GAP (Gemcitabine Abraxane Pancreas) Trial. Codice Eudract Sponsor non profit: Rossana Berardi, MD Alessandro Bittoni, MD

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1 A Phase II randomized trial comparing a combination of Abraxane and Gemcitabine versus Gemcitabine alone as first line treatment in locally advanced unresectable pancreatic cancer. GAP (Gemcitabine Abraxane Pancreas) Trial Codice Eudract Sponsor non profit: Principal Investigator: Co-Investigators: Study coordinators: Data Center: Statistical analysis Statistician: Stefano Cascinu Carlo Barone, MD Rossana Berardi, MD Alessandro Bittoni, MD Luciano Frontini, MD Franco Perrone, MD Clinical Trials Unit, National Cancer Institute of Naples, Italy Medical Statistics, Second University of Naples Ciro Gallo, MD Versione del 12/09/2013

2 CONTACTS Fondazione GISCAD Silvia Rota, DM Via Vittorio Alfieri, Parabiago (MI) Tel fax e-mai:l Investigators Stefano Cascinu Carlo Barone Oncologia Medica Policlinico Gemelli Roma Rossana Berardi Alessandro Bittoni Study Coordinators Luciano Frontini, MD Segretario Fondazione GISCAD Parabiago (MI) Francesco Perrone, MD Direttore Unità Sperimentazioni Cliniche Napoli Data Center Unità Sperimentazioni cliniche Maria Carmela Piccirillo, MD Istituto Nazionale Tumori di Napoli Via M.Semmola Napoli Tel Fax Statistical analysis Ciro Gallo, MD Statistica Medica Seconda Università degli Studi di Napoli

3 SYNOPSIS Protocol Title Acronym Clinical Trial Phase Background and Rationale A Phase II randomized trial comparing a combination of Abraxane and Gemcitabine versus Gemcitabine alone as first line treatment in locally advanced unresectable pancreatic cancer. GAP (Gemcitabine Abraxane Pancreas) Trial Randomized, phase II trial, Pancreatic cancer is the fourth cause of cancer mortality both in men and women. It is generally diagnosed in the advanced setting and only 10-15% present with resectable disease. About 25-30% of the advanced patients present with locally advanced disease without metastases. Median survival for this group of patients is around is around 11 months slightly better than that of patients with metastatic disease (around 8 months) While chemotherapy is the cornerstone of treatment for patients with metastatic disease, the optimal treatment of locally advanced unresectable pancreatic adenocarcinoma is not clearly defined yet. There are in fact different treatment approaches to locally advanced pancreatic cancer management, including single agent or multi-agent chemotherapy, chemotherapy followed by radiochemotherapy or immediate concurrent chemoradiation. Therefore, while in US most of the patients receive immediate chemoradiation, European patients receive chemoradiation only if the tumour remains controlled by chemotherapy for at least three months, according to the French experience Nevertheless, at present time, the treatment options for locally advanced pancreatic cancer confer modest results. Generally, gemcitabine alone is considered a reasonable approach for advanced pancreatic cancer patients. Although we do not have specific data on the activity of gemcitabine alone in this setting of patients, in several trials such as a phase II randomised trial running at the Cancer Research UK it is the reference arm in comparison with a combination with capecitabine as induction chemotherapy. However, we can expect a disease control in less than 50% of the patients. Therefore, we need a chemotherapeutic regimen able to prevent as much as possible a progression of the disease. Nab-paclitaxel (Abraxane) recently demonstrated an interesting activity profile in advanced pancreatic cancer. A combination of Nab-paclitaxel and gemcitabine has been demonstrated superior to gemcitabine alone in metastatic patients. However, data supporting its use also in locally advanced unresectable disease. May be clinically relevant since around one third of pancreatic cancer patients are diagnosed at this stage of disease. Study Period Planned enrolment period: 26 months

4 Duration of follow up: 6 months Study population Primary Study Objective Primary Outcome Measure Secondary Study Objectives Study Design Treatment Schedule Locally advanced unresectable pancreatic cancer patients To explore whether nab-paclitaxel in combination with gemcitabine may reduce the progression rate versus gemcitabine alone in patients with locally advanced unresectable pancreatic cancer and be worthy of further studies. Progression Rate Quality of Response Safety profile Progression Free Survival (PFS) Overall Survival (OS) Multicentre, open-label, randomized, comparative phase II trial in patients with locally advanced unresectable pancreatic cancer. Subjects will be randomized in a 1:1 ratio to receive nab-paclitaxel/gemcitabine (arm A) or gemcitabine alone (arm B), as first-line chemotherapy. Assuming an expected progression rate in the control arm of 40% and an auspicated progression rate in the experimental arm of 20%,with one-tailed alpha=0.05, 80% power, 124 patients are required for the final analysis. With 124 enrolled patients and after 109 events (progression or death without progression) will be observed, the study will have 80% power, with one-tailed alpha=0.05, to detect a 0.62 HR and 61% power to detect a 0.69 HR (similar to the advantage found in the metastatic trial). ARM A: nab-paclitaxel 125 mg/mq over 30 min and gemcitabine 1000 mg/mq weekly on days 1, 8 and 15 of a 28-day cycle. ARM B: Gemcitabine 1000 mg/mq over 30 minutes on days 1, 8 and 15 of a 28-day cycle. All patients not progressing after 3 cycles will receive a combination of capecitabine 600 mg/mq BID and radiotherapy for 5 weeks Main Inclusion Criteria Written informed consent Age >18 < 75 years Histologically/cytologically confirmed locally advanced, unresectable pancreatic cancer At least one lesion measurable with CT or MRI scan Performance Status (ECOG) 0-1 at study entry Life expectancy of at least 3 months Adequate marrow, liver and renal function

5 Effective contraception if the risk of conception exists (in the Informed Consent for the patients the descriptions of possible contraceptives is reported) Main Exclusion Criteria Previous chemotherapy or radiotherapy for pancreatic cancer Severe cardiovascular disease Thrombotic or embolic events Acute or subacute intestinal occlusion or history of inflammatory bowel disease Known hypersensitivity to study drug Known drugs or alcohol abuse Pregnant or breastfeeding women Previous or concurrent malignancy; except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumors treated curatively and with evidence of no recurrence for at least 5 years prior to randomization Unable to sign informed consent