Contributions
Abstract: PB1408
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including that of MEIS1 and the homeobox gene family, which are known to be important for maintenance of leukemia when dysregulated. In 5-10% of acute myeloid leukemia (AML) cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognosis. The Menin-KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations in genes such as NPM1, IDH1/2, FLT3, EZH2, and DNMT3A, with NPM1 mutation accounting for 25-30%. Therefore, there is strong rationale for targeting these AML subsets, which may be exquisitely sensitive to the menin-KMT2A complex inhibition.
Aims
The objectives of the Phase (Ph) 1 dose escalation are to assess safety and tolerability, characterize the pharmacokinetics (PK), determine a recommended Ph2 dose (RP2D), and investigate early signs of anti-leukemic activity. The Ph1 expansion cohorts will assess anti-leukemic activity, PK, safety and tolerability in AML pts with NPM1 mutation or KMT2A rearrangement at doses that have already met the safety threshold to help determine a minimally safe and biologically effective dose. Once a RP2D has been determined, Ph2 expansion cohorts including AML pts with NPM1 mutation or KMT2A rearrangements will be conducted to assess safety, tolerability and efficacy at the RP2D.
Methods
KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction. KOMET-001 (NCT04067336) is an ongoing Ph1/2 open-label study evaluating KO-539 in adult patients (pts) with relapsed or refractory (R/R) AML. Key inclusion criteria include: R/R AML defined as the appearance of > 5% blasts in the bone marrow and who have failed or are ineligible for any approved standard of care therapies, including transplant, ECOG performance status of 0 to 2, and adequate organ function. Key exclusion criteria include: pts with acute promyelocytic leukemia or chronic myelogenous leukemia in blast crisis, clinically active central nervous system leukemia, pts who have undergone transplant and have not had adequate hematologic recovery or with Grade >2 active graft-versus-host disease issues, or pts on concomitant drugs that are strong inhibitors or inducers of CYP3A4 except for antibiotics, antifungals, and antivirals. All pts are being followed for safety during treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. Anticipated efficacy assessment will include assessment of: complete remission (CR) plus complete remission with partial hematologic recovery (CRh) composite; CR with and without minimal residual disease (MRD), and duration of remission (DOR) as key secondary endpoints. Additional anticipated assessments in the expansion cohorts will include transfusion independence, relapse-free survival (RFS), and overall survival.
Exploratory biomarkers will be examined in bone marrow biopsies/aspirate as well as peripheral blood collected serially from all pts pre- and post-treatment.
KOMET-001 is continuing to enroll pts in dose escalation and, in parallel, will be enrolling Ph1 expansion cohorts in genetically defined populations to better inform the RP2D. This will be followed by the Ph2 expansion portion in genetically defined populations once a RP2D is determined.
Results
N/A (trial in progress)
Conclusion
N/A (trial in progress)
Keyword(s): AML, MLL
Abstract: PB1408
Type: Publication Only
Session title: Acute myeloid leukemia - Clinical
Background
The histone-lysine-N-methyltransferase 2A (KMT2A) gene (formerly known as mixed-lineage leukemia (MLL)) plays an essential role in regulating gene expression including that of MEIS1 and the homeobox gene family, which are known to be important for maintenance of leukemia when dysregulated. In 5-10% of acute myeloid leukemia (AML) cases, specific KMT2A gene perturbations can occur which result in an aggressive and poor prognosis. The Menin-KMT2A complex also appears to play a central role in the epigenetic dysregulation in AMLs with co-mutations in genes such as NPM1, IDH1/2, FLT3, EZH2, and DNMT3A, with NPM1 mutation accounting for 25-30%. Therefore, there is strong rationale for targeting these AML subsets, which may be exquisitely sensitive to the menin-KMT2A complex inhibition.
Aims
The objectives of the Phase (Ph) 1 dose escalation are to assess safety and tolerability, characterize the pharmacokinetics (PK), determine a recommended Ph2 dose (RP2D), and investigate early signs of anti-leukemic activity. The Ph1 expansion cohorts will assess anti-leukemic activity, PK, safety and tolerability in AML pts with NPM1 mutation or KMT2A rearrangement at doses that have already met the safety threshold to help determine a minimally safe and biologically effective dose. Once a RP2D has been determined, Ph2 expansion cohorts including AML pts with NPM1 mutation or KMT2A rearrangements will be conducted to assess safety, tolerability and efficacy at the RP2D.
Methods
KO-539 is a novel, once daily, oral investigational drug candidate targeting the menin-KMT2A protein-protein interaction. KOMET-001 (NCT04067336) is an ongoing Ph1/2 open-label study evaluating KO-539 in adult patients (pts) with relapsed or refractory (R/R) AML. Key inclusion criteria include: R/R AML defined as the appearance of > 5% blasts in the bone marrow and who have failed or are ineligible for any approved standard of care therapies, including transplant, ECOG performance status of 0 to 2, and adequate organ function. Key exclusion criteria include: pts with acute promyelocytic leukemia or chronic myelogenous leukemia in blast crisis, clinically active central nervous system leukemia, pts who have undergone transplant and have not had adequate hematologic recovery or with Grade >2 active graft-versus-host disease issues, or pts on concomitant drugs that are strong inhibitors or inducers of CYP3A4 except for antibiotics, antifungals, and antivirals. All pts are being followed for safety during treatment and up to approximately 28 days after treatment discontinuation, or until immediately before the initiation of another anticancer therapy, whichever occurs first. Anticipated efficacy assessment will include assessment of: complete remission (CR) plus complete remission with partial hematologic recovery (CRh) composite; CR with and without minimal residual disease (MRD), and duration of remission (DOR) as key secondary endpoints. Additional anticipated assessments in the expansion cohorts will include transfusion independence, relapse-free survival (RFS), and overall survival.
Exploratory biomarkers will be examined in bone marrow biopsies/aspirate as well as peripheral blood collected serially from all pts pre- and post-treatment.
KOMET-001 is continuing to enroll pts in dose escalation and, in parallel, will be enrolling Ph1 expansion cohorts in genetically defined populations to better inform the RP2D. This will be followed by the Ph2 expansion portion in genetically defined populations once a RP2D is determined.
Results
N/A (trial in progress)
Conclusion
N/A (trial in progress)
Keyword(s): AML, MLL