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Clinical Trial 20166

Cancer Type: Gastrointestinal Tumor
Interventions:Niraparib ()

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Rutika Mehta

Call 813-745-6100
or 1-800-679-0775
Overview

Study Title

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

Summary

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.

Objective

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.

Inclusion Criteria

  • Locally advanced esophageal adenocarcinoma or proximal gastric adenocarcinoma or metastatic adenocarcinoma originating from esophagus, GE junction, or proximal stomach who progress/recur beyond 2 months of receiving a platinum- containing regimen
  • A participant with symptomatic brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off of corticosteroids for ≥ 2 weeks, and are asymptomatic. Participants with asymptomatic brain mets that are untreated will be allowed.
  • Must not have received more than 1 prior line of chemotherapy in the metastatic setting
  • One of the following genetic results: High LOH in tissue, HR mutation in tissue or Germline mutation (blood)
  • Presence of measurable disease by RECIST v1.1
  • Prior cancer treatment must be completed at least 14 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline
  • Demonstrate adequate organ function as defined per protocol
  • Females of childbearing potential must have a negative pregnancy test within 7 days prior to study treatment
  • Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 180 days after treatment discontinuation. Males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 180 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method.
  • Participant must agree to not breastfeed during the study or for 180 days after the last dose of study treatment.
  • Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment

  • Exclusion Criteria

  • Prior therapy with a PARP inhibitor
  • Disease progression during first 2 months of standard dose platinum-based chemotherapy (platinum refractory). This excludes low dose platinum based therapy that is given in a chemotherapy-radiation regimen for locally advanced esophageal cancer.
  • Participant must not be simultaneously enrolled in any other interventional clinical trial.
  • Participant must not have had major surgery ≤ 3 weeks prior to initiating protocol therapy and participant must have recovered from any surgical effects.
  • Participant must not have received investigational therapy ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter, prior initiating protocol therapy.
  • Participant has had radiation therapy encompassing >20% of the bone marrow within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
  • Participant must not have a known hypersensitivity to niraparib components or excipients.
  • Participant must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating protocol therapy.
  • Participant must not have received colony stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte macrophage colony stimulating factor, or recombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
  • Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
  • Participant must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
  • Participant must not have a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
  • No active secondary cancer