CA209-8YD: A phase I/II trial of rucaparib in combination with ramucirumab with or without nivolumab in previously treated advanced gastroesophageal adenocarcinoma (GEA) (RiME).

Abstract

TPS377 Background: GEA is one of the leading causes of cancer-related deaths worldwide and in the US. In chemo refractory GEA, therapeutic options are limited with modest efficacy. About 35% of GC have DNA damage response (DDR) gene alterations and PARP inhibitors have shown to induce synthetic lethality and reduce tumor burden in in vitro and in vivo models of GEA. DDR deficient tumors have increased tumor mutational load, tumor infiltrating lymphocytes, and increased chemokines and PD-L1 expression in the tumor microenvironment. PARP inhibitors like rucaparib enhance antigen presentation, induce pro-inflammatory cytokines, influence PD-1/PD-L1 expression, and modulate T- and B- cell activity. Furthermore, results from multiple GEA early phase trials have supported the immune modulatory impact of VEGF targeted agents like ramucirumab. We hypothesize that modulation of the tumor microenvironment via PARP and VEGF inhibition will enhance anti-tumor immunity and lead to clinical synergy when combined with immune checkpoint inhibitors like nivolumab in this population. Methods: A safety lead in phase of 6-9 patients will be followed by an open label, two parallel cohorts phase II study. A total of 52 patients (26 in each cohort) will be enrolled. A starting rucaparib dose of 600 mg BID in combination with the standard doses of ramucirumab and flat doses of nivolumab will be used for the safety lead in. Rucaparib dose will be lowered for phase II if > 1/6 patients experienced DLTs. Participants enrolled to cohort A will receive rucaparib at the recommended phase II dose (RP2D) PO twice daily + ramucirumab 8mg/kg IV q2w + nivolumab 480mg IV q4w (28-day cycles). Participants in cohort B will receive rucaparib at RP2D PO twice daily + ramucirumab 8mg/kg IV q2w (28-day cycles). Assessment of tumor response using modified RECIST v1.1 will be done every 2 cycles. 50% of Pts who will be enrolled in each of the 2 cohorts must have a deleterious tumor gene alteration in at least 1 gene in a screening 17-gene homologous recombination deficient (HRD) panel. Eligible Pts received ≥1 line of therapy, ECOG PS 0-1, adequate organ function, no prior PARP inhibitors, and have mismatch repair (MMR) proficient tumors with measurable disease. Primary objectives are to determine the RP2D and overall response rate (ORR) in phase I and II respectively. Secondary objectives include safety, overall benefit rate (OBR), median PFS, OS, and ORR in HRD positive and negative cohorts. Enrollment to the RiME trial is currently ongoing. The study is funded by research grants from Bristol Myers Squibb and Clovis. Clinical trial information: NCT03995017.