Aims -  To determine the activity and safety of gemcitabine, cisplatin and panitumumab in patients with K-ras wild-type locally advanced, metastatic or recurrent biliary tract cancer. The primary objective is to determine the objective clinical benefit (combined rates of complete response, partial response and stable disease) of the study treatment. Secondary objectives are to assess the tolerability and safety of the treatment, overall survival, progression free survival, time to treatment failure and quality of life.

Background - Carcinoma of the gallbladder and biliary tract (BTC) is uncommon and characterized by presentation at advanced stage. Valle et al (ASCO 2009) reported a clear survival advantage for gemcitabine plus cisplatin versus gemcitabine alone among 400 UK patients with advanced disease; median survival 11.7 vs 8.2 months. The Australasian Gastro-Intestinal Trials Group has experience with this combination in a multi-centre phase II trial, finding it an active and well tolerated combination (Goldstein et al, 2010). The growth factor receptor family is an important therapeutic target in a number of cancers including breast, bowel and lung cancers. Further work is required to specifically study biliary tract carcinoma to identify molecular characteristics of tumours likely to benefit from these targeted agents. The prevalence of K-ras mutation in BTC may be similar to or lower than that of colorectal cancer with rates as low as 12 % reported (Gruenberger et al, ASCO 2009).

Study design - Multi-centre, phase II, open label, single arm study. 45 patients with histologically or cytologically proven locally advanced, metastatic or recurrent BTC with wild type K-ras will be treated with panitumumab 9mg/kg day 1, gemcitabine 1g/m² on days 1 and 8 and cisplatin 25 mg/m² on days 1 and 8 of each cycle. Patients will continue on study treatment until progression, unacceptable toxicity, investigator discretion or patient request. Subsequent treatment will be allowed per clinician and patient preference

With chemotherapy alone, the clinical benefit rate is estimated to be 40 – 50%. A clinical benefit rate of 70 % with the addition of panitumumab will be of sufficient interest to warrant further investigation. Based on the Simon design, a sample size of 45 patients would be required to detect a 20% increase in clinical benefit with 95% confidence and 80% power. An interim analysis will be conducted after 15 patients completing 2 cycles of treatment have been monitored for 12 weeks to determine whether there is sufficient activity to continue to the full cohort of 45 patients.

Translational research - Formalin-fixed paraffin–embedded (FFPE) tissue blocks of diagnostic tumour tissue will be collected from consenting participants to assess the presence or absence of a BRAF mutation. This diagnostic tissue may include biopsy of primary tumour or biopsy of metastatic lesion. The tissue will be from archival tumour material – no additional biopsy of the participant is required.

FFPE tissue blocks will be collected by sites and sent to a central laboratory for analysis. Patients with KRAS and BRAF mutation who do not respond to panitumumab or who progress while on panitumumab can proceed to vemurafenib treatment.

Study Progress -  The protocol was approved by Amgen in February 2011. Cancer Institute NSW central ethics approval was granted in June 2011 and funding for the study was secured in December 2011. Currently there are 15 sites participating with 35 patients recruited to the study. A total of 60 patients have been screened for KRAS mutations with 15% of patients presenting with mutant KRAS and 85% of patients presenting with wild type KRAS.