A Phase 2 study of SNDX-5613 in combination with chemotherapy for patients with relapsed or refractory KMT2A-rearranged infant leukemia
AALL2121
What is the goal of the study?
KMT2A-rearrangements, which are found in 5-10% of leukemia in all age groups and up to 80% of infant leukemia, generate fusion oncoproteins which contribute to leukemic transformation by altering the epigenetic landscape of target genes. Fusion proteins bind to the chromatin-associated scaffold protein menin, whose recruitment is crucial for activating and maintaining the leukemic transcriptional program. SNDX-5613 is an oral small molecule inhibitor which binds to the KMT2A binding pocket on menin, disrupting the interaction and impairing the activation of leukemia genetic programs, leading to terminal cell differentiation and apoptosis. AALL2121, a COG group-wide phase 2 trial for children with relapsed or refractory KMT2A-rearranged leukemia, will assess the safety, tolerability, and preliminary efficacy of SNDX-5613 in combination with chemotherapy. The trial will consist of two phases: (1) a safety lead-in phase to determine the recommended phase 2 dose (RP2D) of SNDX-5613 in combination with chemotherapy (with both lymphoid- and myeloid-directed blocks), and (2) an expansion phase in which preliminary anti-leukemic activity will be assessed. Patients will receive SNDX-5613 in combination with chemotherapy, with the option to continue monotherapy SNDX-5613 for up to 12 additional cycles. Patients with an acute lymphoblastic leukemia (ALL), acute leukemia of ambiguous lineage (ALAL) or mixed phenotype acute leukemia (MPAL) phenotype can receive either Regimen A (3-drug re-induction followed by fludarabine/cytarabine, FLA) or Regimen B (FLA x 2 cycles) per investigator choice. Patients with an acute myeloid leukemia (AML) phenotype will receive Regimen B (FLA x 2 cycles). KMT2A-R ALL is among the highest risk subsets of pediatric leukemia, and patients with relapsed or refractory disease currently have no effective therapies. The critical dependence of KMT2A-R leukemia on the menin-KMT2A interaction represents a unique vulnerability and provides a rare opportunity to target an oncogenic driver in a population with minimal secondary mutations. Primary Aims 1. To determine the recommended phase 2 dose (RP2D) of SNDX-5613 administered in combination with chemotherapy in patients with relapsed or refractory (R/R) KMT2A-rearranged (KMT2A-R) acute lymphoblastic leukemia (ALL). 2. To estimate the minimal residual disease (MRD) negative remission rate of patients with R/R infant KMT2A-R ALL treated with SNDX-5613 in combination with chemotherapy. See protocol Section 1.0 for secondary and exploratory aims.
Who can participate in the study?
Please contact the study team listed below to learn more.