primitive hematopoietic cells in which azacitidine has reversed the abnormal phenotype to red blood cells for patients in whom inadequate production of red blood cells is the major clinical issue.

OUTLINE: This is an open label, multi-center, randomized study.

Eligible patients will be randomized to one of two treatment arms:

Arm A (Azacitidine + Erythropoietin)

• Azacitidine Treatment 50 mg/m2 subcutaneously every other day (three times a week) for two consecutive weeks every four weeks. A cycle of therapy is defined as two consecutive weeks of subcutaneous azacitidine administered every other day three times a week (e.g. Monday - Wednesday - Friday) and the time to resolution of any treatment associated toxicity.
• Erythropoietin Treatment Patients who are randomized to Arm A will receive a dose of 60,000IU as a single subcutaneous injection weekly without interruption while enrolled on protocol therapy. The dose should be administered to coincide with the first day of each cycle.
• Protocol therapy may be administered for up to six cycles of therapy.

Arm B (Azacitidine Alone)

• Azacitidine Treatment 50 mg/m2 subcutaneously every other day (three times a week) for two consecutive weeks every four weeks. A cycle of therapy is defined as two consecutive weeks of subcutaneous azacitidine administered every other day three times a week (e.g. Monday - Wednesday - Friday) and the time to resolution of any treatment associated toxicity.
• Protocol therapy may be administered for up to six cycles of therapy.

ECOG performance status 0 to 2

Hematopoietic:

To be eligible for randomization, subjects must have documentation of at least 1 of the following:

• A transfusion dependent anemia (defined by a history of two or more episodes of transfusion within a period of 8 weeks).
• An untransfused hemoglobin < 10 gm/dl measured on at least two occasions more than 7 days apart in the month prior to randomization.

Patients must also meet 1 of the following criteria:

• Has not received prior erythropoietin and has a serum erythropoietin level > 200 IU/L within 14 days of randomization.
• Has received prior erythropoietin without clinical benefit in the judgment of the treating physician.
• Adequate iron status defined as serum ferritin > 20 ng/ml and transferrin saturation of > 30% within 90 days prior to randomization.
• Symptoms attributed to the anemia with hemoglobin < 11 g/dL.
• Folate and Vitamin B12 levels within normal limits within 90 days prior to randomization.

Hepatic:

• SGOT (ALT) level < 2 x ULN within 14 days prior to randomization.
• SGPT (AST) level < 2 x ULN within 14 days prior to randomization.
• Serum total bilirubin level < 2 x ULN within 14 days prior to randomization.

Renal:

• Serum creatine < 1.5 x the upper limit of normal (ULN) within 14 days prior to randomization.

Cardiovascular:

• No uncontrolled hypertension (defined as a systolic pressure > 160 mmHg and/or a diastolic pressure > 110 mmHg).
• No history of (within 12 months) deep venous thrombosis (DVT), pulmonary embolism (PE), or other venous thrombosis. Prior superficial thrombophlebitis is not an exclusion criterion.
• No history of (within 6 months) cerebrovascular accident ([CVA] includes ischemic, embolic, and hemorrhagic), transient ischemic attack (TIA), myocardial ischemia (includes Unstable Angina, Q wave Myocardial Infarction [QwMI], and non-Q wave Myocardial Infarction [NQMI]), or other arterial thrombosis.

Inclusion Criteria:

• A bone marrow (BM) aspirate and biopsy that demonstrates MDS with less than 11% blasts.
• Conventional metaphase cytogenetics done within 90 days prior to registration for screening.
• Central pathology review, correlative submission and confirmation of diagnosis is required prior to initiation of therapy (see Study Procedure Manual for details of submission). The FAB and WHO classification of MDS and the IPSS score will be determined at time of central pathology review.
• Correlative marrow aspirate obtained.

To be eligible for randomization, subjects must have documentation of at least 1 of the following:

• A transfusion dependent anemia (defined by a history of two or more episodes of transfusion within a period of 8 weeks).
• An untransfused hemoglobin < 10 gm/dl measured on at least two occasions more than 7 days apart in the month prior to randomization.

Patients must also meet 1 of the following criteria:

• Has not received prior erythropoietin and has a serum erythropoietin level > 200 IU/L within 14 days of randomization.
• Has received prior erythropoietin without clinical benefit in the judgment of the treating physician.
• Adequate iron status defined as serum ferritin > 20 ng/ml and transferrin saturation of > 30% within 90 days prior to randomization.
• Symptoms attributed to the anemia with hemoglobin < 11 g/dL.
• Folate and Vitamin B12 levels within normal limits within 90 days prior to randomization.
• Life expectancy > 6 months as judged by the treating investigator.

Exclusion Criteria:

• No known history of intolerance to erythropoietic agents.
• No prior intensive cytotoxic chemotherapy for a myeloid malignancy including MDS.
• Patients with a history of a non-myeloid malignancy with secondary MDS are eligible for study enrollment provided, in the opinion of the treating investigator and the study chair, the anticipated behavior of the non-myeloid malignancy will not interfere with study participation and evaluation of outcome.
• No known or suspected hypersensitivity to azacitidine or mannitol.
• No hepatic tumors.
• No uncontrolled hypertension (defined as a systolic pressure > 160 mmHg and/or a diastolic pressure > 110 mmHg).
• No known hypersensitivity to mammalian cell-derived products or human albumin.
• No history of (within 12 months) deep venous thrombosis (DVT), pulmonary embolism (PE), or other venous thrombosis. Prior superficial thrombophlebitis is not an exclusion criterion.
• No history of (within 6 months) cerebrovascular accident ([CVA] includes ischemic, embolic and hemorrhagic), transient ischemic attack (TIA), myocardial ischemia (includes Unstable Angina, Q wave Myocardial Infarction [QwMI] and non-Q wave Myocardial Infarction [NQMI], or other arterial thrombosis.
• Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) while on treatment and for a 4-week period thereafter.
• Females with childbearing potential must have a negative pregnancy test within 7 days prior to being randomized. Patients are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.