A Phase 1a/b Dose Escalation Study of Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

INTRODUCTION: APTO-253 has captured attention because of its distinguishing mechanism of action as the only known a small molecule in clinical development to target a conserved structure in the promoter of the MYC oncogene and interrupt MYC gene expression. In preclinical studies of acute myeloid leukemia (AML) cell lines, APTO-253 was discovered to potently down-regulate MYC gene expression, reduce MYC mRNA and protein level, induce apoptosis, and deplete cells of the MYC oncoprotein. APTO-253 demonstrated broad killing of primary mononuclear cells isolated from the bone marrow of patients with AML, MDS or MPN and enhanced AML cell killing when combined with BET bromodomain inhibitors or FLT3 inhibitors (Kurtz, Blood 2017 126:1358). Because dysregulated MYC is considered a major oncogenic operator in AML and myelodysplasias and because APTO-253 has such a distinct mechanism to kill such cells, APTO-253 has been granted orphan drug designation for the treatment of AML by the US FDA and is currently in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS).

METHODS: APTO-253 is being evaluate in an ongoing clinical trial, entitled "A Phase I a/b Dose Escalation and Expansion, Multicenter, Open-label, Safety, Pharmacokinetic and Pharmacodynamic Study of APTO-253 in Patients with Relapsed or Refractory Acute Myelogenous Leukemia or High-Risk Myelodysplasia (NCT02267863)". The protocol provides for patients to be dosed once weekly on days 1, 8, 15, and 22 of each 28-day cycle with the intended dose levels of 20, 40, 66, 100, 140, 180 or 220 mg/m². Eligible patients must be ≥18 years old, have a life expectancy of at least 2 months, and have acceptable hematologic, renal and liver functions and coagulation status parameters. Primary objectives are to determine the safety and tolerability of APTO-253, to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT), and to establish the recommended Phase 2 dose for patients with specific types of hematologic malignancies. Key secondary objectives are to seek evidence of antitumor activity by hematologic and bone marrow evaluations and to assess the impact of APTO-253 on the expression of pharmacodynamic biomarkers (including MYC and p21 gene expression).

RESULTS: To date, R/R AML and high-risk MDS patients have been enrolled and treated at dose levels of 20, 40 and 66 mg/m² APTO-253. As specified by the protocol, only one patient was required at each of the 20 and 40 mg/m² doses. The AML patient on the lowest dose level completed the 28-day cycle and demonstrated approximately a 72% reduction in MYC expression levels in peripheral white blood cells during the cycle. The high-risk MDS patient who received 40 mg/m² demonstrated a 79% reduction in MYC expression during the first cycle. To date (as of July 2019), no drug related TEAEs, SAEs or dose limiting toxicities have been reported. Two patients are receiving treatment with 66 mg/m², and samples are being analyzed for a series of pharmacodynamic markers.

CONCLUSIONS: APTO-253 is a potent molecule with a particularly interesting and novel mechanism of action that results in robust suppression of MYC expression. The Phase 1 a/b trial has successfully enrolled R/R-AML and HR-MDS patients into the first three cohorts at 20, 40 and 66 mg/m². Clinical data to date suggest APTO-253 is generally well tolerated at the doses tested, and target engagement has been evidenced by the reduction in cellular MYC gene expression in whole blood samples from R/R AML and high-risk MDS patients. Recruitment and enrollment are continuing, and updated safety, PK and biomarker data will be presented at the meeting.