Grants and Contracts Details
Description
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.
Status | Active |
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Effective start/end date | 8/1/24 → 7/31/31 |
Funding
- Public Health Institute: $2.00
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