Priming the Tumour MicroEnvironment for Effective Treatment With Immunotherapy in Locally Advanced Rectal Cancer A Phase II Trial of Durvalumab (MEDI 4736) in Combination With Extended Neoadjuvant Regimens in Rectal Cancer

In rectal cancer, strategies to enhance local treatment responses by expanding neoadjuvant regimens are sought to enable organ preservation in more patients. The addition of systemic FOLFOX post long course chemoradiotherapy (LCRT) and post short course radiotherapy (SCRT) has been reported with encouraging results demonstrating higher rates of complete response than with radiotherapy based treatment alone. Immunotherapy using PD-1/ PD-L1 inhibition is recognised to be effective in mismatch repair deficient colorectal cancer (dMMR). Generally, dMMR tumours are characterised by a higher mutational burden, a higher neoantigen load with high density T cell infiltrates and increased expression of PD-1/ PD-L1 in the tumour microenvironment (TME). Mismatch repair proficient (pMMR) colorectal cancer is not thought to be responsive to immunotherapies partly due to the fact they exhibit low levels of tumour infiltrating lymphocytes (TILs) and PD-1/PD-L1 within the TME. Attempts to expand the role of anti-PD-L1 treatment to pMMR CRC is likely to rely on provision of conventional DNA damaging treatments to increase tumour immunogenicity/ T cell infiltration. At baseline few rectal tumours (10-20%) demonstrate moderate-high grade CD3+ responses within the TME, but there is evidence that radiotherapy (e.g. SCRT or LCRT) and systemic chemotherapy (FOLFOX) induce favourable immune responses. In this phase II trial, the investigators plan to evaluate the potential treatment efficacy of anti-PD-L1 systemic anticancer treatment, durvalumab, alongside either SCRT or LCRT with FOLFOX in the gap up to post treatment assessment. This trial will evaluate rates of complete response in each arm as its primary endpoint in addition to safety and toxicity as secondary endpoints. It is a translationally rich trial which involves the collection of biospecimens prior to, during and following treatment in order to understand the molecular and immunological factors underpinning treatment response.

An initial 6 patient safety run-in (3 patients in each arm) will be performed treating patients with metastatic disease with a locally advanced rectal cancer in situ or patients with locally advanced rectal cancer who will never undergo radical surgery due to patient choice, in order to establish safety and lack of significant local toxicity due to the combination (for example colo-proctitis). Depending on the toxicity observed in the first 3 evaluable patients in each of the arm, an additional 3 patients may be add to that arm for the safety run-in cohort. Following an independent safety review and approval by an Independent Data Monitoring Committee (IDMC), the main trial will commence.

Following the safety run-in, 42 patients with non-metastatic, biopsy confirmed rectal adenocarcinoma (cT3b+, N+, EMVI+ based on MRI staging or low rectal tumours requiring abdominoperineal resection) will be recruited to the main trial and randomised to one of two treatment arms. These patients must have adequate physical fitness and no previous pelvic radiotherapy or immunotherapy.

Recruitment to the Safety Run-in period is expected to take 6 months (based on 6 patients in this cohort) with the main trial taking a further 12 months. Recruitment should therefore take place over a total period of 18 months. If the safety run-in requires more than 6 patients, these timelines will be revised. Patients will be followed up for 36 months from date of randomisation.