New Therapeutic Approach to Shut Down Cancer Genes Shows Early Promise

Study could lead to new ways to treat myelofibrosis, a rare blood cancer.

Myelofibrosis is an unusual type of blood cancer. Patients develop scar tissue in their bone marrow, accompanied by symptoms such as enlargement of the spleen and fatigue-causing anemia.

The rare condition is difficult to treat, and many patients do not respond to current approaches or relapse. A new type of potential therapy, being tested in a study led by Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, offers the possibility of improved treatment options.

Preliminary data on the early-stage clinical study was presented by Sylvester physician Justin Watts, M.D., at the American Society for Hematology’s annual meeting Monday, Dec. 11.

The results suggest that the experimental therapy, a so-called BET inhibitor, may be safe at lower doses in patients with myelofibrosis and related cancers. The results also hint that the agent may be effective at reducing spleen size and alleviating other symptoms, when used alone or in combination with a currently-used drug.

Dr. Watts called the BET inhibitor “a totally new type of anti-cancer therapy.”

Finding the Right Dose

BET inhibitors work by shutting down a broad range of genes, including those that drive cancer. Their widespread actions on the genome mean that BET inhibitors have the potential to kill tumors effectively. But this class of experimental agents can also result in unsafe side effects like low platelet count in the blood.

The ongoing phase 1 study is designed to test the safety of the new BET inhibitor—called INCB057643—and identify an ideal dose for future studies. Researchers are evaluating side effects at different doses and also conducting preliminary tests on the agent’s effectiveness against disease.

The data so far suggest that INCB057643 is safe at all but the highest dose in patients with advanced myelofibrosis or related conditions. Some of the patients also showed a reduction in symptoms and indicators of disease. For instance, five of nine patients evaluated after 12 weeks had reduced spleen volume.

Preliminary data from a few patients also hint that INCB057643 may be safe and possibly reduce symptoms when used in combination with the drug ruxolitinib, which is currently used to treat patients.

Opening the Therapeutic Window

“The most important thing about this phase 1 study is that the inhibitor is safe and well tolerated,” said Dr. Watts. In addition, it appears to ease a range of symptoms, including fatigue, bone pain and night sweats. He is particularly heartened by the possibility that the approach may also counteract anemia.

Sylvester Comprehensive Cancer Center researcher Justin Watts, outside the cancer center building
Justin Watts, M.D.

“Anemia is often a major problem in this disease, and it usually gets worse with therapy, not better,” said Dr. Watts. “We’ve had patients get completely transfusion independent who were needing red blood cells transfused every other week,” he added.

The data also suggest that the side-effect profile of INCB057643 may compare favorably to other BET inhibitors under evaluation, he said.

“We’ve been able to dose the drug at a low enough dose, but it’s still active,” said Dr. Watts. “It has an unexpectedly good therapeutic window, where you don’t need that much to have the desired positive effect, especially when you give it in combination with the standard of care agent, ruxolitinib.”

Combinations are the Future

A high proportion of myelofibrosis patients respond “suboptimally” to ruxolitinib, said Dr. Watts. That might be the ideal patient group for combination therapy with the BET inhibitor, he said, noting that the two therapies have different side-effect profiles and may act synergistically at low doses that avoid toxicity.

Ultimately, Dr. Watts and his team aim to build on the phase 1 study with a larger phase 3 study, testing the BET inhibitor or a placebo in combination with ruxolitinib. “The field is likely going to move to combination therapies,” said Dr. Watts.

Questions for the future include the effects of the treatment on bone marrow scarring and patient survival.

Meanwhile, Dr. Watts and his colleagues continue to enroll patients in the phase 1 study, where they plan to continue assessing the optimal dosages for the next steps and evaluating the effects on cancer.

Because myelofibrosis is rare, the study pulls in patients from multiple cancer centers.

“We work with many of the other best cancer centers in the country and globally. And it’s really exciting to have the exchange of ideas and to see how each other’s patients are doing,” said Dr. Watts.

The researchers may also expand the current study to include patients with additional conditions. So far, patients treated with the BET inhibitor alone have had advanced myelofibrosis or the related myelodysplastic syndromes (MDS), including MDS/myeproliferative neoplasm overlap syndromes (MDS/MPN). Patients taking the combination of the inhibitor with ruxolitinib have had myelofibrosis and suboptimal responses to the older drug.

INCB057643 is being developed by Incyte Corporation, which is sponsoring the phase 1 study and also markets ruxolitinib. Dr. Watts is not affiliated with the company.

“I’m proud of bringing these new agents to the patients in the clinic. Our patients have failed standard therapies and they don’t have many options,” said Dr. Watts. “It’s exciting to offer the hope of a new therapy that is unavailable at most cancer centers in the country.”

Tags: ASH2023, blood cancers, Dr. Justin Watts, myelofibrosis, Sylvester Comprehensive Cancer Center