Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: New Epigenetic Approaches
Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety.
Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort).
Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489).
Disclosures: Kropf: Teva Pharmaceuticals: Consultancy . O'Connell: Celgene: Speakers Bureau ; Incyte: Membership on an entity’s Board of Directors or advisory committees . Griffiths: Astex: Research Funding ; Alexion Pharmaceuticals: Honoraria ; Celgene: Honoraria . Rizzieri: Teva: Other: ad board , Speakers Bureau ; Celgene: Other: ad board , Speakers Bureau . Stock: Gilead: Membership on an entity’s Board of Directors or advisory committees . Savona: Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Ariad: Membership on an entity’s Board of Directors or advisory committees ; Sunesis Pharmaceuticals: Research Funding ; TG Therapeutics: Research Funding ; Gilead: Membership on an entity’s Board of Directors or advisory committees ; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees ; Karyopharm Therapeutics: Consultancy , Equity Ownership , Membership on an entity’s Board of Directors or advisory committees , Research Funding . Rosenblat: Astex Pharmaceuticals, Inc.: Research Funding . Berdeja: Abbvie: Research Funding ; BMS: Research Funding ; Celgene: Research Funding ; Takeda: Research Funding ; Onyx: Research Funding ; Janssen: Research Funding ; Novartis: Research Funding ; Curis: Research Funding ; Array: Research Funding ; Acetylon: Research Funding ; MEI: Research Funding . Wilson: Astex Pharmaceuticals, Inc.: Employment . Lowder: Astex Pharmaceuticals, Inc.: Employment . Taverna: Astex Pharmaceuticals, Inc.: Employment . Hao: Astex Pharmaceuticals, Inc.: Employment . Azab: Astex Pharmaceuticals, Inc.: Employment . Issa: Janssen: Consultancy ; Astex Pharmaceuticals, Inc.: Consultancy .
See more of: Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation
See more of: Oral and Poster Abstracts
*signifies non-member of ASH