BL-8040: BEST-IN-CLASS CXCR4 ANTAGONIST FOR TREATMENT OF ONCOLOGICAL MALIGNANCIES

Transcription

1 BL-8040: BEST-IN-CLASS CXCR4 ANTAGONIST FOR TREATMENT OF ONCOLOGICAL MALIGNANCIES 56

2 AML Unmet Medical Need, Current Therapies and Current Pipeline Martin S. Tallman, M.D. Chief, Leukemia Service Memorial Sloan-Kettering Cancer Center Professor of Medicine Weill Cornell Medical College New York, NY November

3 Acute Myeloid Leukemia Introduction Median age of AML: 72 years New patients/deaths in 2013: 14,000/10,000 Arises de novo, therapy-related or evolves from MDS or MPN Outcome varies by prognostic factors Outcome improved among younger, but not older Heterogeneity in genetics, clinical manifestations, and outcome Juliusson et al. Blood, 2009; Ca for Clinicians,

4 Acute Myeloid Leukemia Major Victories Over the Last Decades Insights in understanding biology and prognosis Supportive care improvements Hematopoietic stem cell transplantation Cure of most patients with acute promyelocytic leukemia 59

5 Acute Myeloid Leukemia Progress in AML in the Last Decades Integrated genetic profiling New induction strategies Drug discovery Refinement in transplant techniques Less intensive treatment for older adults Early biomarkers of MRD 60

6 (Some) Remaining Questions How can we tackle resistance in high-risk disease (relapsed or refractory, adverse cytogenetics)? What is best approach to AML in the older adult? Candidates for intensive chemotherapy Not candidates for intensive chemotherapy Are there better rational targets we can leverage? Can we exploit graft-vs-leukemia effect associated with allogeneic stem cell transplantation better? Reduce transplant-related mortality further? 61

7 Gold Standard Induction Regimen Described 40 years ago (1973) Daunorubicin mg/m 2 /d IV x 3 days Cytarabine 100 mg/m 2 /d CI x 7 days Yates et al. Cancer Chemother Rep, 1973; Rai et al. Blood,

8 Acute Myeloid Leukemia Limited Benefits of Standard Induction CR: 70-80% ages % ages >60 DFS (5 yrs): 40% ages 60 15% ages >60 Many cytogenetic, molec genetic, clinical predictors of outcome most predict relapse, and not initial response to chemotherapy 63

9 Probability Probability Survival of Newly Diagnosed AML Consecutive ECOG Frontline Trials 1.0 Age Age > n=2, n=1, Year Year Tallman, Gilliland, Rowe et al. Blood, 2005 and update 64

10 Percent Survival From Relapse by Age 2,441 patients on 8 consecutive ECOG studies Young AML ( 55 years) Older AML (> 55 years) n=570 n=171 5 yr survival 11% 5 yr survival 6% Years Rowe et al. Blood, 2005 (abstr) 65

11 Probability Survival for Patients with Relapsed AML Estey et al Leukemia, Week First CR Pts Deaths Pts Censored at > 1,2 Years ,0 2, , , ,7 Weeks 66

12 Overall Survival (%) AML in Older Adults (>60) Overall Survival with Unfavorable Cytogenetics GAMLCG Data HAM-HAM TAD-HAM Buchner et al. J Clin Oncol, 2006 Years n=

13 Cumulative Percentage Overall Survival by Cytogenetic Group Estimate At Risk Deaths at 5 Years Favorable % Intermediate % Unfavorable % Heterogeneity of 3 Groups: p< Years After Entering Study 8 Slovak et al Blood,

14 Distribution of Cytogenetically and Molecularly Defined Risk Groups in AML 14% Other adverse 5% MLL-PTD 3% inv(3)/t(3;3)/evi-1 ADVERSE 34% 12% FLT-ITD/ NPM1 wt t(15;17)/pml-rara 11% t(8;21)/runx1- RUNX1-T1 8% Inv(16)/t(16;16)/ CBFB-MYH11 5% FAVORABLE 45% NPM1 mut/ FLT3-ITD neg/wt1 wt 18% INTERMEDIATE 21% CEBPA mut (biallelic)/ FLT3-ITD neg 3% Grimwade Hematology Am Soc Hematol Educ Program,

15 Gene Mutations Clinically Important in Everyday Practice Today Gene Incidence Impact FLT3-ITD 25% Unfavorable NPM1 33% Favorable CEBP 8% Favorable (biallelic) C-KIT 15% Unfavorable (for CBF) 70

16 Gene Mutations Clinically Important in Everyday Practice Tomorrow Gene Incidence Associations Impact IDH1/2 6%/8% NPM1+/FLT3- Favorable DNMT3A 22% Intermed-risk Unfavorable TET2 10% NPM1 Unfavorable ASXL1 4% Intermed-risk Unfavorable 71

17 Is There Relevance of Novel Mutations to Clinical Practice? Novel mutations have prognostic value in AML including older adults An integrated mutational analysis can be used to risk-stratify patients Genetic factors influence specific treatment (currently more applicable to younger patients, intermediate-risk, NK) 72

18 New Agents in AML Agent Mechanism Comments CPX-351 New formulations Liposomal fixed ratio of dauno/ara-c High response and reduced mortality Elacytarabine Eliadic ester of ara-c Remission in adv disease Sorafen/AC220 Multikinase inhib CRs w/single agent DOT1L inhibitor Histone methyltransferase Preclinical data against MLL Novel small molecules inhib Volasertib Polo-1 like kinase inhib Improved OS w/lodac AGI-221 IDH2 inhibitor In phase I trial Tosedostat Aminopeptidase inhib CRs in phase II Clofarabine Nucleoside analog Effective in older adults with unfav. prognosis Nucleoside analogs Sapacitabine Nucleoside analog CRs w/single agent Bayne J Pharm Sci, 2008; Feldman J Clin Oncol, 2010; O Brien Blood, 2009; Metzelder Blood, 2009; Cortes Blood, 2009 (abstr) Pollock ASH, 2010; Maertens ASH, 2012; Erba J Clin Oncol, 2010; Kantarjian Blood,

19 CPX-351 A Liposomal Carrier Containing Daunorubicin and Ara-C in a Fixed Ratio DSPC DSPG Cholesterol Cytarabine Daunorubicin 100 nm bilamellar liposomes 5:1 molar ratio of cytarabine to daunorubicin 1 unit = 1.0 mg cytarabine plus 0.44 mg daunorubicin Specifically designed drug delivery vehicle enables specific drug ratios to be maintained Feldman et al. J Clin Oncol,

20 CPX-351 vs EFS and OS in Secondary AML Event-Free Survival Overall Survival 100% 80% 60% 40% Logrank p-value = % 80% Logrank p-value = 0.01 CPX-351 CPX % % 20% 0% % 0% Months from randomization Months from randomization Lancet et al. ASH,

21 Phase 2 of AC220 in Relapsed/Refractory AML CRc: 53% CRc: 36% Cortes et al. J Clin Oncol,

22 What Is Next in FLT3 Inhibition? Novel inhibitors: PLX3397 (inhib. FMS, KIT, FLT3) Combination with chemo; maint. strategies High degree of resistance occurs Constitutively activating mutations at FLT3 activation loop residue D835 assoc. with resistance to AC220 Development of agents active against D835: Crenolanib Smith et al. ASH 2011 (abstr 674); Barton et al. ASH, 2011 (abstr 3632); Smith et al. ASH, 2013 (abstr 674); Gao et al. ASH, 2013 (abstr 3591 and 141) 77

23 DOT1L Inhibitor For MLL-Assoc. Leukemias MLL-fusion proteins interact with DOT1L Aberrant recruitment of DOT1L methylation of H3K79 sustained expression of MLL target genes leukemic phenotype Hypothesis that inhibition of DOT1L activity may treat leukemia with MLL translocation Deshpande et al. Trends in Immunology,

24 Plk1: A Key Regulator of Mitosis Microtubule-kinetochore attachment Mitotic progression Plk1 deficiency Spindle elongation Kinetochores Metaphase Midzone Centrosomal microtubule nucleation Mitotic entry (Cdk1 activation) Prometaphase NH 2 Plk1 COOH Anaphase Midbody Cleavage furrow formation (cytokinesis) Centrosomes Prophase Telophase Checkpoint adaptation and recovery Interphase Plk1 localization Plk functions Microtubules DNA Modified from Takaki et al Curr Opin Cell Biol,

25 Volasertib Preclinical Profile ATP-competitive Polo1-like kinase inhibitor Potency and selectivity Plk1 Plk2 Plk3 >50 other kinases IC 50 (nm) >10,000 Anti-mitotic mode of action perturbation of spindle assembly prometaphase arrest apoptosis In vivo activity efficacy in multiple xenograft models at well-tolerated doses Rudolph et al. Clin Cancer Res

26 Survival distribution function Volasertib + LoDAC vs LoDAC Overall survival LDAC (n=45) V + LDAC (n=42) Median OS 5.2 months (158 days) 8.0 months (245 days) HR = 0.66 (95% CI: ) p= Maertens et al. ASH, 2012 Time (days) 81

27 Summary of Key Parameters: AGI-221 A First-in-Class Inhibitor of IDH2 Mutants AGI R140Q Cell IC 50 (um) Solubility ph 2 / H 2 O (µm) Microsome stability Eh Human/dog/rat PPB hu / mu (% F u ) Mouse PKPD EAUC97 12 h (ng*hr/ml) Rat / Monkey Oral F % Human Oral F% projected Human dose projection BID (g/dose) Brain:Plasma / / 0.26 / / % / 37% AGI-221 Slow tight-binding inhibitors of IDH2 mutant AGI-221 reversed histone hypermethylation & induced differentiation in TF1/IDH2R140Q leukemia cell model AGI-221 projected to reduce 2HG to mm in tumor cells at human dose of 0.4 g g, bid AGI-221 has excellent selectivity against offtargets, including IDHwt and herg AGI-221 has good PK profile in rodent and monkey AGI-221 has acceptable safety profile

28 Tosedostat Oral agent targets aminopeptidase (involved in protein cell cycle) Results in aminoacid depletion selectively in tumor cells leading to upregulation of proapoptotic factors (which induce cell death) Given in form which enters cell easily and then inside cell is changed to a form which does not readily exit the cell Is synergistic with chemotherpay Induces complete remissions in relapsed and refractory patients with acute myeloid leukemia 83

29 Overall Survival (%) Clofarabine in Untreated Older Adults With AML and Unfav Prognostic Factors Overall Survival PR/TF Time (weeks) CR/CRp All patients Kantarjian J Clin Oncol,

30 Very Novel Agents Agent Target CXCR4 antagonist (BL-8040) CXCR4 BET (bromodomian and extraterminal) inhibitor (CPI-0601) C-Met tyrosine kinase inhibitor (carbozantinib, foretinib), targets ATP-binding site of C-Met BET bromodomain C-Met tyrosine kinase Hedgehog pathway inhibitor (Vismodegib) Smoothened membrane protein in Hedgehog pathway PI3K inihibtor (BKM120) mtor inhibitors (Rapamycin, OSI- 027, BEZ235)) PI3K mtorc1 (rapamycin) and mtorc2 (OSI-027); MTORC1 and 2 and PI3K (BEZ235) Pim inhibitor (SGI-1776) PIm (provirus integration site for Maloney murine leukemia virus) 85

31 Future Directions Target CBF FLT3-ITD IDH1/2 NFkB/CD74 NPM1 MLL DNMT3A/NPM1/MLL HDAC Aminopeptidase Novel strategy Gemtuzumab + Dasatinib AC220/PLX3397 AG-221 (IDH inhibitor) Bortezomib ATRA DOT1L inhibitor High-dose daunorubicin Vorinostat Tosedostat 86

32 Broad Suggestions For the Future Address high-risk populations (mutational profiling identifies 40% of newly diagnosed patients with OS</=10%; relapsed or refractory, older adults) Test novel therapies earlier in the natural history of the disease and in best patient population Carry out mutational profiling on all patients Exploit drug discovery and epigenetic/stem cell targeted therapies Make national/international registries a priority 87