BBI608 on overall survival in patients with metastatic CRC who have failed all standard chemotherapy (including a thymidylate synthase inhibitor, an irinotecan-containing regimen, an oxaliplatin containing regimen and, an EGFR inhibitor  for patients whose tumours are K-ras wild type) recommended by their oncologist, and for whom no standard anticancer therapy is available.

BACKGROUND - Standard treatment for unresectable metastatic disease currently includes first and second line 5-fluorouracil (5-FU) chemotherapy based regimens in combination with oxaliplatin or irinotecan, and EGFR inhibitor treatment for patients with KRAS WT. At further progression  treatment options are limited to an investigational regimen or best supportive care. There is an urgent need to identify novel therapies which improve the outcome of patients with advanced chemo refractory CRC.

Accumulating evidence indicates that Cancer Stem Cells (CSC) play a key role in the pathogenesis of CRC, suggesting that the development of CSC inhibitors represents a novel and compelling strategy for the treatment of CRC in this treatment setting. CO.23 will primarily examine the effect of treatment with CSC inhibitor BBI608 on disease outcomes.

STUDY DESIGN - CO23 is an international multi-centre, prospective, double-blind, randomised phase III trial of the CSC inhibitor BBI608 plus best supportive care versus matched placebo plus best supportive in participants previously treated with combination chemotherapy for advanced (metastatic or locally advanced), unresectable, colorectal carcinoma, now refractory and for whom no further standard anticancer therapy is appropriate or available.

Participants will be randomised according to a 1:1 ratio using a permuted block randomisation procedure to receive either BBI608 500 mg bid daily (1000 mg total daily dose) + Best Supportive Care  or  Placebo bid + Best Supportive Care. Participants will be stratified by: ECOG performance status (0 versus 1), K-ras tumour status (wild type versus mutant), prior anti-VEGF therapy (yes versus no) and time from diagnosis of metastatic disease to randomisation (<18 months versus >18 months).

The primary endpoint is overall survival. Secondary endpoints include Progression-Free Survival (PFS), Disease Control Rate (DCR), Safety Profile and Quality of Life (using EORTC QLQ-C30). The planned sample size is 650 patients, with 275 patients to be accrued from Australia and New Zealand.

STUDY PROGRESS - CO23 is collaboration between the NCIC CTG, AGITG, NHMRC Clinical Trials Centre (CTC) and Boston Biomedical.   There are currently 9 sites open to recruitment in Australia with a further 5 due to open by the end of September 2013. Due to restricted study drug further sites are unable to be activated until January 2014 once further study drug supplies are available. 40 ANZ

sites in total are expected to recruit including 1 site in Singapore.   As of 10^th September, 16 patients have been randomised, including 3 from AGITG sites which have only opened to accrual this month.

TRANSLATIONAL RESEARCH - There are 3 components to the correlative studies performed for this study. (i) The submission of a representative block of the diagnostic tumour tissue and of a sample of whole blood is required for participation in this trial.   The tissue may be used by researchers now or in the future to better understand the nature of colorectal cancer and how patients respond to treatment. 

Plasma samples for sparse pharmacokinetics (PK) analysis will also be obtained from all patients at the study visits occurring at 4, 8 and 12 weeks after randomization.    Whole blood (baseline); plasma, buffy coat, RBC pellet, serum @ 4 timepoints (baseline, D1 of weeks 4, 8 and 12) will be recovered from all patients for biomarker research.