CTNI-03. A PHASE I/IIA, OPEN-LABEL STUDY OF THE BRAIN-PENETRANT PARP1-SELECTIVE INHIBITOR AZD9574 AS MONOTHERAPY AND IN COMBINATION IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES (CERTIS1)

Abstract BACKGROUND Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair leading to replication-dependent DNA double breaks. Recent data suggest that only inhibition is required for anti-proliferative effects, while functions in the survival haematopoietic stem progenitor cells. These observations trapping PARP 2 not needed anti-cancer may be a major driver haematological toxicity observed. AZD9574 novel brain-penetrant PARPi potently inhibits traps PARP1, with goal delivering efficacious, less toxic, more combinable PARPi. Furthermore, owing its central nervous system penetration capability, provide new treatment option patients CNS malignancies or brain metastases characterized by homologous recombination deficiency (HRD). METHODS This first-in-human modular study primarily designed evaluate safety tolerability as monotherapy combination agents increasing dose levels advanced solid malignancies, followed expansion cohorts specific indications. The will also characterize pharmacokinetics explore potential biological activity assessing pharmacodynamic exploratory biomarkers anti-tumour activity. Module 1 enrol breast, ovarian, pancreatic prostate tumours harbouring deficiencies. isocitrate dehydrogenase (IDH)1/2 mutated glioma.