NEW YORK – The Leukemia & Lymphoma Society (LLS) will evaluate Kura Oncology's menin inhibitor ziftomenib in its ongoing Pediatric Acute Leukemia (PedAL) master protocol trial in infants and children with KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemia.
The PedAL trial, which began in 2022, is enrolling pediatric patients with relapsed acute leukemias. Patients first enroll in the PedAL screening trial, in which their bone marrow and blood samples are tested for biomarkers, which then inform their enrollment in a PedAL subtrial of a drug for that biomarker.
LLS partners with the US National Cancer Institute, Children’s Oncology Group, and the Innovative Therapies for Children and Adolescents with Cancer consortium to identify PedAL participants for biomarker-defined subtrials. "It's an efficient one-stop shop for enrollment on therapeutic precision medicine trials," LLS CEO E. Anders Kolb said. "This platform makes it easier for companies to open trials for kids."
Researchers plan to test ziftomenib, the latest drug to be added to the PedAL protocol, with different standard treatments, including two chemotherapy regimens and Astellas' FLT3 inhibitor Xospata (gilteritinib), in 20 patients up to 21 years old with relapsed or refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemia. There are currently sites enrolling patients into this Phase I study in the US, Canada, Spain, the Netherlands, France, and Austria from the PedAL screening trial, Kolb said.
Ziftomenib is a small-molecule oral drug that inhibits the interaction between menin and the KMT2A protein. Rather than killing the cancer cells, menin inhibitors lead stem cells to differentiate into normal adult cells.
Before making its drug available within the PedAL study, Kura began testing ziftomenib in adults with AML. The firm is studying ziftomenib as a monotherapy and in combination with other therapies in several ongoing studies in KMT2A-rearranged or NMP1-mutant acute myeloid leukemia (AML) and in gastrointestinal stromal tumors. These studies are enrolling only adult patients with AML.
Kolb noted that pediatric trials, especially studies focusing on young patients with specific biomarker-defined cancers, can be more challenging for pharma companies to enroll because the cohorts are small.
"Anytime we're studying a rare subset of a rare disease … we need to study children across the country [and] across the globe to get enough kids who will be eligible for the study," Kolb said, noting that leukemia itself is rare in children. "Any company that's looking to get into pediatrics, we want to be there to help them develop a trial that's meaningful for kids and that will be able to enroll enough participants and complete its objectives."
Because these trials are challenging, pharma companies often defer studying drugs in pediatric cancers, despite regulatory incentives and requirements, Kolb added. This can lead to a long gap between drug approvals for adult and pediatric patients, he said. "We want to be able to facilitate the rapid and efficient deployment of those trials for kids because the earlier kids get access to these drugs, the better," he said.
Menin inhibitors are a particularly exciting opportunity for the subset of young leukemia patients with KMT2A, NMP1, and NUP98 alterations. Kolb noted that these alterations occur in about 40 percent of children with AML. KMT2A is particularly prevalent in infants with leukemia, he added, with about 80 percent of pediatric acute lymphoblastic leukemia patients having a genetic rearrangement of the KMT2A gene. These alterations cause cellular disruptions that rely on the menin transcription factor, which is a tumor suppressor.
"Menin inhibitors are therapies that LLS has been following for a couple decades now," Kolb said. "It was in the mid-2000s that we first funded basic science research to study menin as a target for the anti-leukemia therapy, and we helped to bring the first molecule out of the lab [and] into the hands of a drug company where it could get developed for commercialization."
Menin inhibitors are just beginning to enter the market for adult patients. For instance, last year, the US Food and Drug Administration approved Syndax Pharmaceuticals' Revuforj (revumenib), making it the first menin inhibitor to reach the market, for treating adult and pediatric patients 1 year and older with relapsed or refractory acute leukemia harboring KMT2A translocations. Syndax is also studying Revuforj in a pivotal trial in adult patients with relapsed or refractory NPM1-mutant AML.
Revuforj raised the profile for menin inhibitors and increased drugmakers' interest in advancing other agents in the class like ziftomenib in adults and kids. In January 2024, Kura reported preliminary results from the Phase I KOMET-007 trial of ziftomenib with either AbbVie's BCL-2 inhibitor Venclexta (venetoclax) and azacitidine or with a standard cytarabine/anthracycline-based chemotherapy regimen in adult patients with NPM1-mutant or KMT2A-rearranged AML. Among 15 relapsed or refractory AML patients in this trial, the overall response rate to ziftomenib and Venclexta was 53 percent, with five patients achieving a complete remission or complete remission with partial hematologic recovery. In the ziftomenib-chemo cohort, all five newly diagnosed AML patients achieved a complete remission.
In March, Kura submitted an application to the FDA seeking approval for ziftomenib for the treatment of adult patients with relapsed or refractory AML with an NPM1 mutation. If investigations in PedAL are successful, it would open an avenue for Kura to seek approval for ziftomenib in pediatric leukemia patients, as well.
Under the terms of Kura's agreement for the PedAL trial, LLS and the Princess Máxima Center are sponsoring the Phase I study of ziftomenib in pediatric patients with acute leukemias. Kura is supplying ziftomenib for the study. The company has not yet disclosed its regulatory plans or submission timelines for ziftomenib in the pediatric setting, a Kura spokesperson said.
"Kura remains committed to developing new treatment options across the continuum of care, including for pediatric patients with acute leukemias where poor outcomes and significant unmet medical need remain," Mollie Leoni, executive VP of clinical development at Kura, said in a statement recently. "We are proud to collaborate with an exceptional organization such as LLS, which recognizes the importance of expanding patient populations beyond adults to provide effective therapies to infants and children with blood cancers."