A Phase Ib/II Study of the Histone Methyltransferase Inhibitor Pinometostat in Combination with Azacitidine in Patients with 11q23-Rearranged Acute Myeloid Leukemia

Background: Chromosomal rearrangements involving the 11q23 locus, resulting in fusions of the Mixed Lineage Leukemia (MLL) gene, are found in 5-10% of adult patients with acute myeloid leukemia and can represent a poor prognostic feature. Patients with this subtype of AML often respond well to standard induction chemotherapy but frequently relapse, even after allogeneic hematopoietic stem cell transplantation. Effective therapy options in the relapsed / refractory setting for this high-risk group represent an urgent unmet clinical need. In MLL-rearranged AML, recruitment of disruptor of telomeric silencing 1-like (DOT1L), a histone H3 lysine 79 (H3K79) methyltransferase, and subsequent changes in methylation of downstream targets HOXA9 and Meis1 is central to leukemogenesis. DOT1L-mediated expression of MLL target genes is critical to developing leukemia in a murine model and inhibition of DOT1L suppressed downstream expression of MLL target genes. Pinometostat is a potent and selective small molecule inhibitor of DOT1L methyltransferase activity. Use of pinometostat in a continuous IV infusion in a rat xenograft model of MLL-rearranged leukemia showed complete, sustained tumor regressions without significant appreciable toxicities. A recent single-agent, phase I trial evaluated pinometostat in R/R patients with MLL-R myeloid malignancies. This study included 43 patients with MLL-R AML and observed that the drug was generally well-tolerated. Responses to pinometostat included one patient with morphologic CR, one with cytogenetic CR, three with resolution of leukemia cutis, and nine with signs of differentiation / leukocytosis. Promoter hypermethylation contributes to the dysregulation of MLL-R target genes HOXA9 and Meis1, and this effect was reversed upon treatment with the hypomethylating agent azacitidine. As such, this combination may lead to a more robust response in this patient population. We now seek to combine the novel, targeted agent pinometostat with azacitidine in R/R MLL-R AML. Study design & methods: We are conducting an open-label, single-arm, phase Ib / II study that will enroll 36-48 patients with R/R MLL-R AML to evaluate the tolerability and preliminary efficacy of pinometostat in combination with azacitidine. Since MLL-R AML is a rare disease and is seen in only 5-10% of patients with AML, we are looking to collaborate with other centers through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN) to