An open-label, multicenter, phase 1b/2 study of navtemadlin (KRT-232) in patients with relapsed/refractory acute myeloid leukemia secondary to myeloproliferative neoplasms.
Authors: Rampal Raajit , Ramanathan Sundra , Papayannidis Cristina , von Bubnoff Nikolas , del Mar Tormo Díaz Maria , Vidriales Maria Belen , de la Fuente Burguera Adolfo , Masarova Lucia , Al-Ali Haifa Kathrin , Lavie David , Niyongere Sandrine , Chan Tiffanie , McGreivy Jesse S. , Rothbaum Wayne P. , Mims Alice S. , Cluzeau Thomas 
Published: June 2022

TPS7063 Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) secondary to myeloproliferative neoplasms (MPN) have limited treatment options, resulting in poor prognosis with median overall survival < 6 months (Dunbar 2020). Although conventional AML therapy can induce responses in a subset of patients, it does not prolong survival in AML secondary to MPN (Khan 2017). Navtemadlin is a potent, selective, orally available murine double minute 2 (MDM2) inhibitor that restores p53 activity to drive apoptosis in TP53 wild-type ( TP53WT) malignancies. MDM2 is frequently overexpressed in AML with the majority being TP53WT, suggesting that MDM2 inhibition may be a rational approach for the treatment of AML secondary to MPN (Rampal 2014; Carvajal 2018). Preclinically, navtemadlin had dose-dependent activity reducing leukemic cell burden and significantly prolonging survival in a murine MPN-blast phase, patient-derived xenograft model (Wang 2021). Evidence of clinical activity of navtemadlin monotherapy in R/R AML was observed among TP53WT patients in a Phase 1b dose-escalation study (Erba 2019). In a Phase 2 study of intermediate-high risk R/R myelofibrosis patients, navtemadlin demonstrated clinical activity that correlated with disease-modifying effects (Al-Ali 2020; Vachhani 2021). Together, these studies provide biological and clinical support for evaluating navtemadlin in patients with R/R AML secondary to MPN. Methods: The open-label, multicenter Phase 1b/2 KRT-232-104 study (NCT04113616) is evaluating TP53WT patients with R/R AML secondary to MPN (myelofibrosis, polycythemia vera, or essential thrombocythemia). Eligible patients are aged ≥18 years with ECOG performance status of 0-2 and adequate hepatic and renal function. Patients must have received ≥1 prior lines of therapy for AML secondary to MPN; prior treatment with a FLT3 or IDH1/IDH2 inhibitor is required if appropriate and available. Patients who have undergone allogeneic or autologous stem cell transplantation within 3 months or have active graft-versus-host disease prior to first study dose will be excluded. Patients (n = 12/arm) will be randomly assigned to receive oral navtemadlin once daily in Arm 1: 360 mg 7 days (D) on/21D off, Arm 2: 360 mg 7D on/21D off in Cycle 1 followed by 240 mg 7D on/21D off in subsequent cycles, or Arm 3: 180 mg 7D on/14D off until disease progression or unacceptable toxicity. The primary endpoint is Recommended Phase 2 Dose of navtemadlin. Secondary endpoints include rates of complete remission (CR; per modified 2017 European LeukemiaNet response criteria), CR with partial hematologic improvement, CR with incomplete hematologic recovery, overall response rate, duration of response, progression-free survival, overall survival, and safety. This trial is ongoing and will enroll patients at 65 global sites. Clinical trial information: NCT04113616.