Montefiore Einstein Comprehensive Cancer Center Awarded FDA Grant for Clinical Trial on Experimental AML/MDS Treatment

Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)—two related blood diseases that disproportionately strike older adults—are notoriously difficult to treat and are associated with high relapse rates. Although new therapies have improved survival, treatment options remain limited, and the prognosis is poor for the 50% of people who experience disease relapse.

Researchers at the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center were recently awarded a four-year, $2.6 million grant from the U.S. Food and Drug Administration (FDA) to conduct an innovative Phase 1 clinical trial of a new drug for patients with relapsed and treatment-resistant forms of AML and MDS. It is one of only 10 grants issued this year by the FDA through its Office of Orphan Products Development.

“This is a tremendous opportunity to apply the knowledge we have developed in our Comprehensive Cancer Center labs over the past decade to develop a novel therapeutic strategy,” said Aditi Shastri, MD, Assistant Director, Translational Research, Stem Cell & Cancer Biology Program and Blood Cancer Institute, Montefiore Einstein Comprehensive Cancer Center, Associate Professor, Oncology, Medicine, and Developmental and Molecular Biology, Albert Einstein College of Medicine, and the grant’s Principal Investigator.

Drugs that initially work against AML are ineffective when the disease returns. Research suggests that those treatments leave behind leukemic stem cells that are resistant to existing medications and lead to relapsed and drug-resistant AML and MDS.

“We have identified a molecular target in leukemic stem cells and a novel drug that performed well against those stem cells in preclinical studies,” Dr. Shastri said.

AML and MDS are rare diseases with the worst prognoses of all cancers: most people who develop relapsed or treatment-resistant disease live for only another 4 to 10 months. Since AML is so difficult to treat, most patients receive care at academic cancer centers. The Comprehensive Cancer Center, with its Blood Cancer Institute and Stem Cell & Cancer Biology Program, is one of few institutions in the country specializing in AML and MDS.

In 2018, Dr. Shastri and colleagues found that relapsed AML and MDS patients with the worst prognosis have leukemic stem cells that express excessive levels of the STAT3 protein. In subsequent studies, her lab found that STAT3 does several things to help MDS and AML cancer cells survive; most importantly, STAT3 prevents cancer cells from undergoing apoptosis, known as programmed cell death—the goal of a major AML/MDS drug called venetoclax. Dr. Shastri hypothesized that blunting the impact of STAT3 could make venetoclax more effective and lead to better outcomes for patients.

Dr. Shastri then looked for compounds that specifically targeted STAT3 and identified the novel targeted drug danvatirsen: a STAT3 inhibitor developed by Flamingo Therapeutics and Ionis Pharmaceuticals that is now being developed as a cancer treatment in early-phase clinical trials. After conducting preclinical tests indicating that danvatirsen shows promise against AML/MDS, Dr. Shastri is investigating the drug in a Phase 1 clinical trial.

The trial will enroll patients with therapy-resistant MDS and AML at the Comprehensive Cancer Center and MD Anderson Cancer Center in Houston, Texas. “Since this is a Phase 1 trial, our first priority is to determine the safety of danvatirsen when used alone and in combination with venetoclax, as well as the optimal dosages for the two drugs,” Dr. Shastri said.

If the researchers find evidence that the experimental treatment has clinical activity, they will expand the study to a Phase 2 trial to further assess the treatment’s effectiveness. The Co-principal Investigator of the clinical trial is Naval G. Daver, MD, at the MD Anderson Cancer Center. Comprehensive Cancer Center Co-investigators on this grant are Marina Konopleva, MD, PhD, Director, Leukemia Program, Co-Director, Blood Cancer Institute, Montefiore Einstein Comprehensive Cancer Center, and Professor, Oncology, Molecular Pharmacology, Albert Einstein College of Medicine, and Ulrich G. Steidl, MD, PhD, Deputy Director, Basic Science, Co-Director, Blood Cancer Institute, Montefiore Einstein Comprehensive Cancer Center, and Chair, Cell Biology, Professor, Cell Biology, Oncology and Medicine, Edward P. Evans Endowed Professor for Myelodysplastic Syndromes, Interim Director, Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine.

The grant is titled “A Phase 1 Study Investigating the Safety & Efficacy of Danvatirsen as Monotherapy Followed by Combination with Venetoclax in Patients with Relapsed/Refractory MDS & AML” (R01FD007836).

Learn more about our clinical trials at Montefiore Einstein Comprehensive Cancer Center.