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A Phase II Study Evaluating Safety and Efficacy of Niraparib in Patients with Previously Treated Homologous Recombination (HR) Defective or Loss of Heterozygosity (LOH) high Metastatic Esophageal/Gastroesophageal Junction/Proximal Gastric Adenocarcinoma
Participants can be prescreened for the study at the time of diagnosis of locally advanced or metastatic disease by determining presence of LOH high status and/or deleterious alterations in HR pathway genes in the most recent available tumor tissue sample or in blood if they are found to have germline mutations. Participants with either somatic or germline mutations will be allowed. At the time of disease progression, patients with high LOH or deleterious alterations in HR pathway genes and satisfying all other inclusion criteria will be enrolled on the study. Participants will be treated with niraparib (flat dose) orally every day for 28 days until disease progression, unacceptable side effects, withdrawal of consent, or death. CT of the chest/abdomen/pelvis will be performed every 2 months and response will be assessed by RECIST 1.1.
Primary Objective: Determine objective response rate (ORR) with niraparib in patients with metastatic esophageal/gastroesophageal junction (GEJ)/proximal gastric adenocarcinoma previously treated with platinum containing chemotherapy and harboring high genome wide loss of heterozygosity (LOH) or defective homologous recombination noted through deleterious alterations in HR genes. Genes analyzed will include: BRCA1/2, PALB2,ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B,RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1. Patients can have somatic and/ or germline mutations. Deleterious mutations in HR genes are defined as those that have been previously characterized to be loss-of-function/pathogenic/or likely pathogenic as specified per the following databases: Clinvar, OncoKB, or BRCAExchange. Mutations or small insertions or deletions that results in truncation, frameshift, stop codon loss, or stop codon gain will also be considered deleterious irrespective of their presence in the aforementioned databases unless previously characterized to be benign. Copy number losses or disruption by fusion will also be considered deleterious irrespective of their presence in the aforementioned databases. Gene amplifications or variants of unknown significance will not be eligible for inclusion. Patients are eligible if they have a deleterious alteration in one of these pre-specified HR genes, including: BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1. Secondary Objectives: -Evaluate the safety and tolerability of niraparib as defined by CTCAE v5. -Determine progression free survival (PFS) with niraparib in above mentioned patient population. -Evaluate disease control rate (DCR) Exploratory Objectives: -Assess the correlation between high genome wide LOH in the tumor samples and response to treatment with niraparib. -Analyze mechanisms of resistance to PARP inhibitors. We will mainly analyze reversion mutations in HR genes as a potential mechanism of resistance. Analyze EZH2 expression and its correlation with response and resistance to PARP inhibitors -Analyze germline mutations of HR genes from DNA collected from blood samples and correlation with response to niraparib. -Correlate CTCs with response to treatment.