OVERVIEW DAGLI STUDI CLINICI CON NAB-PACLITAXEL Studio GAP. Alberto Zaniboni. Oncologia Medica, Fondazione Poliambulanza Brescia

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1 OVERVIEW DAGLI STUDI CLINICI CON NAB-PACLITAXEL Studio GAP Alberto Zaniboni Oncologia Medica, Fondazione Poliambulanza Brescia

2 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 ClinicalTrials.gov Identifier: NCT Principal Investigator: Stefano Cascinu MD Sponsor non profit: Fondazione GISCAD per la ricerca sui Tumori Data Center: Clinical Trial Unit National Cancer Institute of Naples

3 Background and Rationale 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 it is the reference arm in comparison with different combination regimens 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 unresectabledisease. May be clinically relevant since around one third of pancreatic cancer patients are diagnosed at this stage of disease.

4 Study Design Multicentre, open-label, randomized, comparative phase II trial in patients with locally advanced unresectable pancreatic cancer. Subjects will be randomized in a : 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, 24 patients are required for the final analysis. With 24 enrolled patients andafter 09 events (progressionor 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 6% power to detect a 0.69 HR (similar to the advantage found in the metastatic trial).

5 Study Design ARM A Nab-paclitaxel + gemcitabine 3 cycles Pts with locally advanced pancreatic cancer R ALL Capecitabine + RT 5 weeks ARM B Gemcitabine 3 cycles IF PD 2 nd line chemotherapy Treatment Schedule ARM A: nab-paclitaxel 25 mg/mq over 30 min and gemcitabine 000 mg/mqweekly on days, 8 and 5 of a 28-day cycle. ARM B: Gemcitabine 000 mg/mqover 30 minutes on days, 8 and 5 of a 28-day cycle. Patients not progressing after 3 cycles will eventually receive a combination of capecitabine 600 mg/mqbid and radiotherapy for 5 weeks

6 Study population Locally advanced unresectable pancreatic cancer patients Primary Study Objective 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 Primary Outcome Measure Progression Rate Secondary Study Objectives Quality of Response Safety profile Progression Free Survival (PFS) Overall Survival (OS)

7 Main Inclusion Criteria Written informed consent Age < 75 years Histologically/cytologically confirmed locally advanced, unresectable pancreatic cancer At least one lesion measurable with CT or MRI scan Performance Status (ECOG) 0- at study entry Life expectancy of at least 3 months Adequate marrow, liver and renal function Effective contraception if the risk of conception exists Main Exclusion Criteria Previous chemotherapy or radiotherapy for pancreatic cancer CNS metastases 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

8 Centers n= 43 Actived 40 Active 24 Awaiting activation 3 Randomizationsn= 65 Arm n Gemcitabine 3 Gemcitabine Nab-Paclitaxel 34

9 Recruitment by site GEM/ABRAXANE GEMCITABINE

10 Patient Characteristics Gemcitabine n=3 Gemcitabine Nab-Paclitaxel n=34 Total n=65 Age median Gender, n (%) male 4 (48.3%) 5 (5.7%) 29 female 7 (47.2%) 9 (52.8%) 36

11 Trend expected observed

12 Summary of SAEs Gemcitabine (n=2) Gastrointestinal disorders Diarrhea Duodenal preforation - Gemcitabine/ Nab-Paclitaxel (n=7) Total (n=29) General disorders Fatigue Other, cachexia - - Hepatobiliary disorders Other: cholangitis - Investigations Blood bilirubin increased 2-2 Metabolism and nutrition disorders Hyperglycemia - Nervous system disorders Stroke - Respiratory, thoracic and mediastinal disorders Dyspnea - Vascular disorders Thromboembolic event - All 7 4

13 DETERMINA 26 gennaio 205 Regime di rimborsabilita' e prezzo a seguito di nuove indicazioni terapeutiche del medicinale per uso umano «Abraxane» (paclitaxel-albumina). (Determina n. 57/205). Art. Classificazione ai fini della rimborsabilita' Le nuove indicazioni terapeutiche: Abraxane in associazione con gemcitabina e' indicato per il trattamento di prima linea di pazienti adulti con adenocarcinoma metastatico del pancreas del medicinale ABRAXANE (paclitaxel-albumina) Innovazione terapeutica importante per l'indicazione: in associazione con gemcitabina per il trattamento di prima linea di pazienti adulti con adenocarcinoma metastatico del pancreas, senza applicazione delle riduzioni temporanee di legge.