Dr Mascarenhas on the Goals of the Phase 1/2 KRT-232-109 Study in Myelofibrosis

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses the goals of the phase 1/2 KRT-232-109 study (NCT04485260) evaluating the addition of the first-in-class MDM2 inhibitor navtemadlin to ruxolitinib (Jakafi) in patients with primary or secondary myelofibrosis and highlights the eligibility criteria of this trial.

The goal of the phase 1 part of the study was to determine the recommended phase 2 dose (RP2D) of navtemadlin in combination with ruxolitinib for patients with suboptimal myelofibrosis, Mascarenhas begins. Investigators evaluated 3 different dose levels and dose schedules, he explains, adding that the RP2D, based on the clinical and pharmacokinetic results of the phase 1 part, was defined as 240 mg of navtemadlin 7 days in a row out of a 28-day cycle. Therefore, patients were treated with navtemadlin for 1 week on and 3 weeks off in 28-day cycles with at least 8 weeks of stable ruxolitinib dosing, Mascarenhas adds.

The purpose of the ongoing phase 2 portion of the study is to document the efficacy of navtemadlin plus ruxolitinib as measured by spleen volume reduction and symptom improvement at 24 weeks, Mascarenhas continues. At the 2023 EHA Congress, Mascarenhas and investigators presented interim results from the study, demonstrating clear signals of clinical activity.

To be eligible for the study, patients needed to have platelet counts of at least 100 x 109/L, as well as p53 wild-type disease, he expands. Importantly, this approach is speculated to be ineffective in patients who have p53-mutant disease, because MDM2 doesn't regulate mutant p53, he says. Patients with wild-type disease who had been on ruxolitinib for at least 18 weeks were eligible because 18 weeks is the minimum amount of time needed to determine whether a patient has an optimal or suboptimal response to ruxolitinib, Mascarenhas concludes.