Lo sviluppo clinico di nab-paclitaxel Discussant: Nicola Silvestris III Sessione - Il carcinoma del pancreas Chair: C. Pinto - Moderatori: F. de Braud, A. Falcone Lo sviluppo clinico di nab-paclitaxel Discussant: Nicola Silvestris Studio PACT-19 Michele Reni IRCCS Ospedale San Raffaele, Milano • Studio PACT-19 M. Reni • Studio NABUCCO F. Di Costanzo • Studio GAP A. Zaniboni • Studio APACT A. Bittoni • Studio LAPACT A. Sobrero

PACT-19 BACKGROUND - 1 PEFG was the 1st regimen to significantly  PFS & OS over GEM in a phase III trial GEM-nab-PTX significantly  OS over GEM in a phase III study in M+ PA N Engl J Med. 2013 Oct 31;369(18):1691-703

PACT-19 BACKGROUND - 2 Taxanes yield synergism with platinum compounds, GEM and fluoropyrimidines :  intra-cellular activity of thymidine phosphorylase thus  the conversion of capecitabine into FU1  integration of gem-triphosphate & its interaction with mRNA2  multi-drug resistance proteins thus  cytotoxicity of DDP3 Sawada N, et al CCR 1998; 4: 1013-1019 Ricotti L, et al CCR 2003; 9: 900-905 Maeda S, et al Cancer Sci 2004: 95: 679-684

PACT-19 - OBJECTIVE to define the RP2D of nab-PTX combined with cisplatin, capecitabine, and GEM (PAXG regimen; phase Ib study) Secondary endpoints were OS, PFS, response rate, resection rate, toxicity

PAXG regimen phase I GEM (800 mg/m2 day 1, 14) CDDP (30 mg/m2 day 1, 14) CAPE (1250 mg/m2 day 1 to 28) nab-paclitaxel : level 1 100 mg/m2 level 2 125 mg/m2 level 3 150 mg/m2

PACT-19 MTD: dose at which > 2 of 3-6 pts develop DLT during the 1st month of therapy DLT G≥4 neutropenia lasting ≥ 7 days; G≥3 febrile neutropenia, PLT, nausea diarrhea, or vomiting fever ≥38.5°C, thrombocytopenia G≥2 neurological toxicity failure to recover to grade ≤1 toxicity or to baseline values after delaying the initiation of next cycle by > 2 weeks

ELIGIBILITY CRITERIA Chemo-naive patients age 18-75 yr Karnofsky PS >70 pathological diagnosis of PA locally advanced (stage III) adequate baseline organ functions

PACT-19 BACKGROUND - 3 PDXG PEXG PEFG (n=23) (n=75) (n=59) mOS 17.9 16.7 16.4 1yOS 74% 64% 66% 2yOS 35% 27% 20% 5yOS 17% 3% 3%

TRIAL POPULATION Characteristic N° (%) Patients enrolled (Dec 12-Apr 14) 24 Median age (range) 63 (50-75) Male 17 (71) KPS 90-100 21 (88) Biliary Stent 8 (33) Disease Site Head 17 (71) Median CA19.9 (range) 295 (1-4591) > ULN 19 (79) Dose Level Level 1 3 Level 2 5 Level 3 16

TOXICITY Grade 3 (%) Grade 4 (%) FFX Neutropenia 29% 17% 46% Febrile Neutropenia 0 0 5% Platelets 0 0 9% Hemoglobin 13% 0 8% Nausea 4% 0 nr Vomiting 0 0 15% Diarrhea 4% 0 13% Fatigue 17% 0 24% Hand-foot syndrome 8% 0 0 Neuropathy 0 0 9% Thromboembolism 0 0 7%

#4 – BG; 63 y

#9 – BR; 67 y

#6 – BM; 53 y

#10 – BA; 56 y

RESULTS TC N=24 PET N=21  CA19.9 N=19 LEVEL N PR SD CR >90% >50% 100 3 2 1 125 5 - 150 16 10 6 7 TOTAL 24 17 9 8 71% 29% 43% 48% 9% 42% 53% PDXG 23 61% 26% 56% 28%

RESULTS PAXG PDXG PEXG PEFG Surgery 25% 13% 15% 14% N0 80% 67% 55% 63% mFU (12 alive) 16.4 + mOS 14.2 + 17.9 16.4 16.7 mPFS (5 PF) 11.5 + 9.6 10.4 10.4 PFS-6 96% 78% 80% 81%

open-label, randomised, monocentric PACT-19 - PHASE II open-label, randomised, monocentric Stage III and IV R PAXG Gem+nab-paclitaxel