Lo sviuppo clinico di nab-paclitaxel Lo studio APACT Alessandro Bittoni Scuola di Dottorato di Ricerca- Clinica di Oncologia Medica AOU Ospedali Riuniti - Università Politecnica delle Marche Ancona

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment: Rationale NCCN and ESMO guidelines recommend 5-FU (NCCN: + leucovorin) or Gem as adjuvant chemotherapy options Recurrence rates with adjuvant Gem were 77% and 81% in 2 phase III trials, suggesting a need for improved therapies nab-P + Gem demonstrated superior efficacy vs Gem alone for the treatment of metastatic PC in the phase III MPACT trial Median OS: 8.5 vs 6.7 months; HR 0.72; 95% CI, 0.62 - 0.83; P < 0.001 Median PFS: 5.5 vs 3.7 months; HR 0.69; 95% CI, 0.58 - 0.82; P < 0.001 ORR By independent review: 23% vs 7%; P < 0.001 By investigator review: 29% vs 8%; P < 0.001 5-FU, 5-fluorouracil; ESMO, European Society for Medical Oncology; Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; NCCN, National Comprehensive Cancer Network; ORR, overall response rate; OS, overall survival; PC, pancreatic cancer; PFS, progression-free survival. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162].

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Trial Rationale (cont) The goals of adjuvant therapy are to reduce recurrence and improve DFS and OS following surgery for resectable PC There are few ongoing phase III trials of adjuvant therapy in PC Trial No. Treatment Estimated Enrollment NCT01013649 Gem ± radiotherapy with Cape or 5-FU N ≈ 950 NCT01526135 Gem vs mFolfirinoxa N ≈ 490 NCT01150630b Neoadjuvant and adjuvant Gem ± Cis, Epi, and Cape vs adjuvant Gem N ≈ 370 a Modified: oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, folinic acid 400 mg/m2, 5-fluourouracil 1200 mg/m2/day (no bolus), q2w × 24 weeks. b Phase II/III. 5-FU, 5-fluourouracil; Cape, capecitabine; Cis, cisplatin; DFS, disease-free survival; Epi, epirubicin; Gem, gemcitabine; nab-P, nab-paclitaxel; OS, overall survival; PC, pancreatic cancer; q2w, every 2 weeks. 3

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment: Objectives Primary To compare disease-free survival between patients randomized to nab-P + Gem vs Gem alone Secondary Assess OS between patients randomized to nab-P + Gem vs Gem alone Assess safety and tolerability of the 2 treatment regimens Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer. 4

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment: Study Design Max 12 weeks from surgery Randomization 1:1 Stratification Factors: resection status (R0 vs R1), nodal status (LN- vs LN+), geographical region (North America vs Europe vs Australia vs Asia Pacific) Primary Endpoint: independently assessed DFS (defined as time from randomization to disease recurrence or death) Secondary Endpoint: OS, safety Exploratory Endpoints: Molecular profiling of tumor tissue to correlate tumor heterogeneity with clinical outcome Quality of life as measured by EORTC QLQ-C30 and EORTC QLQ-PAN26 DFS, disease-free survival; EORTC, European Organisation for Research and Treatment of Cancer; Gem, gemcitabine; LN, lymph node; nab-P, nab-paclitaxel; OS, overall survival; PC, pancreatic cancer; QLQ, quality of life questionnaire; qw 3/4, first 3 of 4 weeks. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162]. 5

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Key Inclusion Criteria Histologically confirmed resected pancreatic adenocarcinoma with macroscopic complete resection (R0 and R1) Stage T1-3, N0-1, M0 Able to begin treatment ≤ 12 weeks after resection Age ≥ 18 years ECOG PS 0 or 1 ECOG PS, Eastern Cooperative Oncology Group performance status; Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162]. 6

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Key Inclusion Criteria (cont) Adequate hematologic and blood chemistry levels Absolute neutrophil count ≥ 1500 cells/mm3 Platelet count ≥ 100,000/mm3 Hemoglobin ≥ 9 mg/dL AST/SGOT and ALT/SGPT ≤ 2.5 × ULN Total bilirubin ≤ ULN Serum creatinine clearance ≥ 50 mL/min/1.73 m2 CA19-9 < 100 U/mL assessed within 14 days of randomization ALT, alanine aminotransferase; AST, aspartate aminotransferase; Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162]. 7

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Key Exclusion Criteria Neuroendocrine tumors Prior neoadjuvant treatment or radiation therapy for pancreatic adenocarcinoma Presence or history of metastatic PC Any other malignancy within ≤ 5 years of randomization, excluding adequately treated in situ cervical, uterine, or nonmelanomatous skin cancer Treatment should have been completed 6 months before randomization Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer. 8

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Key Exclusion Criteria (cont) Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy Infection with hepatitis B or C History of HIV or use of immuno/myelosuppressive medications that could increase the risk of neutropenia History of hypersensitivity to study drugs Gem, gemcitabine; HIV, human immunodeficiency virus; nab-P, nab-paclitaxel; PC, pancreatic cancer. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162]. 9

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Dose Modifications Two dose reductions are allowed for hematologic and other toxicities Patients will be discontinued from the study if more than 2 dose reductions are required Dose Levela nab-P, mg/m2 Gem, mg/m2 Starting dose 125 1000 −1 100 800 −2 75 600 a Dose reductions may or may not be concomitant in the nab-P + Gem arm. Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162]. 10

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Patient Follow-up DFS CT/MRI scans will be performed at screening, every 8 weeks for the first 24 weeks, every 12 weeks for the first 3 years, then every 24 weeks until disease recurrence for up to 5 years from last treatment Patients who discontinue treatment in the absence of disease recurrence should undergo repeat imaging until disease recurrence, death, or the start of new therapy Post-treatment OS will be monitored every 3 months until death, withdrawal of consent, or end of study A data monitoring committee is in place for this trial CT, computed tomography; DFS, disease-free survival; Gem, gemcitabine; MRI, magnetic resonance imaging; nab-P, nab-paclitaxel; OS, overall survival; PC, pancreatic cancer. 11

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Statistical Analysis DFS was reported with a median of 13.4 months and 14.3 months for patients with surgically resected pancreatic adenocarcinoma who received Gem as adjuvant therapy in 2 separate randomized phase III studies The planned enrollment of ≈ 800 in this trial was selected based on the following assumptions Gem will result in a median DFS of 14 months nab-P + Gem will result in a median DFS of 19 months, representing an HR of 0.74 At least 489 DFS events from 800 patients would allow 90% power to detect the HR of 0.74 at a 2-sided significance level of 0.05 DFS, disease-free survival; Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; PC, pancreatic cancer. 12

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Statistical Analysis (cont) Two interim efficacy analyses are planned The first will be conducted at 33% information time (ie, after 163 DFS events) to assess futility The second will assess both futility and superiority at either 70% information time (ie, after 342 DFS events) or the enrollment of 800 patients, whichever is later One interim safety analysis is planned after 100 patients are treated for at least 2 cycles Patient enrollment is ongoing DFS, disease-free survival; Gem, gemcitabine; nab-P, nab-paclitaxel; PC, pancreatic cancer. Tempero MA, Cardin D, Biankin A, et al. APACT: a phase III, multicenter, open-label, randomized study of nab® -paclitaxel plus gemcitabine vs gemcitabine alone as adjuvant therapy in patients with surgically resected pancreatic adenocarcinoma. Poster presented at: American Society of Clinical Oncology Annual Meeting; May 30 - Jun 3, 2014; Chicago, IL [abstract TPS4162]. 13

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Global Enrolment

APACT : Phase III Trial of nab-P + Gem vs Gem as Adjuvant PC Treatment Italian Enrolment

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