September 23, 2021

Clinical trial tests ATR inhibitor in difficult-to-treat cancers


by Tom Wilemon

A clinical trial has been launched to test a new targeted therapy in patients with advanced and difficult-to-treat cancers.

Satya Das, MD, MSCI, assistant professor of Medicine at Vanderbilt-Ingram Cancer Center (VICC), is the national principal investigator for the trial (NCT04514497) that is now enrolling people with metastatic small cell lung cancer, metastatic pancreatic cancer, metastatic neuroendocrine cancer and other types of advanced solid tumors.

It is a phase 1 trial that will evaluate a novel drug in combination with standard chemotherapy. The drug is elimusertib, which in preclinical studies has demonstrated tumor shrinkage. It is an ATR inhibitor, a promising class of new drugs that target the ATR (ataxia telangiectasia mutated and Rad3-related) kinase, which is involved in DNA damage repair. The drug inhibits the growth of tumor cells by limiting their ability to repair damaged DNA. ATR inhibitors work similarly to PARP inhibitors, which have already been approved by the U.S. Food and Drug Administration for ovarian cancer and breast cancer.

Satya Das, MD

“Unfortunately, PARP inhibitors have a pretty limited activity for patients with the types of cancers in this clinical trial,” Das said. “ATR is a pathway that is actually activated by single strand DNA breaks. A lot of our chemotherapies induce DNA breaks. ATR is a very commonly activated pathway, so ATR inhibitors are being tested in multiple disease sites, mostly in early phase studies. What makes elimusertib quite interesting is that in preclinical models it seems to be the most potent. It induces the most tumor shrinkage across cancer types.”

The trial has two portions: an escalation part and an expansion part. The dose escalation has two arms, with patients receiving the novel drug in combination with either topotecan or irinotecan. The dose expansion focuses specifically on patients with poorly differentiated neuroendocrine cancer, pancreatic cancer and small cell lung cancer.

“Those three cancers are defined by very poor prognosis and very rapid growth,” Das said. “Cancers that have very rapid growth have what we call unchecked replication stress. It turns out that ATR inhibitors in preclinical models were highly active in tumor cells with high levels of replication stress, such as high-grade neuroendocrine cancer and pancreatic cancer. That is the reason that we have chosen those specific three cancers for the expansion cohort to really look at activity. We imagine that the majority of the patients in the trial will possess those three cancers, but we also wanted to open up the escalation portion to patients with other cancers in which the chemotherapies were already used to see if there was anti-tumor activity in those tumor types.”

For more information about this clinical trials and others at VICC, call 800-811-8480.