Combination Study of Guadecitabine/ASTX727 and Pembrolizumab

This is a multi-centre, dose escalation, Phase I trial. There are two parts to this study. Part A: dose escalation, and Part B: dose expansion. Part A (Dose Escalation): Patients with advanced solid tumours will be recruited in cohorts of 3 to 6 patients to investigate the combination of 200 mg of pembrolizumab administered as an intravenous injection (first dose given in Cycle 2 Day 8 and then Day 1 of subsequent Cycles) with escalating doses of guadecitabine administered via a subcutaneous injection once a day for 4 days (Days 1-4) of a 21-day cycle. Once the MTD is reached (or under the advice from the SRC) patients will be enrolled to the dose expansion phase (Part B). Part B1 (Dose Expansion): 20 patients will be recruited to Part B1 (expansion phase) to further explore the safety and activity of the combination of guadecitabine and pembrolizumab. This cohort will include, but not be limited to, patients with: secondary resistance to PD-1/PD-L1 inhibitors, patients with primary resistance to PD-1/PD-L1 inhibitors in subgroups predicted to benefit such as those with microsatellite-instability high (MSI-H) tumours and/or those with deficient mismatch repair (dMMR) and, possibly other solid tumours based on emerging anti-tumour activity data from Part A and any other relevant preclinical or clinical published data. Part B2 (NSCLC Dose Expansion): Up to 25 evaluable patients will be recruited to Part B2 (expansion phase) to further explore the safety and activity of the combination of ASTX727 and pembrolizumab. This cohort will include patients with NSCLC with primary or secondary resistance to PD-1/PD-L1 inhibitors. Utilising a Simon's minimax two-stage design, Part B2 will have 80% power with a one-sided significance level of 5% to discount a response rate of 10% in favour of a response rate of 30%. Fifteen patients will be enrolled to stage one, and if two or more patients experience a response (PR or CR by RECIST v1.1), then a further 10 patients will be enrolled to stage two, totaling 25 patients overall.