APAL2020K/ITCC-101: A Phase I Trial of the Menin Inhibitor Ziftomenib in Combination with Chemotherapy in Children with Relapsed/Refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant Acute Leukemias
Authors: Salzer Elisabeth , Stutterheim Janine , Cuglievan Branko , Tomkinson Blake E. , Leoni Mollie , Van Tinteren Harm , Huitema Alwin D.R. , Willemse Marieke , Nichols Gwen L , Bautista Francisco , Tasian Sarah K. , Cooper Todd M , Zwaan Christian 
Published: December 2024

Background and Significance: Aberrant expression of HOX family and MEIS1 genes, commonly found in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemias, leads to arrested differentiation and leukemia development. HOX family genes are crucial regulators of normal hematopoiesis, and their expression is controlled by the KMT2A-menin interaction. Robust preclinical activity of ziftomenib, a potent and orally bioavailable inhibitor of this interaction, against these high-risk leukemia subtypes has been demonstrated. Initial data from the KOMET-001 phase 1/2 clinical trial (NCT04067336) reported 35% complete remission rates in adults with relapsed/refractory NPM1-m acute myeloid leukemia (AML) treated with ziftomenib monotherapy (Fathi EHA 2023 abstract #LB2713). Given the high-risk nature and prevalence of these leukemias in pediatric patients, we designed a phase 1 clinical trial to assess the safety and determine the recommended phase 2 dose (RP2D) of ziftomenib in combination with chemotherapy for children with relapsed/refractory acute leukemias.
Study Design and Methods: ITCC-101/APAL2020K (NCT06376162) is an international multicenter phase 1 clinical trial investigating ziftomenib administered orally once daily with fludarabine 30 mg/m2 and cytarabine 2000 mg/m2 administered intravenously once daily on days 1-5 (FLA regimen) in pediatric patients 0 to 21 years of age with first or greater relapsed/treatment-refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant AML, acute lymphoblastic leukemia (ALL), mixed phenotype acute leukemia (MPAL), or acute undifferentiated leukemia (AUL). In cycle 1, ziftomenib therapy will start on day 8 to investigate the potential to mitigate risk of differentiation syndrome and will be continued for 28-42 days. Subsequent therapy may continue in 28-day cycles with ziftomenib given as monotherapy or in combination with FLA chemotherapy at investigators' discretion depending upon response and safety data.
Patients must have performance status ≥50%, adequate end-of-organ function, and sufficient wash-out of prior anti-cancer therapies. Exclusion criteria include isolated CNS relapse and symptomatic CNS3, known bone marrow failure syndromes, juvenile myelomonocytic leukemia or acute promyelocytic leukemia, uncontrolled infection, and concomitant proton pump inhibitor use. The study will employ a rolling six design in its primary objective to explore the safety and pharmacokinetics (PK) of ziftomenib with FLA chemotherapy and to identify the recommended phase 2 dose of ziftomenib in cohorts of patients with AML or with ALL/MPAL/AUL. Given potential for differential ziftomenib metabolism and PK in youngest children, participants &lt;2 years old (stratum B) may enroll following establishment of safe ziftomenib/FLA dosing in at least three children 2 years of age (stratum A).
Secondary and exploratory objectives include investigation of ziftomenib pharmacodynamics and preliminary assessment of clinical efficacy within a phase 1 trial, including estimation of remission induction with flow cytometric and molecular measurable residual disease assessments, rates of subsequent allogeneic hematopoietic stem cell transplantation (HSCT), and 2-year event-free and overall survival. The study will also assess the feasibility of single-agent ziftomenib post-transplant ‘maintenance’ therapy for relevant patients and as continuation therapy for those in ziftomenib/FLA-induced remission who do not proceed to HSCT. Up to 32 participants will be enrolled.
Conclusion: The overarching goal of the APAL2020K/ITCC-101 phase 1 trial is to develop a safe and effective therapeutic regimen of ziftomenib in combination with multi-agent chemotherapy for children, adolescents, and young adults with high-risk genetic subtypes of acute leukemias targetable by menin inhibition. If successful, this precision medicine approach could significantly improve clinical outcomes for this challenging pediatric patient population with persistent unmet medical need.