This phase I trial studies the safety of enasidenib in improving blood counts in patients with clonal cytopenia of undetermined significance (CCUS) and an IDH2 mutation. CCUS is a condition in which low levels of certain kinds of blood cells occur without a known cause. Some blood cells have a change (mutation) in a gene called IDH2 (isocitrate dehydrogenase 2); this mutation changes the proteins that the gene expresses (makes). When IDH2 proteins are mutated, they produce too much 2-hydroxyglutarate (2-HG), a substance found in low levels in normal cells. Too much 2-HG can cause changes in cells, and these changes may cause low blood cell counts. CCUS can lead to a pre-cancerous condition called myelodysplastic syndrome (MDS) or a blood cancer called acute myeloid leukemia (AML). Giving enasidenib may can shrink or stabilize cancer with a change in the IDH2 gene and improve blood counts.
Additional locations may be listed on ClinicalTrials.gov for NCT05102370.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVE:
I. Assess whether treatment with enasidenib can induce a hematologic response in patients with clonal cytopenia of undetermined significance (CCUS), thereby establishing that enasidenib has clinical activity in IDH2-mutant CCUS.
SECONDARY OBJECTIVES:
I. Assess the safety and tolerability of enasidenib in patients with IDH2-mutant CCUS.
II. Modification of disease biology as assessed by a decrease in mutant IDH2 variant allele fraction.
III. Determine acute myeloid leukemia (AML)–free or myelodysplastic syndrome (MDS)–free survival among patients with CCUS treated with enasidenib.
EXPLORATORY OBJECTIVES:
I. Evaluate 2-hydroxyglutarate (2HG) levels before, during, and after treatment with enasidenib.
II. Characterize the effects of enasidenib on cellular differentiation, as measured by flow cytometry performed at study entry and at serial points throughout the study.
III. Characterize the effects of enasidenib on promotor methylation patterns, as measured by enhanced reduced representation bisulfite sequencing performed at study entry and at serial points throughout the study.
IV. Evaluate the effects of enasidenib on gene expression.
V. Evaluate changes in the gene mutation status of leukemic cells after treatment with enasidenib by assessing the variant allele frequency of non-IDH2 mutations, by use of next generation sequencing at study entry and at serial points throughout the study.
VI. Assess the clonal structure of co-occurring non-IDH2 mutations, by use of single-cell sequencing.
VII. Compare changes in variant allele frequency (VAF) of IDH2 mutations and the rate of detection of new mutations during the study period in individuals who are receiving enasidenib compared with external longitudinal cohorts of individuals with clonal hematopoiesis (CH) drawn from Memorial Sloan Kettering (MSK) and the Chalit database.
OUTLINE:
Patients receive enasidenib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days for up to 18 months in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and bone marrow and/or aspiration at screening and throughout study.
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorEytan M. Stein
