A Randomized Phase II Trial to Simultaneously Evaluate Two Schedules of the Histone Deacetylase Inhibitor Entinostat in Combination with 5-Azacytidine (5AC, NSC 102816) in Elderly Patients with Acute Myeloid Leukemia (AML)
The primary objectives of the study are: 1. To estimate the major response rate (complete and partial responses by the International Working Group (IWG) response criteria) in patients with AML who are greater than 60 years old and unable to tolerate or decline cytotoxic chemotherapy or patients who have relapsed despite one prior regimen and are treated with (a) 5AC 50mg/m2 subcutaneously for 10 days on days 1 ï¿½ 10 of a 28 day cycle given in combination with entinostat 8 mg (flat dose) administered orally on days 3 and10 of each cycle or (b) the same regimen of 5AC with entinostat given on days 10 and 17. 2. To estimate the overall response rate (complete, partial, and hematologic improvement- major by IWG criteria) following treatment with two different dose schedules of 5-Azacytidine and entinostat in patients with AML greater than 60 years old who are unable to tolerate or decline cytotoxic chemotherapy or those who have relapsed despite one prior regimen. The secondary objectives of the study are: 1. To identify changes in gene promoter methylation and gene expression in response to combination therapy with 5AC and entinostat and compare the dynamics and kinetics of these alterations in promoter methylation and gene re-expression in the two different dosing schedules. 2. To evaluate the effect of entinostat on the induction of hyperacetylation of histones from peripheral blood and/or bone marrow samples. 3. To evaluate changes in DNA damage in response to combination therapy using gammaH2AX determination by western blotting. 4. To evaluate the pharmacodynamics of 5AC and entinostat when given at either dosing schedule and to evaluate these in relation to pharmacokinetic and clinical outcomes. 5. To evaluate duration of response.
Inclusion Criteria 1.One of the following: Untreated AML in (de novo or treatment related) patients of age greater than 60 years in the following categories: ï¿½Medical conditions that compromise the ability to give cytotoxic chemotherapy as the primary modality. ï¿½Patients who decline cytotoxic chemotherapy. Patients with AML of age ï¿½ 60 years who have relapsed despite one prior regimen 2.ECOG performance status 0, 1, or 2 (see Appendix A). 3. Age greater than 60 years 4.Patients must not have untreated active infections at the time of study entry. 5. Normal organ function as defined below: ï¿½Creatinine less than 2 mg/dl. ï¿½Total serum bilirubin within institutional limits unless due to hemolysis, Gilbertï¿½s syndrome, or ineffective erythropoiesis. ï¿½AST(SGOT)/ALT(SGPT) ï¿½2.5 X institutional upper limit of normal. 6. Life expectancy of at least three months. 7. Patients must be informed of the investigational nature of the treatment, results that might be expected, and potential toxicities. They must be able to understand and give informed written consent according to federal and institutional guidelines. 8. Declined or ineligible for potentially curative options such as allogeneic stem cell transplant. 9.No chemotherapy or study drugs for greater than 3 weeks prior to starting study. 10. Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study as described below: Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study or to abstain. Exclusion Criteria 1.Any of the Following: ï¿½Treatment for AML, including hematopoietic growth factors, less than 3 weeks prior to study registration. Exception: Hydroxyurea may be administered to patients with WBC greater than 30,000/ÂµL (see Section 8) ï¿½Radiotherapy less than 4 weeks prior to study registration ï¿½Failure to recover (to less than grade 1) from all adverse events associated with prior therapy. ï¿½Valproic acid less than 2 weeks prior to study registration. ï¿½Hypersensitivity to azacytidine, deoxyazacytidine, mannitol, entinostat or components of the entinostat tablet ï¿½Any advanced malignant hepatic tumor(s) 2.Prior therapy with demethylating agents for leukemia treatment within the last year. 3. Clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia. 4. Serious or uncontrolled medical conditions. 5.Concurrent use of any other investigational agents. 6.Known HIV-positive patients. 7.Pregnancy or breast feeding 8.Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy during the study and for a minimum of 30 days after study treatment.
This is a randomized phase II study to evaluate two different dose schedules of combination therapy with 5AC 50mg/m2 given subcutaneously for 10 days with Entinostat given orally for 2 days to determine if sequential or concurrent administration of these agents have different response rates or different impacts on secondary endpoints. 108 patients will be enrolled with 54 patients randomized to each arm. Arm A will be given an overlapping schedule of drugs with 5AC given at 50mg/m2 subcutaneously daily for 10 days on days 1 â?? 10 of a 28 day cycle and entinostat given at a flat dose of 8 mg orally on days 3 and 10. In Arm B the agents will be administered sequentially with 5AC given at 50mg/m2 subcutaneously daily for 10 days on days 1 â?? 10 of a 28 day cycle followed by entionostat at a 8 mg flat dose on days 10 and 17. Overall response rate (complete, partial and hematologic improvement- major) will be graded according to standard international response (IWG) criteria for AML. (1) Each arm will be compared against a historical standard of care and will be analyzed separately.
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