On January 20, 2022 Celleron Therapeutics, the UK-based company developing personalised medicines for cancer patients, reported that a 14.5% patient two-year survival rate following treatment in their Phase II clinical trial testing the immune check point inhibitor (ICI) nivolumab in combination with zabadinostat in patients suffering from advanced micro-satellite stable colorectal cancer (MSS CRC) (Press release, Celleron, JAN 20, 2022, https://cellerontherapeutics.com/celleron-therapeutics-reports-survival-data-from-zabadinostat-combined-with-nivolumab-in-micro-satellite-stable-colorectal-cancer-patients/ [SID1234605617]).
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Celleron Therapeutics’ Phase II clinical trial (the CAROSELL Study) tested the effect of zabadinostat (formerly CXD101) in combination with nivolumab in MSS CRC, which typically does not respond to immune checkpoint inhibitors agents as mono-therapy. The clinical trial strategy rests on compelling pre-clinical results which provide novel insights into how zabadinostat and ICI drugs work together to re-engage recognition of tumours by the immune system, frequently described as turning ‘cold’ tumours ‘hot’. The patients studied, had advanced or metastatic disease, having relapsed after at least two previous lines of therapy.
Enrolment to the Phase II study was completed in May 2019, and all ongoing subjects have completed the study treatment. Interim analysis of the evaluable MSS CRC subjects saw a significant level of durable disease control (stable disease plus partial response) and overall response rate (ORR). Patients have now been followed-up for survival post-study treatment, where 14.5% of the subjects had survived for two years or more, from first dose of study treatment. This clinical activity compares favourably with products that have been approved to treat MSS CRC, such as Stivarga (regorafenib) and Lonsurf (trifluridine/tipiracil tablets).
Professor David Kerr, Chief Medical Officer and Founder of Celleron Therapeutics, commented:
"We continue to be extremely excited by these encouraging Phase II trial results which add to the continuing evidence that zabadinostat is a clinically viable drug with wide utility in metastatic colorectal cancer. We expect to further develop our understanding of these responses with our upcoming precision-medicine Phase III study".
About Colorectal Cancer
Colorectal cancer is the second most common tumour type in women, and the third most common in men, globally. The approximate five-year survival rate for colorectal cancer patients in the United States is 10% for those with advanced metastatic disease (Stage IV).
Surgery is indicated for localized disease, whilst chemotherapy has been the standard management for patients with metastatic colorectal cancer. Two agents have been approved for third line management of advanced colorectal cancer, namely regorafenib (Stivarga) and Trifluridine-tipiracil hydrochloride (Lonsurf).
A subset (5%) of colorectal cancers is characterized with deficient DNA mismatch repair (dMMR or microsatellite instability, MSI). These tumours tend to have a high expression of checkpoint proteins (PD-1 and PD-L1), which interfere with the body’s normal anti-tumour T-cell response. By disabling these proteins, immune checkpoint inhibitors (ICI) such as nivolumab allow the immune system to function properly, and T-cells to kill tumour cells.
However, the majority of patients with a normal Mismatch Repair proficient expression, the microsatellite phenotype is stable (MSS), antigen presentation is believed to be much decreased, and the tumour is thus resistant to checkpoint inhibition. Most MSS patients will ultimately relapse or become resistant to chemotherapy. There remains a very significant unmet clinical need to find novel agents, singly or in combination, for the treatment of these late-stage patients.