1. 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

2. 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, ; P < 0.001
Median PFS: 5.5 vs 3.7 months; HR 0.69; 95% CI, ; 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].

3. 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
NCT
Gem ± radiotherapy with Cape or 5-FU
N ≈ 950
NCT
Gem vs mFolfirinoxa
N ≈ 490
NCT b
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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

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

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

16. Grazie per l’attenzione!