A phase II study of M6620 and irinotecan in TP53 mutant gastric and gastroesophageal junction (GEJ) adenocarcinoma patients (pts) [NCT03641313

Abstract

TPS175 Background: Progressive metastatic or unresectable gastric/GEJ adenocarcinoma pts carry dismal prognoses with a significant need for novel systemic therapies. One avenue for drug development in this disease is targeting salvage DNA repair pathways. TP53, a central gene to DNA damage repair (DDR), is mutated in 50% of gastric/GEJ cancer pts. Pre-clinical models from multiple cancer types demonstrate that cancer cells with TP53 mutations rely on the ataxia telangiectasia and Rad-3 related protein kinase (ATR) axis as a primary pathway of salvage DDR in the face of cytotoxic stress. The ATR pathway is typically triggered by single strand DNA breaks such as those generated by topoisomerase I inhibitors. Irinotecan is already known to be active in later line gastric/GEJ pts, thus, there appears to be an opportunity to combine the agent with the ATR inhibitor M6620 in TP53 mutant pts with the disease. Methods: Our trial is a single arm phase II study of M6620 plus irinotecan in progressive gastric/GEJ adenocarcinoma pts. Only pts with TP53 mutations in exon 2 and exons 4-11, as determined by next-generation sequencing from archived tissue, will be eligible. Pts will receive 180 mg/m^2 of irinotecan immediately followed by M6620 every 2 weeks; the M6620 dose will be determined based on the recommended phase 2 dose from the ongoing phase I trial. CT scans will be repeated every 2 months to assess response. The primary endpoint of the study is overall response rate (ORR), with a pre-specified target of 35%. Correlative studies will be performed on fresh tumor tissue from the first 9 pts, obtained by biopsies on day 1 of cycle 1 post-irinotecan and day 2 of cycle 2, to assess dynamic changes in the biomarkers Y-H2AX, KAP1 p-Ser 824, and p-ATR. Our study employs a Simon’s two-stage design (α = 0.1, power = 0.8) where an initial analysis will be performed after 9 pts are enrolled. If < 2 pts demonstrate objective response, the trial will stop for futility. If > 2 pts demonstrate response, the study will enroll 14 more pts. If ≥ 6 pts experience an objective response, the trial will achieve its efficacy threshold. Accrual will be ensuing in the near future. Clinical trial information: NCT03641313.