Aims – The aim of this study is to evaluate the response rates of wTCF/X given with or without panitumumab in the treatment of patients with metastatic or locally recurrent oesophago-gastric cancer. The secondary objectives are to assess overall survival, progression-free survival, treatment related toxicity, disease associated symptoms and quality of life during treatment.

Background – Most cases of oesophageal and gastric cancer are locally advanced or metastatic at presentation. Chemotherapy prolongs survival and improves quality of life in such patients, but standard chemotherapy for this disease has not been defined. 

Docetaxel is a taxane with promising single agent activity in oesophago-gastric cancer. Combination chemotherapy regimens based on docetaxel have also shown significant activity.  A phase III study demonstrated that a triplet regimen comprising docetaxel, cisplatin and 5-FU (TCF) was associated with improved response rates, time to tumour progression (TTP) and overall survival.  A major limitation of this regimen was a significant rate of toxicities, especially febrile neutropenia and neutropenic infection.  The Australasian GI Trials Group (AGITG) therefore devised a modified TCF regimen involving weekly docetaxel (wTCF) which was associated with much lower rates of myelosuppression.  The AGITG modified schedule wTCF achieved comparable efficacy data to the original 3-weekly TCF regimen but was associated with a much more favourable toxicity profile (Tebbutt NC, Cummins MM, Sourjina T, Strickland AH, Van Hazel G, Ganju V, Gibbs D, Stockler M, Gebski V, Zalcberg J; on behalf of the Australasian Gastro-Intestinal Trials Group. Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial. British Journal of Cancer 2010; 102: 475–481. Published online 12 Jan 2010). 

In other cancers it is clear that targeted biological therapies may provide additional benefits over and above that which can be achieved using standard chemotherapeutic approaches.  Therefore, this study aims to evaluate the impact of panitumumab a fully humanized monoclonal antibody (mAb) to the EGFR when given in combination with weekly docetaxel based chemotherapy.

Study design – Multicentre, randomised, open label, phase II study, comprising 100 patients (50 per arm) with advanced oesophago-gastric cancer. Patients will be randomised to receive either Arm A: wTCF/X (Docetaxel, Cisplatin, PVI 5-FU for 21d or capecitabine for 21d (at investigator discretion) or Arm B: wTCF/X plus panitumumab (Docetaxel, Cisplatin, PVI 5-FU for 21d or capecitabine for 21d and Panitumumab).  Capecitabine is available via the PBS from August 2010 and the choice of 5FU or capecitabine is at investigator discretion. 

Each cycle will be administered 3 weekly for a total of 8 cycles. CT scans will evaluate response every 2 cycles ie every 6 weeks

The primary endpoint will be objective tumour response rate, with secondary endpoints of overall survival, progression-free survival, treatment related toxicity, disease associated symptoms, quality of life and the ccorrelation of clinical outcomes with tissue biomarkers.

Study progress – The ATTAX 3 study opened to recruitment in March 2010 with a total of 20 sites opened across Australia. The original plans for this study were to recruit 100 patients over 18 months. The ATTAX 3 study was temporarily suspended to recruitment on the 11th November 2011 following the release of the REAL3 results.  The REAL-3 study was a  randomised open-labelled multicentre trial assessing the efficacy of epirubicin, oxaliplatin and capecitabine (EOX) with or without panitumumab in previously untreated advanced oesophago-gastric cancer. There was a statistically significant difference in overall survival between the two arms of the REAL3 trial, with inferior outcomes demonstrated in patients treated in the experimental arm (reduced dose EOX + panitumumab) compared to the standard dose EOX chemotherapy.  As the REAL-3 trial was the same patient group and similar in design to the ATTAX3 trial (although with important differences in the chemotherapy agents and dosing schedule), an unplanned interim analysis was carried out by the AGITG Independent Data Monitoring Committee (IDMC) and subsequently ATTAX 3 Trial Management Committee (TMC). After the review of the REAL-3 data and interim data from the ATTAX3 study, the IDMC recommended that the ATTAX 3 trial be closed to further recruitment.  The IDMC noted that whilst there did not appear to be any detrimental impact from the use of panitumumab in ATTAX3, it was considered statistically unlikely that the trial would achieve its primary endpoint.  A total of 77 patients were recruited to the ATTAX 3 trial, and the TMC allowed continuation of panitumumab at investigator discretion.

Median follow up was 24m. Treatment arms (TCF/TCF-P respectively) were well balanced; median age (59y;64y), male (77%;87%), PS 0-1 (95%;90%), adenocarcinoma (90%;90%), and capecitabine (67%;66%).

Common grade 3/4 toxicities for TCF/TCF-P respectively, include infection (18%;24%), febrile neutropenia (10%;5%), anorexia (10%;24%), nausea (18%;30%), stomatitis (3%;5%), diarrhoea (15%;24%), acneiform rash (0%;8%), fatigue (18%;30%), hypomagnesemia (10%;16%).

Efficacy outcomes are summarised in table.

In conclusion, the addition of panitumumab to docetaxel based chemotherapy in advanced OG cancer showed no significant gain in tumour response rates, PFS or OS. There was an increase in some toxicities with the use of panitumumab. This is similar to the findings from other trials which used a combination of chemotherapy and EGFR inhibitors in advanced OG cancer, such as the EXPAND study. Unlike the REAL-3 trial, where patients receiving panitumumab also received lower doses of chemotherapy than the control arm, there was no evidence of a significant detriment in overall survival for those receiving panitumumab.

The final results were accepted in a poster at ASCO 2013. 

Translational research- As consent to tissue banking was an inclusion criterion for ATTAX 3, all patients have consented to translational research.  Tissue samples were obtained from previous diagnostic or therapeutic procedures. Patients did not undergo any biopsies solely for the purposes of this study.  Specimens (tumour blocks) are currently being sent to the central laboratory (Austin Health Laboratory) for testing.  Relevant biomarkers that will be evaluated include K-ras mutations in tumour tissue that are associated with resistance to panitumumab in colorectal cancer, but other relevant markers such as B-raf mutations and beta-tubulin-3 expression may also be assessed as predictors of outcome.