Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients (pts) with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS)
Authors: Naval Daver , Kantarjian Hagop M. , Garcia-Manero Guillermo , Pemmaraju Naveen , Kadia Tapan M. , DiNardo Courtney D. , Jain Nitin , Borthakur Gautam , Jabbour Elias , Konopleva Marina , Cortes Jorge E. , Craig Adam , Ravandi Farhad 
Published: October 2019

Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, has limited toxicity, and is currently under evaluation for the treatment of pts with AML and high-risk MDS.
Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ³ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ² 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This dose was well tolerated with no dose limiting toxicity identified and pts were then enrolled on phase II at this dose and schedule. However, due to mucositis in a few subsequent pts, the induction dose of vosaroxin was reduced to 70 mg /m2, starting with pt #25. The vosaroxin dose could be maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality.
Results: To date, 35 pts (32 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-78) have been enrolled; 34 (97%) pts were older than 60 years. They included 15 (43%) pts with diploid cytogenetics, 12 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 8 (23%) with other miscellaneous abnormalities. 13 (37%) pts with AML had antecedent hematological disorders (AHD) including 7 (20%) with MDS, 4 (11%) with myeloproliferative neoplasm and 2 (6%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 5 (15%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, median white blood cell, hemoglobin, & platelet counts were 40% (9-97), 4.1 x 109/L (0.4-57.0), 9.4 g/dL (6.8-11.5), and 40 x 109/L (7-333), respectively. 34 pts were evaluable for response; 17 (50%) achieved CR, 6 (18%) CRp, and 3 (9%) CRi for an overall response rate of 77%. One pt is too early for response assessment. Responses by age, cytogenetic and molecular characteristics are shown in table 1. The median follow-up is 5.1 months (range, 0.9-11.0). Pts have received a median of 2 (1-6) treatment cycles with the median number of cycles to response being 1 (1-4). Three pts have relapsed and the median duration of CR/CRp/CRi has not been reached (0.5-9.9+ months). Four (12%) pts have proceeded to allogeneic stem cell transplant (ASCT). 4-week and 8-week mortality were 0% and 14%, respectively. The regimen is well tolerated with the main grade ³ 3 toxicity being mucositis in 9 (26%) pts and liver enzyme elevation in 3 (9%).
Conclusion: Combination of vosaroxin and decitabine is effective and feasible in older pts with AML and high-risk MDS. Enrollment is ongoing.
Table 1: Response by baseline characteristics Parameter Category N Overall response Too early to evaluate Age* 60-70 16 14/16 (88%) 0 >70 18 12/17 (71%) 1 Cytogenetics Diploid 15 11/14 (79%) 1 -5/-7/other adverse 12 8/12 (67%) 0 Miscellaneous 8 5/8 (63%) 0 Mutation Status IDH2 7 7/7 (100%) 0 IDH1 5 1/4 (25%) 1 TP53 9 6/9 (67%) 0 RAS 9 4/9 (44%) 0 *1 pt below the age of 60 years was unsuitable for standard chemotherapy and was enrolled on study.

Disclosures
Naval: Sunesis: Advisory board membership Other, Research Funding. Off Label Use: Vosaroxin (Qinprezo) has not been approved for AML. In this clinical trial we are evaluating the efficacy and safety of vosaroxin (Qinprezo) in combination with decitabine in elderly patients with AML. . Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Craig:Sunesis: Employment. Ravandi:Sunesis: Advisory board membership Other, Research Funding.