Emerging Therapeutics in Hematologic Malignancies

Transcription

1 Emerging Therapeutics in Hematologic Malignancies Brian A. Jonas, MD, PhD Assistant Professor of Medicine UC Davis Comprehensive Cancer Center September 26, 2015

2 16th Annual Advances in Oncology 2015 September 25-26, 2015 Sacramento, CA Emerging Therapeutics in Hematologic Malignancies Brian Jonas, M.D., Ph.D. Relevant financial relationships in the past twelve months by presenter or spouse/partner: Grant/Research Support: Ambit, Abbvie, Esanex, Kalobois Consultant: Glycomimetics Speakers Bureau: Celgene, Onyx, Incyte The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational.

3 Talk Outline 1. Updates on FLT3 inhibitors for acute myeloid leukemia (AML) 1. Other new targeted agents for AML, acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS) 1. Immunotherapeutic approaches for acute leukemia 1. UC Davis Clinical Trials in AML, ALL and MDS

4 Updates on FLT3 Inhibitors for AML

5 Molecular Pathology of AML Patel et al. NEJM 2012.

6 Fms-Related Tyrosine Kinase 3 (FLT3) FLT3-ITD FLT3-TKD Stirewalt et al. Nat Rev Cancer 2011.

7 FLT3 Inhibitors ASP2215 FLT3/AXL inhibitor active against FLT3-ITD and FLT3- D835 mutations Mori et al, ASCO 2014 Abstract Kiyoi et al. Nag J Med Sci, 2015.

8 Sorafenib plus Azacitidine Sorafenib 400mg BID daily 28 Day cycles Days: Azacitidine 75mg/m2 IV/SC Med Dur CR: Med OS: Med EFS: 2.3 mo 6 mo 4 mo Ravandi et al. Blood, 2013.

9 SORAML Study DA -> DA or HAM -> HiDAC -> HiDAC -> HiDAC* AML age patients FLT3-ITD+ 17% R 1:1 Above plus Sorafenib 800mg/day DA/HAM -> days HiDAC -> days 3 onwards Maintenance Sorafenib x12 months *HCT in CR Int Risk (MRD), High risk (MRD, MURD) Rollig et al, ASH 2014 Abstract# 6.

10 SORAML Outcomes Placebo CR rate 59% 60% Med RFS 23mo NR Sorafenib 3yr RFS 38% 56%* p=0.017 Med OS NR NR 3yr OS 56% 63% p=0.382 Median 36mo Observation FLT-ITD+: no difference EFS, trend for OS and RFS improvement in Soraf arm G3+ AE: fever (40%), infections (22%), bleeding (2%), HFS (all higher in Soraf arm) 9.2mo 20.5mo 1 st to show benefit for TKI in untreated AML CALGB10603/Ratify Trial (Midostaurin) restricted to FLT3+ patients Rollig et al, ASH 2014 Abstract# 6.

11 Summary of Quizartinib Trials Trial Population FLT3-ITD+ FLT3-ITD- Med DOR Ph 1 N=76, R/R, 23-86yr Ph 2 N=133, R/R 1 prior reg, >60yr Ph 2 N=138, R/R 2 prior regs, >18yr ORR 53% ORR 14% 13.3wks CRc 46% CRc 32% 12.1/22.1wk CRc 54% CRc 31% 12.1/7wks (37% to HCT) Quizartinib daily dosing mg Toxicities: QTc prolongation, GI, cytopenias ASH 2014 Abstract #388 (Borthakur et al): Quiz plus LDAC or Aza for R/R AML/MDS/CMML 69% ORR, 82% ORR (FLT3-ITD+), mttr 57d ASH 2014 Abstract #428 (Sandmaier et al): Quiz maintenance after Allo-HCT feasible, safe, 1 relapse in 13 subjects Sudhindra et al, Curr Hematol Malig Rep, 2014.

12 ASP2215 for R/R AML ASP2215 FLT3/AXL inhibitor active against FLT3-ITD and FLT3- D835 mutations (NCT ) P1/2 R/R AML Response FLT mg (n=127) FLT3+ 80mg (n=106) FLT3wt mg (n=57) CR 8 (6.3%) 7 (6.6) 0 CRp 5 (3.9) 5 (4.7) 1 (1.8) CRi 39 (30.7) 38 (35.8) 2 (3.5) PR 14 (11) 11 (10.4) 2 (3.5) CRc (CR+CRp+CRi ) 52 (40.9) 50 (47.2) 3 (5.3) ORR (CRc+PR) 66 (52) 61 (57.5) 5 (8.8) MTD 300mg (DLT diarrhea, AST elevation) AE: GI, liver, infection, cytopenias Med DOR 18 wks Levis et al, ASCO 2015 Abs #7003.

13 Resistance to FLT3i Emergence of a FLT3-ITD- clone (e.g. D835Y/V/F or F691L [Gatekeeper]) Kindler et al, Blood, 2010.

14 Overcoming Resistance to FLT3i Type I FLT3i that are sensitive to TKD mutations (e.g. Crenolanib and Asp2215*) *Randhawa et al, ASH 2014 Abstract# 389. Levis et al, ASCO 2015 Abs #7003. Fathi AT, Blood, Smith et al, Leukemia, 2015.

15 Overcoming Resistance to FLT3i Combine FLT3i with chemotherapy Co-targeting FLT3-dependent and independent pathways Kiyoi et al. Nag J Med Sci, Leung et al, Leukemia, 2013.

16 Select FLT3i Trials ID Phase Population Therapy NCT RR FLT3+ AML ASP2215 vs salvage NCT RR FLT3+ AML Quizartinib vs salvage NCT /2 AML in CR1 Ponatinib plus HiDAC NCT FLT3+ AML post allo Crenolanib NCT Untreated FLT3+ AML Crenolanib plus IC/C NCT Untreated FLT3+ AML Midostaurin plus IC/C NCT FLT3+ AML post allo Midostaurin NCT Untreated AML Sorafenib plus IC/C

17 Other New Targeted Agents for AML, ALL and MDS

18 Targeting Mutated IDH Mutation frequency = ~15-20% Neomorphic activity Cooperates with FLT3, RAS, DNMT3A mutations to drive leukemia AG-120 (IDH1i) NCT AG-221 (IDH2i) NCT Prensner et al, Nature Med, 2011.

19 AG-221 Targets IDH2 AG-221: first-in-class, oral, potent, reversible, selective inhibitor of mutant IDH2, triggers blast differentiation P1 study (NCT ) Advanced IDH2 mutant heme malignancies BID and QD dosing with dose-escalation 48 patients dosed, no MTD, 9 deaths within 28 days AG-221 N 48 Evaluable 32 CR/CRi/CRp 12 PR 8 SD 5 PD 7 Durable responses seen, some bridged to Allo-HCT Sustained plasma 2-HG inhibition (97% in R140Q, 50% in R172K) Stein et al, ASH 2014 Abstract# 115.

20 Targeting Bcl-2 Apoptosis is dysregulated in AML ABT-263 (Navitoclax) is an oral inhibitor of Bcl-2, Bcl- XL and Bcl-w Bcl-xL inhibition leads to thrombocytopenia ABT-199 engineered from ABT-263 to be a selective inhibitor of Bcl-2 Preclinical activity in AML

21 ABT-199 Targets Bcl-2 P2 study of oral ABT-199 in R/R AML or front-line for unfit pts Intra-patient dose escalation from 20mg to 1200mg Patients ABT-199 N 32 Med Age 71 (19-84) R/R 30 saml Prior Rx 14 IDH1 mut 2 IDH 2 mut 9 FLT3-ITD+ 6 Response/AE ABT-199 CR/CRi 5 (15.5%) 50% blast reduction 6 (19%) PD 10 Febrile neutropenia 8 Anemia 3 Pneumonia 3 TLS 0 3 of CR/CRi had IDH mutations NCT : P1/2 ABT-199 plus HMA (older AML) NCT : P1/2 ABT-199 plus LDAC (older AML) Konopleva et al, ASH 2014 Abstract# 118.

22 Targeting BTK in AML BTK pbtk CD34+ AML (example) Rushworth et al, Blood, 2014.

23 Summary of BTK in Myeloblasts and Lymphoblasts BTK downstream of FLT3, TLR9, CXCR4 in AML AKT, ERK and NFkB signaling decreased by inhibition of BTK by Ibrutinib BTK is expressed in B-ALL and is targeted by Ibrutinib Ibrutinib also inhibits ITK in T-cells and ITK plays a role in both T-ALL and in Th1 vs Th2 immunity NCT : P2 Ibrutinib -/+ LDAC RR AML NCT : P2 Ibrutinib RR ALL P1b Ibrutinib + Aza for MDS Rushworth et al, Blood, Zeitseva et al, Oncotarget, Oellerich et al, Blood, Dubovsky et al, Blood, 2013.

24 SGN-CD33a ADC CD33 expressed in 85-90% of AML SGN-CD33a: anti-cd33 ab conjugated to pyrrolobenzodiazepine

25 SGN-CD33a ADC P1 study CD33+ AML, Relapsed after initial CR>3mo or refuse standard Rx SGN-CD33a 5-60mcg/kg IV q3 weeks x 4 plus maintenance Patients SGN-CD33a N 40 Prior Intensive Rx 20 Int Risk 70% High Risk 18% NPM1 8% FLT3-ITD 13% Response/AE SGN-CD33a Blast Clearance 42% (n = 38) 40mcg level N = 17 CR 2 CRi 3 MLFS 3 Febrile neutropenia DLTs 55% PE (20 mcg) Hypocellular marrow (40mcg) 30d Mortality 2.5% Stein et al, ASH 2014 Abstract 623.

26 Novel Immunotherapeutic Approaches for Acute Leukemia

27 Chimeric Antigen Receptor (CAR) T-cells ~2-4 weeks from apheresis to patient P1 KTE-C19 study for R/R B-ALL opening at UCD Maude et al, Hematology, Maus et al, Blood, 2014.

28 CD19 CAR-T Cells Have Activity in R/R ALL Carl June, Special Scientific Symposium: 27/30 patients with CR with R/R B-ALL and CTL019 (U Penn) Park et al, Abstract 382: 20/22 patients with CR with 18/20 MRD negative with R/R B-ALL and 19-28z CAR T (MSKCC) CRS 0/10 treated at MRD and 9 of 13 treated with morphologic disease Lee et al, Abstract 381: 14/20 patients with CR with 12/14 MRD negative with R/R B-ALL and 19-28z CAR T (NIH) G3/4 CRS correlated with disease burden, CAR T cell expansion and total CAR T cells Grupp et al, NEJM, 2013.

29 CD33 and CD123 CAR T-Cells Have Pre-Clinical Activity in AML Pilot clinical trials in AML have shown modest anti-aml activity with anti-aml CAR T-cells. Kenderian et al, Leukemia, 2015.

30 Bispecific T-cell Engagers (BiTE) Bauerle et al, Can Res, 2009.

31 Blinatumomab for B-ALL P2 study of Blinatumomab in R/R Ph- B-ALL. Dosing (42 day cycles) 9 mcg/day days 1-7 then 28mcg/day days 8-28 for cycle 1 28 mcg/day days 1-28 after cycle 1 Up to 5 cycles Primary Endpoint: CR/CRh within Cycles 1-2 Secondary Endpoints: RFS, OS, transplant, safety Topp et al, Lancet Onc, 2015.

32 Blinatumomab for B-ALL # Patients Proportion CR/CRh (during C1-2) 81/189 43% CR 63 33% CRh 18 10% No response 90 48% Allo-HCT after CR/CRh 32/81 40% 100d mortality p Allo 32 11% MRD response (during C1-2) 60/73 82% 79% of responders achieved CR/CRh in C1 AE: most common G3/4: FN, neutropenia, anemia, CNS Topp et al, Lancet Onc, 2015.

33 Blinatumomab for B-ALL Med RFS 5.9mo (95% CI ) Med OS 6.1mo (95% CI ) Med Follow-up 8.9 and 9.8mo Topp et al, Lancet Onc, 2015.

34 Select Blinatumomab Abstracts at ASH 2014 Goekbuget et al, Abs #3704: MRD response after Blin therapy Goekbuget et al, Abs #379: Blin for MRD+ B-ALL after intensive therapy (BLAST trial) Complete MRD response 78% 98% achieved response after C1

35 Select Blinatumomab Abstracts at ASCO 2015 Kantarjian et al, Abs #7057: Zhu et al, Abs #2561: Blin responders lower BM CD19+ cells, higher CD3+ cells and granulocytes

36 Cytokine Release Syndrome Lee et al, Blood, 2014.

37 PD1 Pathway and AML/MDS/CMML NCT : P2 Maintenance Nivol AML NCT : P2 Nivol plus Aza AML Miller et al, Cell, Yang et al, Leukemia, 2014.

38 UC Davis Clinical Trials in AML, ALL and MDS

39 UCD AML Clinical Trials Age < 60 SWOG S1203 (P3 Induction and Consolidation) New AML Dx Age 60 (fit) GMI (P2 E-Selectin Inhibitor plus 7+3)* Age 65 (unfit) M (P1b ABT-199 plus decitabine) PHII-134 (P2 Nivolumab Maintenance)* AML Pathway Protocol/Molecular Tissue Bank* Relapsed or Refractory AML AC (P3 Quizartinib vs salvage chemo for FLT3-ITD+) GMI (P1 E-Selectin Inibitor plus MEC) PCYC-1131-CA (P2 Ibrutinib plus/minus Low-Dose Ara-C)* UCDCC#230 (P2 Bortezomib, Doxil and Decitabine) UCDCC#228 (P1 High-dose Lenalidomide)

40 UCD MDS Clinical Trials Lower Risk E2905 (P3 Lenalidomide -/+ Procrit) New MDS Dx Higher Risk UCDCC#256 (P1b Ibrutinib plus Azacitidine)* Relapsed or Refractory MDS UCDCC#256 (P1b Ibrutinib plus Azacitidine)* KB (P1/2 anti-epha3 MoAb also for 1 /2 myelofibrosis) KB (P1 anti-gm-csf MoAb for CMML)*

41 UCD ALL Clinical Trials Age < UCHMC1401 (P2 multiagent chemo, age 18-60) UCDCC#246 (P1 Carfilzomib plus HyperCVAD, age 18-65)* New ALL Dx Age Protocol in development* Relapsed or Refractory ALL PHII-132 (P2 Ibrutinib, B-ALL) KTE-C (P1/2 CAR-T cells, B-ALL)*

42 Summary Current management of AML and ALL focuses on age- and disease-based risk stratification to determine intensity of therapy Many new targeted agents are emerging as viable options in these diseases Immunotherapy is poised to play a major role in the management of these diseases Ongoing and future clinical trials are required to determine the optimal timing and combinations of these new agents

43 Questions?