Protocol Title: INTEGRATE II – A Randomised Phase III Double-Blind Placebo-Controlled Study of regorafenib in Refractory Advanced Gastro-Oesophageal Cancer (AGOC).
Study Chairs: A/Professor Nick Pavlakis (Royal North Shore Hospital, Sydney); and Conjoint Professor David Goldstein (Prince of Wales Hospital, Sydney)
Project Manager: Eric Tsobanis
Trial Coordinator: Brad Green
Contact Email: INTEGRATEII@ctc.usyd.edu.au
Detailed information available on the Australian and New Zealand Clinical Trials Registry – INTEGRATE II
This study follows the success of the Phase II INTEGRATE study which demonstrated a positive signal in the intervention arm. The purpose of INTEGRATE II is to determine whether regorafenib (BAY 73-4506, Stivarga) improves overall survival as a third line therapy in refractory AGOC. The primary objective is overall survival, while secondary objectives include progression free survival, objective response rates, safety, quality of life, and investigation of the prognostic/predictive role of circulating biomarkers and Regorafenib pharmacokinetics in patient populations from different geographic regions.
Advanced Gastro-oesophageal Carcinoma (AGOC) has a poor prognosis, and there is no established standard treatment following failure of first and second line chemotherapy. Regorafenib (BAY 73-4506) is an investigational oral multi-targeted tyrosine kinase inhibitor (TKI) which targets angiogenic (VEGF, TIE-2), stromal (PDGF-Î²), and oncogenic (RAF, RET and KIT) receptor tyrosine kinases, and has shown activity in other solid tumours. Regorafenib was shown to prolong PFS across all regions/subgroups in INTEGRATE.
The current standard first-line chemotherapy treatment of AGOC has regional differences, but usually includes a fluoropyrimidine and a platinum agent. In Asia, a doublet regimen with flurouracil or S1 or capecitabine with a platinum agent, such as cisplatin or oxaliplatin (remains the standard of care first line (Van Cutsem et al, 2010). In Europe and the USA, fluoropyrimidine and platinum-based combinations with or without the addition of a third drug, typically docetaxel (D) or epirubicin (E), are the most widely used chemotherapy combinations for first-line AGOC (Van Cutsem et al., 2011).
After failure of first line treatment for AGOC, patient performance status can often decline rapidly. However, second-line chemotherapy is now established as a standard care option in appropriately selected patients, based on three randomized studies, each of which demonstrated a survival advantage with chemotherapy over best supportive care alone, using taxanes (paclitaxel and docetaxel) or irinotecan (Thuss-Patience et al., 2011; Kang et al., 2012; Ford et al., 2014). A meta-analysis of these studies demonstrated a HR for OS of 0.73 (95% CI, 0.58 to 0.96), and in patients with performance status 0-1 the HR was 0.57 (95% CI, 0.36 to 0.91 (Iacovelli R et al., 2014).
INTEGRATE was a randomized placebo controlled multicentre international (ANZ, Korea, Canada) Phase II trial that evaluated the activity of regorafenib versus placebo in AGOC (Pavlakis 2015). Regorafenib was effective in prolonging PFS 11.1 wks (95% CI: 7.7 — 13.3) v placebo 3.9 wks (3.7 – 4.0), HR 0.40, p < 0.0001. A trend in overall survival was observed with regorafenib (Median OS 25 wks (95% CI: 18.9-29.6) v placebo 19.4 wks (95% CI: 14.9 — 22.7), HR 0.74, p = 0.11, allowing for the fact 29/50 (58%) of placebo patients crossed over to receive regorafenib at progression. Pre-specified analyses found the regorafenib effect greater in Korea than ANZ/Can (HR 0.12 v 0.61, p = 0.0009) but consistent across age, NLR (neutrophil : lymphocyte ratio), primary site, lines of CT, peritoneal metastases (mets) presence, number of metastatic sites, and baseline VEGF-A. Regorafenib was well tolerated, with expected spectrum of toxicities (Pavlakis 2015).
The findings from INTEGRATE provide a strong signal for activity of regorafenib in AGOC and raise the interesting question about possible differential efficacy by geographic region. The trend toward a survival benefit is a seen as a strong signal for overall clinical benefit, particularly given the fact 58% of placebo patients crossed over at disease progression to receive regorafenib, thus diluting the ability to demonstrate an effect of regorafenib on survival. Consequently, in order to confirm this survival benefit, the design of INTEGRATE II cannot allow crossover of placebo patients to receive regorafenib.
The purpose of this Phase III study is to determine whether regorafenib is effective in prolonging survival in patients with refractory AGOC overall and in the Asian sub-population.
INTEGRATE II is a randomised phase III, double-blind, controlled trial with 2:1 (regorafenib:placebo) randomisation with stratification by the location of tumour (GOJ vs Gastric), geographic region and prior VEGF inhibitors. 350 patients will be recruited from Australian, New Zealand, Canadian, USA, South Korea, Japan and Taiwan sites over a 24 month recruitment period.
Biological samples from patients will be used to identify biomarkers that are prognostic/predictive for study endpoints relating to survival, response, and safety. Additional blood samples for Regorafenib pharmacokinetics will be collected at selected centres.
How to Enrol Your Patient:
The process of enrolling an eligible person to participate in the study is registration immediately followed by randomisation. At registration, prospective participants must meet all of the protocol specified inclusion criteria and none of the exclusion criteria to be eligible for this trial. Participants that are successfully registered will then be randomised 2:1 (regorafenib: placebo) and stratified by location of tumour, geographic region (GOJ vs gastric) and prior VEGF inhibitors.
To view study schema click here