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Novel Targets and Therapies in Clinical Trials for Pancreatic Cancer Maeve Lowery MD Memorial Sloan Kettering Cancer Center.

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Presentation on theme: "Novel Targets and Therapies in Clinical Trials for Pancreatic Cancer Maeve Lowery MD Memorial Sloan Kettering Cancer Center."— Presentation transcript:

1 Novel Targets and Therapies in Clinical Trials for Pancreatic Cancer Maeve Lowery MD Memorial Sloan Kettering Cancer Center

2 (ACS 2009). Ries LA. SEER, The Problem and Challenges… New diagnoses U.S. 2009: 42,470 Mortality U.S. 2009: 35, th most common cancer (3% new cancers) 4 th leading cause of cancer mortality (6%) Overall 5-year survival ~3-4% Risk of developing PC: 1 in 9-11,000 (~0.01%)

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4 Overall Survival in Advanced Pancreatic Ca by Performance Status (Pooled Data CALGB ) Kindler, et al. ASCO, 2007 (Abst #4508) PS 0: 8.0 mos PS 1: 4.8 mos PS 2: 2.8 mos p= Months from Study Entry Proportion Surviving

5 Landmark Phase III Trial APC Gemcitabine vs 5-FU Burris, et al. J Clin Oncol, 1997 Median Survival Gemcitabine 5.6 mos 5-FU 4.3 mos p= (Log-Rank Test) 0 Survival Time (months) 0 % Patients Surviving

6 PA.3 trial : Gemcitabine +/- Erlotinib Overall Survival *Adjusted for PS and extent of disease at baseline † From Cox regression model ‡ From 2-sided log-rank test Moore, et al. J Clin Oncol, 2007 G + Erlotinib (N=261) G + Placebo (N=260) Med. Survival (mos) Year Survival23%17% CR + PR8.6%8% CR + PR + SD57%49% HR=0.82 (95% CI: ), p=0.038 Months Survival Function

7 Conroy, et al. NEJM, 2011 FOLFIRINOX vs Gemcitabine Prodige 4- ACCORD 11 Randomization 1: 1 Stratification ₋ PS: 0-1 vs 2; Primary tumor location, Center Primary Endpoint: Overall Survival Untreated Metastatic Panc Adenocarcinoma ECOG 0-1 Gemcitabine (N= 169) FOLFIRINOX (N= 167) RANDOMIZERANDOMIZE

8 Gemcitabine FOLFIRINOX FOLFIRINOX vs Gemcitabine Overall Survival Number at risk Gemcitabine FOLFIRINOX P r o b a b i l i t y Months Median 11.1 mo Median 6.8 mo HR = 0.57 P < Conroy, T. NEJM, 2011

9 FOLFIRINOX vs Gemcitabine Secondary Endpoints Conroy T, et al. NEJM, 2011 FOLFIRINOX (N= 167) Gemcitabine (N= 169) P-Value Febrile neutropenia5.4%0.6%0.009 Thrombocytopenia9.1%2.4%0.008 Peripheral neuropathy9%—0.001 Vomiting14.5%4.7%0.002 Diarrhea12.7%1.2% Filgrastim support42.5%5% Overall response rate31.6%9.4% Median PFS6.4 mths3.3 mths HR= 0.47

10 Gemcitabine Nab-Paclitaxel vs Gemcitabine MPACT Trial N=842 patients, primary endpoint overall survival Prospective evaluation of SPARC expression as predictive biomarker Recruitment complete, results awaited Untreated Met Panc Adenoca ECOG 0-1 Nab-Paclitaxel & Gemcitabine RANDOMIZERANDOMIZE N= 861 Primary endpoint: OS Stratification: KPS, primary tumor location, Center

11 GemGem & Nab-P Stats Median OS6.7 mo8.5 moHR=0.71 P= year OS22%35%P= Median PFS3.7 mo5.5 mo 1 year PFS5.5%3.7%P= Time to treat failure 5.1 mo3.6 moHR=0.7 P< RR7%23%HR=0.70 p< MPACT: Efficacy Outcomes Von Hoff et all, NEJM 2013

12 MPACT: Toxicity GemGem & Nab-P Grade 3 / 4 neutropenia 27%38% Febrile neutropenia 1%3% Fatigue7%17% Neuropathy<1%17% Von Hoff et all, NEJM 2013

13 Gemcitabine Combinations Meta-Analysis (N= 4,465, 15 Trials) HR95% CI, P-value Gem vs Gem + X , p= Gem vs Gem + Platin , p= 0.01 Gem vs Gem + 5-FU , p= 0.03 PS= 0, Combination , p< Heinemann, et al. BMC, 2008

14 Selected Phase III Trials PC

15 Where do we go from here? Targeted therapy for genetic subgroups Immunotherapy Stromal Depletion Targeting stem cells Specific inhibitors of key signaling pathways Radioimmunotherapy

16 Pancreas Cancer & BRCA Mutations Rare in general population – Increased prevalence in Ashkenazi population – Founder mutations BRCA 1 185delAG, 5832insC BRCA delT MSKCC data – Resected pancreas ca 5.5% BRCA mutation (selected on basis of Ashkenazi heritage) – Ashkenazi breast-pancreas families 14.2% BRCA positive Ferrone, C. J Clin Oncol, Stadler, ZK. Cancer, 2012

17 PALB2 (FANCN) Partner and localizer of BRCA2 Binds to BRCA2 stabilizing it and anchoring to structures in the nucleus allowing BRCA2 to repair DNA Jones, S. Science, Tischkowitz, MD. Gastroenterol, Stadler, ZK. Clin Gen, Slater, EP. Clin Gen, 2010

18 PC, BRCA & PARP Inhibition BRCA 1, 2 function integral to DS DNA repair PARP inhibition established value in ovary, breast cancer with BRCA-related mutations Preclinical data in PC – Capan-1 – Very susceptible to KU – Susceptible to alkylating agents Anecdotal clinical data in PC Friedensen. Med Gen Med, Couch. Can Epid Biom Prev, McCabe. Cancer Biol Therapeut, Goggins, M. Cancer Res, 1996

19 Loss of Functional BRCA-1 or 2 Affects DNA Double-Strand Break Repair Pathway Ashworth, et al. J Clin Oncol, 2008

20 Poly (ADP-Ribose) Polymerase (PARP) DNA damage – endogenous, cytotoxics, radiation, etc. If PARP is inhibited, SSB repair prevented, leading to increased double strand DNA breaks

21 Sensitivity of BRCA Mut. + Wild-type PC Cell Lines to AZD-2281 (Olaparib) Lowery, MA, Moynahan, ME (MSKCC)

22 Stage IV Panc with BRCA1 187delAG Mutation: Response to Gemcitabine/ AZD-2281

23 Randomized Phase II Cisplatin + Gem +/- Veliparib in BRCA/ PALB2 mutated PC Eligibility – Untreated LA or metastatic PC with BRCA 1-2, PALB2 m – ECOG 0-1 Randomized phase II (N= 50) Arm A: Cisplatin + gemcitabine + veliparib Arm B: Cisplatin + gemcitabine Gemcitabine + cisplatin d3+10, q 21 Veliparib dosing day 1-12, BID, PO Dosing veliparib from ongoing phase I (NCT ) PI: E.M. O'Reilly (CTEP, Lustgarten Foundation)

24 Gemcitabine + Cisplatin + ABT-888 Chemotherapy +/- PARP Inhibitor ABT-888 in BRCA 1 / 2 Mutated PC Phase I trial do determine MTD currently enrolling (no randomization) Randomized phase II trial will evaluate addition of PARP inhibitor Untreated Met or LA Panc Adenoca. BRCA 1/ 2 or PALB2 mutation ECOG 0-1 Gemcitabine + Cisplatin RANDOMIZERANDOMIZE

25 Targeting Stroma to Improve Drug Delivery Feig C et al. Clin Cancer Res 2012;18: ©2012 by American Association for Cancer Research

26 Hedgehog Pathway and PC Developmental pathway – neural, teeth, GI tract, lungs, etc Expressed abnormally in 70-80% pancreas adenoca Activation of pathway important in carcinogenesis, progression of panc ca Hh pathway: stroma/desmoplasia, stem cells SMO inhibitors – Cyclopamine, GDC-0449, IPI-926, LDE225 Von Hoff, D. NEJM, Thayer, S. Nature, Feldmann, G. Gut, Jimeno, A. Mol Can Ther, Oliver, K. Science, 2009

27 Rand. Phase II: Gem + Vismodegib/P Interim Analysis after 50% PFS Events Gem/ Vismodegib (N= 53) Gem/ Placebo (N= 56) CR/ PR- / -3%/ 11% Stable Disease49%31% Med. PFS (95% CI)3.7 months ( )2.4 months ( ) Adjusted HR 0.92 ( ) Med. OS (95% CI)6.3 months ( )5.4 months ( ) Adjusted HR 0.97 ( ) One- Year survival24% Catennaci, D. Proceedings ASCO, 2012 Abst # 4022 Correlatives: [Shh], CT perfusion

28 PEGPH20: Recombinant Hyaluronidase HA is a glycosaminoglycan abundant in the extracellular matrix of PDA. Combination therapy with PEGPH20 and gemcitabine inhibited tumor growth and prolonged survival in a genetically engineered mouse model of PAC – Degrades hyaluronan – Facilitates drug delivery – Reduces interstitial fluid pressure Jacobeth, M. Gut, Hingorani, S. Cancer Cell, NCT

29 mFOLFIRINOX & PEGPH20 SWOG S1313 (NCT ) Randomized phase Ib/II MPACT Trial N=842 patients, primary endpoint overall Recruitment complete, results awaited Untreated Met Panc Adenoca ECOG 0-1 mFOLFIRINOX RANDOMIZERANDOMIZE N=138 patients Primary endpoint: OS Correlatives: plasma & tumor HA

30 Gem & Nab-Paclitaxel & PEGPH20 HALO (NCT ) Randomized phase II MPACT Trial N=842 patients, primary endpoint overall Recruitment complete, results awaited Untreated Met Panc Adenoca KPS ≥ 70% Gem & Nab-Paclitaxel RANDOMIZERANDOMIZE N=132 patients Primary endpoint: PFS

31 TH-302: A Hypoxia-Activated Prodrug Weiss G J et al. Clin Cancer Res 2011;17: ©2011 by American Association for Cancer Research

32 TH CR-404 Borad et al, ESMO 2012

33 Gem & TH-302 MAESTRO Trial (NCT ) Randomized phase III MPACT Trial N=842 patients, primary endpoint overall Recruitment complete, results awaited Untreated Met Panc Adenoca ECOG 0/1 Gem & Placebo RANDOMIZERANDOMIZE N=660 patients Primary endpoint: OS

34 Immune checkpoints as therapeutic targets Kandalaft L E et al. JCO 2011;29: ©2011 by American Society of Clinical Oncology

35 CTLA4 Blockade: Success in Melanoma Ipilimumab + gp100 vs gp100; HR=0.68 (95% CI: 0.55, 0.85), P= Ipilimumab vs gp100; HR=0.66 (95% CI:0.51, 0.87), P= Ipilimumab + gp100 Ipilimumab Ipilimumab + gp100 Ipilimumab gp100

36 Zheng et al, Gastroenterology, Volume 144, Issue 6, 2013, Immune cell infiltrates during pancreatic tumor progression

37 Phase II: VY/GVAX +/- CRS-207 Metastatic PDA patients ECOG 0-1,n=90 previously treated, randomized 2:1 to either CY/GVAX followed CRS-207 or CY/GVAX Primary endpoint was overall survival Results: OS arm A 6 months, arm B 3.4 months P= HR ? Increased benefit in 3 rd line patients Both vaccines well tolerated Le et al GI ASCO 2014

38 CRS-207 Eclipse Trial (NCT ) Randomized phase III MPACT Trial N=842 patients, primary endpoint overall Recruitment complete, results awaited Previously Treated Met Panc Adenoca ECOG 0/1 GVAX & Cyclophosphamide & CRS-207 RANDOMIZERANDOMIZE N=240 patients Primary endpoint: OS *Gem/Capecitabine/Erlotinib/Irinotecan Chemotherapy*

39 Immunotherapy Trials in Met PAC Algenpantucel-L: human PAC cell lines genetically engineered to express αGal, ongoing phase III studies in locally advanced/borderline resectable and resected PAC (IMPRESS, PILLAR) Ipilimumab & Nivolumab combination phase I: dose expansion cohort for met PAC (anti-CTLA4 &PD1 inhibition) MEDI4736 phase I with expansion cohort for met PAC (PDL1 inhibition)

40 Radioimmunotherapy for Met PAC hPAM4, monoclonal antibody targeting an antigen found in > 85% of panc ca Conjugate labeled with yttrium-90 ( 90 Y-hPAM4), a therapeutic β-emitting radionuclide Ocean et al, Cancer May 2012

41 Phase III Trial of Gem +/- 90 Y-hPAM4 in Refractory Met PAC (NCT NCT ) Gemcitabine* + Placebo Metastatic PC, at least 2 prior chemotherapy regimens ECOG 0-1 Gemcitabine* + 90 Y-hPAM4 RANDOMIZERANDOMIZE N= 440 patients *Low dose gemcitabine

42 Recent Negative Trials… PhaseDrugOutcomeRef III GAMMA Gem +/- AMG- 479 (IGF-IR) No differencePress release 08/12 III BAYPANGem +/- Sorafenib Med PFS 5.7 vs 3.8 P=0.902 Gonclaves,Ann Oncol 2012 II LEAPGem _/- Masitinib Med OS 7.7 vs 7.0 HR 0.9, p=0.74 Deplanque GI symposium 2013 IIGem +/- IPI-926Med OS 6.0 vs 5.9 HR NS Press release 01/12 IIGem +/- Vismodegib Med OS 6.3 vs 5.3 HR 0.97 Catenacci ASCO 2012 II/IIIGem +/- Rigosertib No differencePress release 12/13

43 1 st line Randomized Phase II Trials: Met PAC NCTTrial DesignNTargetSponsor Gem/Nab-P +/- PEGPH20132HyaluronHalozyme Gem + nab-P +/- M402148Anti-stromalMomenta Gem + nab-P +/- OMP59R5140Notch inhibitor Stem cells OncoMed Gem +nab-P +/- OGX HSP27OncoGenix Gem +/- MSC B174MEKMerck,EU Gem +/- Afatinib117EGFR, Her2, 4Boehringer, EU Gem +/- TL-11880AngiogenesisTitan Pharm LY chemo(inv choice) 120MyostatinEli-Lilly Carbo+Paclitaxel +/- Reovirus 70RasNCI Gem, Cisplatin +/- Veliparib70PARP (BRCA+)NCI, Lustgarten Gem, Erlotinib +/- Metformin 120MultipleU Amsterdam PEXG +/- Metformin82Stem cellsSan Raffaele

44 RECAP Trial Randomized phase II study, Capecitabine +/- Ruxolitinib N= 138 patients with progressive PAC on 1 line of prior chemotherapy (gem) Primary endpoint: OS ITT HR= 0.79, p=0.12 NS BUT: Subgroup HR=0.47, p=0.005 & 6 month OS 42% vs 11% (Press release 08/13)

45 Ongoing 2 nd /3 rd Line Phase II-III Trials: Met PAC NCTTrial DesignNTarget/DrugSponsor Randomized Phase III MM-398 +/- 5FU/LV 405 (fully enrolled, results pending) Liposomal irinotecan Merrimack Pharm NAPOLI Randomized Phase III 5FU/LV (bolus) vs Glufuosfamide 480Conjugate of ifosfamide Eleison Pharm Randomized Phase I FOLFOX vs Selumetinib +MK MEK, AKTSWOG1115

46 Conclusion Nab-paclitaxel & gem likely favored backbone for development of combination therapies Multiple agents in development, esp phase II 2 nd /3 rd line therapy trials feasible and area for drug development Future looks brighter…

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