This phase Ib/II trial studies the side effects and best dose of FT-2102 when given together with ASTX727 in treating patients with IDH1-mutated myelodysplastic syndrome or acute myeloid leukemia that has come back (recurrent) or does not respond to treatment (refractory). ASTX727 is an oral deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor. DNA methylation is necessary for cell differentiation and development. Changes to the methylation profile can lead to DNA instability which can cause diseases like cancer. DNMT inhibitors target and inhibit these changes. FT-2102 is an isocitrate dehydrogenase 1 (IDH1) inhibitor. IDH1 is a type of protein involved in metabolism, or the process of providing the body’s cells with energy. FT-2102 may stop the abnormal IDH1 protein and may reduce 2-HG levels in diseased cells to levels found in normal cells. Giving ASTX727 and FT-2102 may work better in treating patients with myelodysplastic syndrome or acute myeloid leukemia compared to ASTX727 and FT-2102 alone.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04013880.
PRIMARY OBJECTIVES:
I. To evaluate the safety of IDH-1 inhibitor FT-2102 (FT-2102) in combination with CDA inhibitor E7727/decitabine combination agent ASTX727 (ASTX727) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients with IDH1 R132 mutations. (Phase Ib)
II. To evaluate the response rate (overall response rate [ORR], complete response [CR], complete remission with partial hematologic recovery (CRh), complete remission with incomplete blood count recovery [CRi], morphologic leukemia-free state [MLFS], partial response [PR]) of the combination of ASTX727 and the IDH1-inhibitor, FT-2102 in subjects with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with IDH1 R132 mutations. (Phase II)
SECONDARY OBJECTIVES:
I. To confirm the phase II recommended dosing level of FT-2102 and ASTX727 in combination. (Phase Ib)
II. To determine the pharmacokinetics of FT-2102 and ASTX727 in combination. (Phase Ib)
III. To determine the reduction of bone marrow blasts. (Phase II)
IV. To determine the overall survival and event-free survival. (Phase II)
V. To determine the levels of 2-HG in the blood and blood cells after treatment. (Phase II)
VI. To determine the relationship of 2-HG reduction to clinical response. (Phase II)
EXPLORATORY OBJECTIVES:
I. To determine genetic biomarkers of treatment response or resistance in IDH1-mutated MDS/AML via next generation sequencing (NGS). (Phase II)
II. To characterize genome methylation and epigenetic alterations before and after treatment within bone marrow mononuclear cells from responders and non-responders. (Phase II)
III. To determine gene expression changes from pre-treatment to post-treatment via ribonucleic acid (RNA) sequencing. (Phase II)
IV. To conduct single cell assessment of differentiation, signaling, transcriptional responses, clonal architecture and cellular microenvironment via mass cytometry (CyTOF) and single cell genomic and transcriptomic sequencing. (Phase II)
OUTLINE: This is a phase Ib, dose-escalation of IDH-1 inhibitor FT-2102 followed by a phase II study.
Patients receive CDA inhibitor E7727/decitabine combination agent ASTX727 orally (PO) once daily (QD) on days 1-5 and IDH-1 inhibitor FT-2102 PO QD or twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, every 3 months for 12 months, and then periodically for up to 5 years.
Lead OrganizationVanderbilt University/Ingram Cancer Center
Principal InvestigatorPaul Ferrell
