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 LAPACT Alberto Sobrero IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro, Genova

Study Title nab®-paclitaxel (Abraxane®) plus gemcitabine in subjects with locally advanced pancreatic cancer (LAPC): An international, open- label, multi-center, Phase 2 study (LAPACT).

Study Objectives Primary Objective Secondary Objectives time to treatment failure (TTF) in induction therapy followed by Investigator’s Choice of treatment Secondary Objectives Disease control rate (DCR) after the first 6 cycles ORR PFS and OS Safety profile QoL Exploratory Objective Changes in circulating nucleic acids correlate with response

Primary Study Endpoints TTF is first dose of study therapy to treatment failure. Treatment failure is discontinuation of study therapy due to disease progression, death (of any cause), or the start of a non- protocol-defined anticancer therapy. Target 5.1  6.6 mo N = 110

Abraxane 125 mg/m2 + Gemcitabine 1000 mg/m2 on Days 1, 8, and 15 Overall Study Design Screening for Eligibility (14 Days) (N = 110) Induction phase Abraxane 125 mg/m2 + Gemcitabine 1000 mg/m2 on Days 1, 8, and 15 6 cycles (28 day/c) CT/MRI If CR, PR, or SD Investigator’s Choice Continue Abraxane + Gemcitabine (PD/tox) Chemoradiotherapy Surgical Intervention CT/MRI Follow-up Period

Inclusion Criteria (1 of 3) Histologically or cytologically confirmed adenocarcinoma of the pancreas. Unresectable pancreatic cancer according to radiographic criteria (CT or MRI scans) or exploration: Superior mesenteric vein and portal vein: occlusion, thrombosis, or encasement extending several centimeters Superior mesenteric artery: tumor abutment > 180 degrees or thrombosis of artery Celiac axis: abutment or encasement of the celiac axis Lymph nodes: involvement Without distant metastasis as defined by whole body CT scan or MRI. ECOG performance status of 0 or 1. Acceptable hematology parameters: Absolute neutrophil count (ANC) ≥ 1500 cell/mm3 Platelet count ≥ 100,000/mm3 Hemoglobin (Hgb) ≥ 9 g/dL

Inclusion Criteria (2 of 3) Acceptable blood chemistry levels: AST/ SGOT and ALT/ SGPT ≤ 2.5 x upper limit of normal range (ULN) Total bilirubin ≤ 1.5 ULN Alkaline phosphatase ≤ 2.5 x ULN Serum albumin > 3 g/dL Serum creatinine ≤ 1.5 ULN

Chemoradiation therapy Chemoradiation therapy consisting of the concurrent use of capecitabine or gemcitabine with radiation according to institutional practice *M - institution treatment plans need to be recorded in source documents to assess if patient completes the Chemoradiation (with start & stop dates)

Table of Events – Induction: Abraxane Plus Gemcitabine (1 of 2) Assessment Reference to Protocol Section Screening/ Baseline Treatment Period Every 28-day Cycle Follow-Up Period Day -14 to Day -1 Day 1 ( ±2 days) Day 8 (±1 days) Day 15 Every 56 days (-3/+7 (starting C1D1) 28-day Follow-up Visit (after last dose of IP) Survival Follow- Up Every 90 Days (± 14 Days) Informed Consent Section 6 X - Medical History, Prior Medication and Procedures Sections 6.1, 6.5 Demographics Section 6.2 AbraxaneAdministration/Accountability Section 4.1.1 Gemcitabine Administration/Accountability Physical Examination Section 6.3 Will be done as per standard of care during the study and as clinically indicated Vital Signs Section 6.4 Pregnancy Test (Serum) Section 6.6 Pregnancy Test (Urine) CT Scan and Any Other Studies Required for Tumor Imaging Section 6.7 Height Section 6.8 Weight

Study Efficacy Induction phase CT/MRI scan with/with-out contrast: every 56 days (-3/+7 days) Investigator’s Choice Part every 56 days (-3/+7 days) and 28-day Follow-up Visit (after the last dose of IP and chemoradiation), and post surgery. *Scans will be done every 56 days (-3/+7 days) until disease progression, withdrawal of consent, lost to follow-up, death (of any cause), or the start of a non-protocol-defined anticancer therapy.

Quality of Life Questionnaires QLQ-C30 and QLQ-PAN26 at: Screening Day 1 of every cycle of A+G 28 Day F/U during the nab-Paclitaxel plus Gemcitabine induction phase and during the Investigator’s choice period.

Pharmacogenomic Analyses: Blood sampling for pharmacogenomic analyses: Collected prior to administration of IP, chemoradiation and/or surgery for ALL subject that undergo surgery as an Investigator’s Choice: just prior to surgery Kit by sponsor/Covance Ship to Covance Tumor tissue for molecular profiling: For All pts that undergo surgery: Surgical specimen formalin-fixed, paraffin-embedded (FFPE) block ort least 15 slides surgical pathology report for the tumor should be sent with the tissue. Samples will be ship to Covance