A Randomized Phase II/III Study of Azacitidine in Combination With Lenalidomide (NSC-703813) vs. Azacitidine Alone vs. Azacitidine in Combination With Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)
Overview
- Phase
- Phase 2
- Intervention
- Azacitidine
- Conditions
- Chronic Myelomonocytic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 282
- Locations
- 571
- Primary Endpoint
- Response Rate (Phase II)
- Status
- Active, not recruiting
- Last Updated
- last month
Overview
Brief Summary
This randomized phase II/III trial studies how well azacitidine works with or without lenalidomide or vorinostat in treating patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, stopping them from dividing, or by stopping them from spreading. Lenalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether azacitidine is more effective with or without lenalidomide or vorinostat in treating myelodysplastic syndromes or chronic myelomonocytic leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. To select based on response rate (complete remission, partial remission, or hematologic improvement) either the combination of lenalidomide and azacitidine or the combination of vorinostat and azacitidine for further testing against single-agent azacitidine among patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase II) II. To compare overall survival between the combination arm selected in the Phase II portion of the trial to single-agent azacitidine among patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). (Phase III) SECONDARY OBJECTIVES: I. To estimate relapse-free survival, overall survival and cytogenetic response rate of patients treated on each regimen. II. To estimate the frequency and severity of toxicities of the three regimens in this patient population. III. To investigate in a preliminary manner the frequency of subgroups from prestudy cytogenetic studies and correlate these subgroups with clinical outcomes in this patient population. IV. To collect specimens for banking for use in future research studies. TERTIARY OBJECTIVES: I. To evaluate the prevalence of a pre-specified list of molecular lesions (48 total lesions). II. To assess associations of these lesions with outcomes (response, event-free survival, relapse-free survival, and overall survival). III. To develop a deoxyribonucleic acid (DNA) methylation biomarker predictive of response to DMTi treatment in MDS. IV. To harness gene expression profiles as clinical biomarkers of primary resistance to DMTi in MDS. OUTLINE: Patients are randomized to 1 of 3 treatment arms. In Phase III, patients are randomized to 1 of 2 treatment arms (the combination arm selected in Phase II or the single-agent azacitidine arm). ARM I: Patients receive azacitidine subcutaneously (SC) or intravenously (IV) on days 1-7 or days 1-5 and 8-9, and lenalidomide orally (PO) once daily (QD) on days 1-21. ARM II: Patients receive azacitidine as in Arm I. ARM III: Patients receive azacitidine as in Arm I and vorinostat PO twice daily (BID) on days 3-9. In all arms, treatment repeats every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for up to 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) based on one of the following:
- •French-American-British (FAB) classifications:
- •Refractory anemia with excess blasts (RAEB - defined as having 5-20% myeloblasts in the bone marrow)
- •Chronic myelomonocytic leukemia (CMML) with 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood
- •World Health Organization (WHO) classifications:
- •Refractory anemia with excess blasts-1 (RAEB-1 - defined as having 5-9% myeloblasts in the bone marrow)
- •Refractory anemia with excess blasts-2 (RAEB-2 - defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
- •Chronic myelomonocytic leukemia-1 (CMML-1 - defined as having \< 10% myeloblasts in the bone marrow and/or \< 5% blasts in the blood)
- •Chronic myelomonocytic leukemia-2 (CMML-2 - defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood) OR
- •International prognostic score (IPSS) of intermediate 2 (1.5-2.0 points) or high (\>= 2.5 points); a score of intermediate 1 (0.5-1.0 points) is only allowable in the setting of \>= 5% myeloblasts
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I (azacitidine and lenalidomide)
Patients receive azacitidine SC or IV on days 1-7 or days 1-5 and 8-9, and lenalidomide PO QD on days 1-21. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm I (azacitidine and lenalidomide)
Patients receive azacitidine SC or IV on days 1-7 or days 1-5 and 8-9, and lenalidomide PO QD on days 1-21. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm I (azacitidine and lenalidomide)
Patients receive azacitidine SC or IV on days 1-7 or days 1-5 and 8-9, and lenalidomide PO QD on days 1-21. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Lenalidomide
Arm II (azacitidine)
Patients receive azacitidine as in Arm I. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm II (azacitidine)
Patients receive azacitidine as in Arm I. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm III (azacitidine and vorinostat)
Patients receive azacitidine as in Arm I and vorinostat PO BID on days 3-9. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm III (azacitidine and vorinostat)
Patients receive azacitidine as in Arm I and vorinostat PO BID on days 3-9. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Arm III (azacitidine and vorinostat)
Patients receive azacitidine as in Arm I and vorinostat PO BID on days 3-9. Courses repeat every 28 days for up to 5 years in the absence of disease progression or unacceptable toxicity.
Intervention: Vorinostat
Outcomes
Primary Outcomes
Response Rate (Phase II)
Time Frame: Up to 5 years
A response is any of complete hematological remission, partial remission, or hematologic improvement.
Overall Survival (Phase III)
Time Frame: Up to 5 years
OS is calculated for all patients from the date of initial registration to date of death due to any cause. The follow-up for patients last known to be alive is censored at the date of last contact. Stratified Cox regression models will be used to compare OS of the combination arm selected in the Phase II portion of the trial to OS of the single-agent azacitidine arm.
Secondary Outcomes
- Overall Survival(Up to 5 years)
- Relapse-free Survival(Up to 5 years)
- Pre-study Cytogenetic Abnormalities(Up to 5 years)
- Toxicity Rate(Up to 5 years)