Phase I/II Study of Vosaroxin and Decitabine in Newly Diagnosed Older Patients with Acute Myeloid Leukemia (AML) and High Risk Myelodysplastic Syndrome (MDS) Naval Daver 1, Hagop Kantarjian 1, Guillermo Garcia-Manero 1, Elias Jabbour 1, Naveen Pemmaraju 1, Kenneth Vaughn 1, Sherry Pierce 1, Marina Konopleva 1, Tapan Kadia 1, Courtney DiNardo 1, Gautam Borthakur 1, Jorge Cortes 1, Adam Craig 2, and Farhad Ravandi 1 1 Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas; 2 Sunesis Pharmaceuticals, Inc, South San Francisco
Background Key Characteristics Targeted topoisomerase II inhibitor Active in anthracyclineresistant settings Evades common drug resistance pathways (Pgp) Lower potential for offtarget damage (cardiotoxicity) Quinolone Core H 3 C HN H 3 CO Vosaroxin O N N N S N CO 2 H Vosaroxin intercalates DNA and inhibits topoisomerase II, causing replicationdependent, site-selective DNA breaks, G2 arrest and cell death by apoptosis. Evanchi. Drug Metab Disp 2009; Hoch. Cancer Chemother Pharmacol 2009; Scaten. ibid 2010; Advani Clin Cancer Res 2010; Hawtin. PLoS One 2010; Hawtin. Oncotarget 2010; Haematologica 2011; Lancet Leukemia 2011.
Background Vosaroxin in newly dx pts with AML 60 yr (REVEAL-1): CR/CRp = 32%, Med survival = 7.0 mos, 30-day mortality = 12% Vosaroxin Plus Cytarabine Vs Placebo Plus Cytarabine in first relapse AML (VALOR, n=711) HiDAC HiDAC+V P-value CR/CRp 16% 30% <0.0001 Med OS 6.1 m 7.5 m P=0.06 Stratified P=0.02 OS 60 yr 5.0 m 7.1 m P=0.003 OS censoring for SCT 5.3 m 6.7 m P=0.02 60-day Mortality 19.4% 19.7% NS Stuart RK, et al. Br J Haematol. Nov 2014 Ravandi F, et al. Lancet Oncology Sept 2015
Inclusion Criteria Untreated AML ( 20% blasts) HR-MDS or HR-CMML ( 10% blasts) Therapy for prior MDS before progression to AML acceptable Age 60 years and unsuitable for standard induction* Adequate hepatic and renal function No uncontrolled infection *Kantarjian H, et al. Cancer. 2006.
Design Induction Reinduction (if needed) C1 C2 C3 C4 C5 Maintenance Decitabine Vosaroxin 70 90 mg/m 2 on Day 1 and 4 Decitabine 20 mg/m 2 IV daily x 5 days Max up to 7 cycles on protocol Cycles repeated every 4-6 weeks depending on count recovery and toxicity
Inclusion Criteria Phase I 6 pts received vosaroxin 90 mg/m 2 D1 and 4 No dose-limiting toxicities Phase II 16 pts received vosaroxin 90 mg/m 2 D1 and 4 - Grade 3 mucositis in 4 pts Subsequent 39 pts received vosaroxin 70 mg/m 2 D1 and 4
Characteristics (N=61) Characteristic Age Diagnosis Prior Rx for AHD Category 60-69 70 AML de novo 2 AML HR MDS de novo 2 MDS HMA agent Lenalidomide N (%); Median [range] 69 [60-78] 37 (61) 24 (39) 40 (66) 14 (23) 5 (8) 2 (3) 3 (5) 1 (2) BM blast % 36 [9-97] WBC 3.6 [0.4-57.0] Platelets 34 [7-333]
Characteristics (N=61) Characteristic N (%) Cytogenetics Molecular (N = 59) Diploid Miscellaneous -5/-7/complex Insufficient TP53 IDH2 IDH1 TET2 RAS (K/N) DNMT3A CEBPA ASXL1 JAK2 FLT3 EZH2 23 (38) 14 (23) 21 (34) 3 (5) 12 (20) 11 (18) 9 (15) 10 (16) 9 (15) 6 (10) 8 (13) 5 (8) 3 (5) 3 (5) 2 (3)
Response (N=61) Response / Outcome N (%) Evaluable 61 CR 32 (52) CRp 9 (15) CRi 4 (7) ORR (CR + CRp + CRi) 45 (74) No Response 8 (13) Early Death 4 wks 0 (0) Early Death 8 wks 8 (13) MRD (-) by multi-parameter flow 22 (67)
Response (N=61) Parameter Age Cytogenetics Mutation status Category 60-69 70 Diploid Miscellaneous -5/-7/Complex IDH2 TET2 TP53 RAS IDH1 Overall Response; N (%) 29/37 (78) 17/24 (71) 19/23 (83) 13/17 (76) 14/21 (67) 10/11 (91) 9/10 (90) 9/12 (75) 6 (67) 3/9 (33)
Response by Induction Dose (N=61) Induction dose Pts Deaths 8 wks Responders Need 1 course to response 90 mg/m 2 22 6 (27%) 16 (73%) 3/16 (19%) 70 mg/m 2 39 2 (5%) 30 (77%) 12/30 (40%)
Related toxicities(n=61) Toxicities G1/2 G3/4 Total (%) Bilirubin 33 8 41 (67) Diarrhea 2 0 2 (3) Mucositis 39 11 50 (82) Nausea/Vomiting 9 1 10 (16) Fungal infections 0 2 2 (3%) Major infections (pneumonia, sepsis) 0 34 34 (56%) Other infections 0 6 6 (10%)
Disposition (N=61) Parameter N (%); Med [Range] Median follow-up (mos) 7.7 [2.2-24.5] Median cycles to response 1 [1-4] Median cycles delivered 5 [1-7] Disposition Still on study Stem cell transplant Completed D+V (continue DAC alone) Completed D+V (on surveillance) Death < 8 weeks Primary refractory Relapse (16 relapse, 1 extramedullary) Death in CR 4 (7) 11 (19) 9 (16) 2 (3) 8 (14) 9 (16) 17 (29) 2 (3)
Vosaroxin+DAC in Newly Dx Older AML-MDS
OS by Age and Dose-level
OS (Censored for SCT)
OS by Karyotype
Vosaroxin + Decitabine vs Decitabine alone
Vosaroxin + Decitabine vs Decitabine Age 60-74
Vosaroxin + Decitabine vs Decitabine Age 75+
Conclusions Vosaroxin plus decitabine CR/CRi = 75%, 8 wk mortality = 13%. 70 mg/m2 well tolerated; better outcomes; 8 wk mortality 5%. Future Plan: MDACC: Vosaroxin+DAC alternating with Cladribine+LDAC:? vosaroxin 50/m2 vs 70/m2 Multicenter: Compare Vosaroxin+DAC vs HMA alone vs 3+7 in AML 60 yrs.