Researchers at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center are leading a multi-site phase II study through the Hoosier Cancer Research Network for previously treated metastatic esophageal cancer patients with specific genetic mutations. The study is now open to accrual at the IU Simon Cancer Center, Moffitt Cancer Center, and Roswell Park Cancer Institute.

The study, HCRN ESO17-325, “A Phase II Study Evaluating Safety and Efficacy of Niraparib in Patients with Previously Treated Homologous Recombination Defective or Loss of Heterozygosity high Metastatic Esophageal/Gastroesophageal Junction/Proximal Gastric Adenocarcinoma,” will test the effectiveness of using the PARP inhibitor, niraparib, versus the current standard of care, in treating patients with one of three genetic mutations, including homologous recombination (HR) mutation in tumor tissue; high rate of loss of heterozygosity (LOH) in tumor tissue; or a germline mutation in the blood. The study uses precision medicine by applying patients’ genetic information to guide treatment decisions.

In this study, niraparib will be used as a second-line treatment for people with cancer that began in the esophagus, GE junction or stomach who were previously treated with a platinum-containing chemotherapy regimen.

Niraparib is a poly ADP ribose polymerase (PARP) inhibitor that kills tumor cells with certain genetic mutations. PARP is part of a family of proteins that are often involved in DNA repair and cell-cycle control. Inhibitors such as niraparib block PARP proteins from repairing damaged DNA and cause cell death.

People with metastatic esophageal cancer who have experienced disease progression after their first treatment typically undergo chemotherapy using docetaxel and ramucirumab with or without paclitaxel. Some patients experience neuropathy and bleeding following this type of chemotherapy. Trastuzumab is another form of second-line treatment used in some patients.

About 17,300 new cases of esophageal cancer were estimated for 2018. Some researchers estimate less than half of patients with metastatic esophageal cancer possess the gene mutations that could benefit from this study.

“This is mainly an esophageal adenocarcinoma clinical trial,” said Shadia I. Jalal, MD, sponsor-investigator of the trial and a medical oncologist at the IU Simon Cancer Center. “These are patients on genomic sequencing. When we analyze and get a look at the genetic targets of the tumor, we find that they have specific abnormalities in a bunch of genes. If they do, or if their tumor shows a lot of genome instability,” she said, “then they could qualify for this DNA repair inhibitor.”

“If you have a homologous recombination abnormality,” Dr. Jalal added, “you can use another DNA repair pathway to fix things. What we do on this trial is we actually inhibit that second pathway.”

A pathway called the homologous recombination pathway plays a critical role in repairing DNA damage throughout a person’s life.

Dr. Jalal explains that genetically smart tumors that some patients possess may actually help treat their cancer, much like the BRCA1 mutation in some patients with breast cancer.

“In this same pathway, there are far more genes than the BRCA gene,” Dr. Jalal said. “We’re trying to identify the potential fact that not all genes in the pathway are equal. So, it’s possible if you have genetic change in one protein in the homologous recombination pathway, you are far more sensitive in having a genetic change in another protein in the same pathway. We’re doing a lot of those clinical analyses and laboratory analyses and tumor tissue analyses to try to identify who will benefit, and if they do and they stop benefitting, why did they stop.”

She said that people with esophageal cancer develop genetic changes in their tumors in either one or multiple proteins in a pathway, which potentially could make them more sensitive to niraparib.

“The main goal of this trial is to assess the chance of metastatic esophageal cancer shrinking when we give patients niraparib,” Dr. Jalal said, and to assess whether or not patients with the abnormality in the homologous recombination genes respond to niraparib.

Researchers also want to determine whether participants with this type of metastatic esophageal cancer respond for a longer period using niraparib versus the standard second-line treatment.

“You’re using a drug in a smart way to overcome a cancer,” Dr. Jalal said. “It’s trying to develop a targeted treatment for esophageal cancer. If their tumor shows a lot of genome instability, and it seems like a very genetically smart tumor, then they could qualify for this DNA repair inhibitor. Unfortunately, that means that not everybody qualifies because you have to have the target to benefit from the targeted treatment.”

Up to 43 people may participate in this study. Subjects will take study drug, niraparib, orally once a day. Participants may continue taking niraparib until their disease worsens or they experience severe side effects. Participants may discontinue treatment any time in consultation with their doctor. All participants will be monitored every three months for a year after completion of the study treatment.

Niraparib is approved by the U.S. Food and Drug Administration (FDA) as maintenance therapy for adults with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer after the cancer has responded to treatment with platinum-based chemotherapy. Niraparib is not FDA-approved to treat metastatic esophageal cancer and should be considered investigational for this study.

The study is supported by TESARO, Inc.

Blood and tissue will be collected during the study to support correlative research objectives such as analyzing the genetic changes and how they associate with treatment in the pathway. Researchers will assess loss of heterozygosity (LOH) and conduct a genome-wide analysis of loss of heterozygosity in tumor tissue to see if it could be a marker for a response to niraparib. Researchers also will study reversion mutations, which have been shown to contribute to PARP inhibitor resistance.

“These have been identified in certain cancers and we’re trying to study if these phenomena happen in esophageal cancer,” Dr. Jalal said.

To qualify for this study, patients must be adults age 18 or older with metastatic esophageal cancer who possess one of the three genetic mutations and previously received platinum-containing chemotherapy. Patients interested in participating will be pre-screened for the genetic mutations to determine whether they qualify.

For more information about this research study, including full eligibility requirements, visit www.clinicaltrials.gov (study #NCT03840967).

About Hoosier Cancer Research Network:

Hoosier Cancer Research Network (formerly known as Hoosier Oncology Group) conducts innovative cancer research in collaboration with academic and community physicians and scientists across the United States. The organization provides comprehensive clinical trial management and support, from conception through publication. Created in 1984 as a program of the Walther Cancer Institute, Hoosier Cancer Research Network became an independent nonprofit clinical research organization in 2007. Since its founding, Hoosier Cancer Research Network has conducted more than 210 trials in a variety of cancer types and supportive care, resulting in more than 350 publications. More than 8,500 subjects have participated in Hoosier Cancer Research Network clinical trials.