A Phase 2/3 clinical trial is again recruiting participants to continue investigating the immunomodulator Leukine (sargramostim) in combination with checkpoint inhibitors Yervoy (ipilimumab) and Opdivo (nivolumab) as an initial treatment for patients with melanoma.
The decision to resume enrollment follows positive — but as yet, undisclosed — safety and survival results from the first 250 patients included in the EA6141 trial (NCT02339571).
After a go-ahead from a Data Safety Monitoring Committee, the Phase 3 part is enrolling at more than 500 sites in the U.S.
A total of 600 adults, ages 18 and older, are expected to participate. All will receive an intravenous (into-the-vein) infusion of Yervoy and Opdivo on day 1 of each treatment cycle, and some will be randomly assigned to receive a daily subcutaneous (under the skin) injection of Leukine given in the first two weeks of a cycle. Patients will ultimately undergo four treatment cycles, each lasting 21 days.
The goal is to determine whether the triple combination is better than Opdivo and Yervoy alone at extending patients’ lives. But researchers also will evaluate how long the participants live without disease progression (progression-free survival), the incidence of side effects, the responsiveness of the immune system, and clinical responses as secondary measures.
This Phase 3 trial is intended to confirm the findings from a prior Phase 2 clinical trial, called E1608 (NCT01134614), which showed an improvement to efficacy and a reduction in toxicity when Leukine was added to Yervoy for the treatment of advanced melanoma.
But rather than combining Leukine only with Yervoy, EA6141 will test Leukine plus a combination of Opdivo and Yervoy, which has been found to double the five-year survival of advanced melanoma patients compared with Yervoy.
“The prior data with sargramostim supporting improvement in survival and reduction in immune-related toxicity, as observed in the E1608 study, highlights the importance of further clinical evaluation in combination with checkpoint inhibitors,” Ahmad Tarhini, MD, PhD, a co-leader of the study, said in a press release.
“EA6141 is a very important study in front line melanoma with the possibility of changing the standard of care and I expect a rapid enrollment across a large number of centers throughout the U.S.,” added Tarhini, professor of oncologic sciences and director of cutaneous and clinical translational research at the H. Lee Moffitt Cancer Center and Research Institute, in Florida.
Developed by Partner Therapeutics, Leukine is a version of the protein granulocyte macrophage colony-stimulating factor (GM-CSF), which stimulates the growth of immune system cells and reparation of inflamed tissue.
The treatment was approved by the U.S. Food and Drug Administration (FDA) in 1991 for blood cancer patients undergoing bone marrow transplants, and later in 1996 for recovery of immune system activity following chemotherapy.
As immune checkpoint inhibitors like Yervoy and Opdivo are designed to stimulate the immune system to attack cancerous cells, the addition of Leukine may help improve this response.
“Sargramostim has proven immunologic effects through enhanced T cell priming as well as the ability to repair and restore inflamed tissue, which can result in positive benefits in both efficacy and safety as a combination therapy with checkpoint inhibitors,” said Fiona Garner, executive director of clinical development at Partner Therapeutics.
E1608 enrolled a total of 245 patients with advanced stage melanoma. It found that adding Leukine to Yervoy increased median survival to 17.5 months, compared with 12.7 months with Yervoy alone.
It also decreased the frequency of severe adverse events. In particular, there were significant reductions in the proportion of patients with gastrointestinal side effects (16.1% vs. 26.7%) and pulmonary side effects (0% vs. 7.5%).
These findings prompted the FDA to designate Leukine an orphan drug for the treatment of stage 2b-4 melanoma in 2019, facilitating further development.
“GM-CSF has unique immunomodulatory properties that have the potential to substantially benefit patients with cancer,” said F. Stephen Hodi, MD, a co-leader of the study and director of the center for immuno-oncology at the Dana-Farber Cancer Institute in Boston. “I am particularly pleased, given the many years we have spent in understanding the role of GM-CSF in the laboratory and the clinical setting.”
