• A phase I/IIa study to evaluate the safety and efficacy of CCS1477, a first in clinic inhibitor of p300/CBP, as monotherapy in patients with selected molecular alterations

      Crabb, S.; Plummer, R.; Greystoke, A.; Carter, Louise; Pacey, S.; Walter, H.; Coyle, V. M.; Knurowski, T.; Clegg, K.; Ashby, F.; et al. (2021)
      Background CCS1477 is a potent, selective, orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in cancer. In vitro and in vivo models demonstrate molecular alterations that increase sensitivity to p300/CBP inhibition with CCS1477. Tumours with loss of function mutations in either p300 or CBP become dependent on the corresponding non-mutated paralogue (twin) protein. When the non-mutated twin is inhibited, this drives synthetic lethality leading to apoptosis/cell death. Recently, loss of function mutations in ARID1A have also demonstrated functional dependence upon p300/CBP. Trial design This Ph I/IIa study sponsored by CellCentric, evaluates the clinical activity of CCS1477 in patients with advanced solid tumours harbouring molecular alterations indicating sensitivity to p300/CBP inhibition. Specifically, potential markers determined by local testing, include loss of function mutations in p300, CBP or ARID1A; myc and AR amplification or over expression. Acceptable tests are next generation sequencing or equivalent, in archival or fresh tumour biopsies or in cell free DNA from a pre treatment blood sample. IHC may be used for over expression of proteins such as myc or AR. Patients with cancers where there is strong molecular rationale for a potential response to CCS1477 (e.g. myc over expression in Small Cell Lung Cancer and Radiation induced breast sarcoma) may be entered following discussion with sponsor. The trial is in 2 parts. Part 1 commenced Dec 2020 in the UK, and is opening in US & EU mid 2021, recruiting 20 patients to receive CCS1477 at a dose and schedule previously declared tolerated from the rising dose tolerability arm of the trial being separately conducted in men with metastatic castrate resistant prostate cancer (NCT03568656). In Part 2, up to 30 patients will receive CCS1477 at the recommended phase 2 dose and schedule. Anti-tumour activity will be determined by standard imaging according to RECIST guidelines. Paired tumour biopsies for biomarker assessment are being collected.