PARP Inhibition. DNA Repair Machinery

Transcription

1 UNIVERSITY UNIVERSTY OF TORINO OLOGICAL SCIENCES PARP Inhibition Silvia Novello, MD PhD University of Torino Italy Thoracic Oncology Unit OLOGICAL SCIENCES DNA Repair Machinery An intact DNA repair machinery is critical to withstand damage to cellular DNA DNA are constantly subject to DNA damage Multiple DNA repair mechanisms have been described Base excision repair Nucleotide excision repair Mismatch repair Recombination repair Translesion synthesis Beljanski et al, Mol Pharmacol 2004

2 DNA Repair Machinery and Cancer A number of tumors are characterized by the loss of functionality in one or several DNA repair pathways Some breast and ovarian cancers: BRCA1 or BRCA2 repression/mutation, which are essential genes in the homologous recombination repair pathway Colon cancer: methylated promoter/loss of hmlh1 or MSH2 expression, essential proteins in the mismatch repair pathway Gliomas: methylated promoter/loss of MGMT expression Lung cancer: loss of ERCC1 expression Matteo Giaj Levra, Ken André Olaussen, Silvia Novello, Jean Charles Soria Current Pharmaceutical Design 2012 Submitted Paper DNA Repair Pathway Pathways Lesions Biomarkers Modified from Ding et al. Trends in Pharm. Sciences, 2006

3 At least 17 members of PARP family have been described PARP-1 localizes to the site of DNA damage and recruits proteins that 18 mediate members repair of PARP super-family identified to date PARP-1 Double abundant knockout nuclear of PARP enzyme 1 & activated 2 results by and binds with in embryonal high affinity lethality to DNA single to mice and double strand breaks via N zinc fingers Dantzer et al, Biochemistry 2000; McCabe et al, Cancer Res 2006 PARP-1 essential for the repair of damaged bases and single strand breaks via the Base Excision repair pathway PARP-1 Role of PARP 1 in BER/SSBR A - DNA binding domain ZF D - Automodification domain ZF NLS C BRCT B - Nuclear localisation signal E F - Catalytic domain C XRCC1 Courtesy of JC Soria OLOGICAL SCIENCES Consequence of PARP Inhibition The affinity of PARP1 for platinum modified DNA in vitro has been established using modified cisplatin analogues to synthesize 25 bp DNA duplexes carrying platinum intrastrand crosslinks 1 PARP could facilitate the dissociation of nuclear proteins from platinum modified DNA that in turn could facilitate recruitment of DNA repair proteins 2 PARP inhibitors also radiosensitize cancer cells 3 1 Guggenheim ER et al, Chembiochem 2009; 2 Nguewa PA Med Chem 2006; 3 Calabrese CR et al J Natl Cancer Inst 2004

4 Powell C et al, Cancer Treat Review 2010 OLOGICAL SCIENCES Veliparib + XRT in H460 Tumors Albert et al, Clin Cancer Res, 2007.

5 PARP 1 Inhibitors in Development Company Product (Route) Single/Combination Development BiPar Sciences (Sanofi Aventis) BS 201/Iniparib (IV) Combination with: RT, GemCarbo, CisGem, temozolomide Phase III Astra Zeneca AZD2281/Oliparib Single/Combination Phase III (oral) Pfizer AG (IV) Single/Combination Phase II Abbott ABT 888/Veliparib Single/Combination Phase I/II (oral) Cephalon CEP 9722 (IV) Combination with temozolomide Phase I MGI Pharma GPI (oral) Combination with Phase I temozolomide Merck MK 4827 (oral) Single Phase I Inotek/Genentech INO 1001 (IV) Single/Combination with temozolomide Phase I Lung Trials Ph II closed, Ph III ongoing Some Designs None None None None None None OLOGICAL SCIENCES Olaparib Phase I Trial Expansion phase: enriched for BRCA 1 or 2 mutation carriers (N=22) Daily oral dosing 19 evaluable patients with BRCA mutation 12 patients (63%) had meaningful clinical benefit 9 patients had an objective partial response Ovarian, breast and prostate cancers Fong PC et al, N Engl J Med, 2009

6 Olaparib Phase I Trial Fong PC et al, N Engl J Med, 2009 OLOGICAL SCIENCES UNIVERSITY UNIVERSTY OF TORINO Olaparib Phase I Trial Most toxicities were Grade 1 2 ( 95%) Most common toxicities were: nausea 28%, vomiting 18%, dysgeusia 13%, anorexia 12% fatigue 28% Grade 3 4 toxicities were rare: myelosuppression ( 5%) nausea and vomiting (2 3%) CNS: dizziness or mood changes (2 3%) No increase in the frequency of grade of adverse events was observed comparing known BRCA1 or BRCA2 mutation carriers with non carriers Fong PC et al. NEJM 2009

7 Olaparib as Monotherapy: Phase II Trials OLOGICAL SCIENCES Ovarian Cancer N=57 patients with BRCA 1/2 mutation ORR: 38% 400mg bd; 13% 100mg bd Grade 3,4 toxicities in 51% 100mg bd and 58% 400mg bd (nausea, fatigue) Audeh MW et al. The Lancet 2010 Refractory Breast Cancer N=54 patients with BRCA 1/2 mutation ORR: 41% 400mg bd; 22% 100mg bd PFS: 5.7 mo 400mg bd; 3.8mo 100mg Good Tolerability (grade 3 tox in 5 pts as nausea, fatigue, anemia) Tutt A et al. The Lancet 2010 OLOGICAL SCIENCES Olaparib as Monotherapy: Phase II Trials ICEBERG 3 phase II randomized Metastatic Ovarian Cancer Carrying BRCAmutation Audeh MW et al. The Lancet 2010 Olaparib (400 or 200 mg) pegylated liposomial Doxorubicin Refractory Breast Cancer N=54 patients with BRCA 1/2 mutation ORR: 41% 400mg bd; 22% 100mg bd PFS: 5.7 mo 400mg bd; 3.8 mo 100mg Good Tolerability (grade 3 tox in 5 pts as nausea, fatigue, anemia) Tutt A et al. The Lancet 2010

8 Platinum + PARP Inhibition Platinum compounds exert cellular cytotoxicity Enhanced DNA repair capacity is a known mechanism for resistance to platinum Combination ofparp inhibitor with platinum has demonstrated pre clinical synergy Miknyoczki SJ et al, MolCancerTher2003; Nguewa PA et al Med Chem OLOGICAL SCIENCES Veliparib + Platinum Cisplatin Carboplatin Donawho et al, Clin Cancer Res, 2007

9 BSI 201 and Breast Cancer Randomized phase II study Primary objective Clinical benefit rate Metastatic Breast cancer Triple negative disease N=123 patients Carboplatin AUC2 Gemcitabine 1000mg/mq days 1,8 every 21 days BSI 201 5,6 mg/kg i.v. biweekly on days 1, 4, 8 and 11 Carboplatin AUC2 Gemcitabine 1000mg/mq days 1,8 every 21 days ASCO 2009 O Shaughnessy J et al., abstract 3; O Shaughnessy J et al., Cancer Res 2009, abst 3122; NEJM 2011 Results: RR 52% vs. 32% Clinical benefit 56% vs. 34% PFS 5.9 vs 3.6 mo (HR 0.59; 95% CI, 039to ; P = 001) 0.01) OS 12.3 mo vs 7.7 mo (HR 0.57; 95% CI, 0.36 to 0.90; P = 0.01) OLOGICAL SCIENCES O Shaughnessy J et al., NEJM 2011 BSI 201 and Breast Cancer

10 O Shaughnessy J et al., NEJM 2011 BSI 201 and Breast Cancer OLOGICAL SCIENCES PARP Inhibitors in NSCLC: Potential Roles Usein combination with platinum based regimens Platinum compounds continue to be the cornerstone of treatment of both SCLC and NSCLC Use in combination with radiotherapy Monotherapy is unlikely to be useful since BRCA mutation are not noted frequently in lung cancer

11 Results of a Phase2 Study of Gemcitabine/Cisplatin/iniparib (GCI) Versus Gemcitabine/Cisplatin (GC) in Patients with Advanced NSCLC Novello S, 1 Felip E, 2 Barlesi F, 3 Mazieres J, 4 Zalcman G, 5 von Pawel J, 6 Reck M, 7 Cappuzzo F, 8 Ferry D 9 and Soria JC 10 1 University of Torino San Luigi Hospital Orbassano, Torino/ITALY, 2 Vall d'hebron Institute of Oncology, Barcelona/SPAIN, 3 Hôpital Nord, Marseille/FRANCE, 4 CHU Toulouse Hopital Larrey, Toulouse/FRANCE, 5 Caen University Hospital/FRANCE, 6 Asklepios Fachkliniken München-Gauting, Gauting/GERMANY, 7 Hospital Grosshansdorf, Grosshansdorf/GERMANY, 8 Istituto Toscano Tumori-Ospedale Civile, Livorno/ITALY, 9 New Cross Hospital, Wolverhampton/UNITED KINGDOM, 10 Institut Gustave Roussy, Villejuif/FRANCE OLOGICAL SCIENCES Background Backbone upfront therapy for inoperable non small cell lung cancer (NSCLC) is platinum based chemotherapy Gemcitabine/cisplatin (GC) is a widely used regimen In a Phase 3 trial (N=863) in patients with NSCLC treated with GC 1 Overall survival (OS) was10.3 months (1 year survival rate, 41.9%) Progression free survival (PFS) was 5.1 months Objective response rate (ORR) was 28.2% Rationale for iniparib (BSI 201) in NSCLC A novel, investigational anticancer agent Preclinical studies with iniparib have shown: 2 5 Induction of g H2AX marker of DNA damage Does not inhibit PARP1/2 at physiologic drug concentrations Potentiation of cell cycle arrest induced by DNA damaging agents No potentiation of chemotherapy related toxicities observed when combined with gemcitabine/carboplatin 6 1. Scagliotti GV, et al. J Clin Oncol 2008;26: ; 2. Ossovskaya V, et al. SABCS 2010, Abstr P ; 3. Ossovskaya V, et al. AACR 2009, Abstr 5552; 4. Ossovskaya V, et al. AACR 2011, Abstr LB-401; 5. Ji J, et al. AACR 2011, Abstr 4527; 6. O Shaughnessy J, et al. N Engl J Med 2011; 364:

12 O Study Design Multi-center, multi-national, randomized open-label Phase 2 (N=119) Study Population Untreated stage IV NSCLC ECOG PS 0 1 Measurable disease Randomization stratified by: - squamous vs. non-squamous - ever smoker vs. never Study Objectives* R 2:1 Gem/Cis + Iniparib (N=80) Gemcitabine 1250 mg/m 2 iv d 1, 8 Cisplatin 75 mg/m 2 iv d 1 Iniparib 5.6 mg/kg iv d 1, 4, 8, day cycles Gem/Cis (N=39) Gemcitabine 1250 mg/m 2 iv d 1, 8 Cisplatin 75 mg/m 2 iv d 1 21-day cycles Primary endpoint: ORR (RECIST 1.1; investigator assessed) Secondary endpoints: Safety, PFS, OS Exploratory molecular substudy: Biomarker analysis; PD ECOG PS, Eastern Cooperative Oncology Group performance status; Gem/Cis, gemcitabine/cisplatin; ORR, overall response rate; OS, overall survival; PD, pharmacodynamics; PFS, progression-free survival. *Efficacy populations intent-to-treat (ITT) all randomized patients. 6 Cycles max with no maintenance phase NCT OLOGICAL SCIENCES GC (N=39) GCI (N=80*) All Patients (N=119) Age, years median (range) 58 (29 73) 59 (37 73) 59 (29 73) ECOG PS, % Patient Baseline Characteristics 0/1 49/51 61/39 57/43 Male gender, % Smoking status, % Smoker/never smoker 90/10 89/11 89/11 Stage at diagnosis, % Stage I/III/IV 3/8/90 1/3/96 2/4/94 Histology, n (%) Adenocarcinoma 28 (72) 57 (71) 85 (71) Squamous cell carcinoma 5 (13) 10 (13) 15 (13) Large cell carcinoma 5 (13) 6 (8) 11 (9) Other 1 (3) 7 (9) 8 (7) *2 patients on the GCI arm were randomized but not treated.

13 Summary of Drug Exposure (Safety Population) Relative dose intensity, median (%) GC (N=39) GCI (N=78) Gemcitabine (G) Cisplatin (C) Iniparib (I) 91 Cycles completed, n (%) (33) 19 (24) (23) 20 (26) (44) 39 (50) OLOGICAL SCIENCES Response Rates (ITT Population) Best response, n (%)* GC (N=39) GCI (N=80) Complete response (CR) 0 (0) 1 (1) Partial response (PR) 10 (26) 15 (19) Stable disease (SD) 17 (44) 44 (55) Progressive disease (PD) 8 (21) 11 (14) Not evaluable (NE) 4 (10) 9 (11) ORR (CR + PR) 26% 20% (95% CI) (13 42) (13 32) *According to RECIST 1.1: Confirmation of response after 4 weeks required; SD required 35 days after first dose. No differences in response by subgroups were seen (data not shown).

14 Max. change from baseline (% %) Best Target Lesion Response* CR PR SD/PD/NE GC Order of subjects *In patients with post-baseline tumor assessments. Max. change from baseline (% %) GCI Order of subjects OLOGICAL SCIENCES UNIVERSITY UNIVERSTY OF TORINO l Probability of surviva Progression Free Survival (ITT Population) 100 GC GCI (N=39) (N=80) 90 Median PFS, months (95% CI) (2.8, 5.6) (4.6, 6.6) HR (95% CI) 0.89 (0.56, 1.41) 70 p-value Time (Months) Number at Risk G/C G/C/I Median follow up time for PFS was 4.1 months

15 OLOGICAL SCIENCES UNIVERSITY UNIVERSTY OF TORINO Probability of surviva al Preliminary Overall Survival (ITT Population) 100 GC GCI (N=39) (N=80) 90 Median OS, months (95% CI) (5.5, NE) (8.9, NE) HR (95% CI) 0.75 (0.44, 1.27) 70 p-value Time (Months) Number at Risk G/C G/C/I At the time of the analysis 56% of patients in GC and 48% in GCI were dead Median follow up time for OS was 8.4 months OLOGICAL SCIENCES Safety Deaths within 30 days for GC vs. GCI arms Due to adverse events (AEs): 2 (5%) vs. 3 (4%) Due to disease progression: 1 (3%) vs. 2 (3%) Summary of treatment emergent AEs (TEAEs): *N=39 and N=78 are the safety populations for the GC and GCI arms, respectively. GC (N=39)* n (%) GCI (N=78)* n (%) Patients with any Grade 3/4 TEAE 32 (82) 66 (85) Patients with any related Grade 3/4 TEAE 25 (64) 51 (65) Patients with any treatment-emergent SAE 17 (44) 40 (51)

16 Treatment Emergent Adverse Events* GC (N=39) GCI (N=78) Adverse Event All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%) Neutropenia 18 (46) 15 (39) 34 (44) 28 (36) Febrile neutropenia 3 (8) 3 (8) 0 0 Thrombocytopenia 10 (26) 9 (23) 19 (24) 17 (22) Anemia 11 (28) 4 (10) 23 (30) 12 (15) Nausea 34 (87) 1 (3) 49 (63) 11 (14) Asthenia 31 (80) 11 (28) 52 (67) 6 (8) Decreased appetite 16 (41) 4 (10) 33 (42) 8 (10) Vomiting 16 (41) 3(8) 29 (37) 6(8) Hypertension 9 (23) 3 (8) 12 (15) 6 (8) Hyponatremia 6 (15) 6 (15) 5 (6) 5 (6) Fatigue 4 (10) 2 (5) 11 (14) 4 (5) Pulmonary embolism 3 (8) 3 (8) 5 (6) 5 (6) Hypokalemia 2 (5) 2 (5) 4 (5) 4 (5) * 5% Grade 3/4 in GCI arm except for febrile neutropenia. OLOGICAL SCIENCES Conclusions for Phase II Trial Addition of iniparib to GC did not improve ORR in this population of patients with NSCLC Caution should be used when interpreting the 1.4-month increase in median PFS and preliminary 2.7 months in median OS seen in the GCI vs. GC arm due to baseline imbalances in PS and gender distribution PFS and OS in the control arm are below published efficacy for gemcitabine and cisplatin in NSCLC The toxicity profile of GCI was similar to that observed with GC alone Biomarker studies are ongoing to potentially define a subgroup of patients that may benefit from iniparib treatment

17 O Phase 3 Squamous Cell Lung Cancer Study International, Open-label Patient Population: Advanced SCC Endpoints: Primary: OS Secondary: PFS, TTP, ORR, safety/tolerability, QoL Doses: Gemcitabine 1000 mg/m 2 D 1 & 8 + Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk N= 825 (planned) R 1:1 Gemcitabine + Carboplatin (G/C) Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks) Patients may remain on study after 6 cycles if there is no evidence of PD or the presence of DLTs G/C + iniparib First Patient Enrolled: March 5, OLOGICAL SCIENCES Conclusions PARP inhibition is one of the novel strategies for the treatment of cancer Early phase clinical trials have demonstrated good tolerability of PARP inhibitors and promising efficacy Studies with PARP inhibitors are underway in NSCLC