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

INTRODUCTION: APTO-253 is the only known small molecule in clinical development to target a conserved G-quadruplex 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 potently down-regulates MYC gene expression, reduces MYC mRNA and protein level, depletes cells of the MYC oncoprotein and induces apoptosis (Local et al., 2018). 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, et al., 2017). Fe(253)₃, a ferrous complex formed from parental APTO-253 when it chelates iron, exhibits similar in vitro anti-tumor potency as its monomeric form (Tsai, et al., 2018). Because dysregulated MYC is considered a major oncogenic operator in AML and myelodysplasias, and because APTO-253 has such a distinct cytotoxic mechanism, 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 (NCT02267863) in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS).

AIMS: Primary objectives are to determine the safety and tolerability of APTO-253, to determine the maximum tolerated dose and the dose limiting toxicities (DLT), and to establish the recommended Phase 2 dose for future clinical trials in patients with R/R AML or high-risk MDS. Key secondary objectives are to assess the pharmacokinetic (PK) profile, pharmacodynamic (PD) activity, and preliminary evidence of antitumor activity.

METHODS: Eligible patients are those with R/R AML or high-risk MDS for which either standard treatment has failed, is no longer effective, or can no longer be administered safely. Treatment- emergent adverse events (TEAEs) and tumor responses are evaluated using International Working Group criteria. APTO-253 is administered by IV infusion once weekly on days 1, 8, 15, and 22 of each 28-day cycle; ascending dose cohorts will enroll at a starting dose of 20 mg/m² with planned escalating to 403 mg/m².

RESULTS: As of July 28, 2020, a total of 10 patients (age 66.1 ± 13.58 years, male 50%, female 50%, 8 AML and 2 MDS) have been treated with APTO-253 in this clinical trial at doses of 20 mg/m² (n=1), 40 mg/m² (n=1), 66 mg/m² (n=4), and 100 mg/m² (n=4). All 8 AML patients and 1 MDS patient were RBC and platelet transfusion dependent; 1 MDS patient was RBC transfusion dependent. No DLTs or drug-related serious adverse events have been reported. Possible drug related grade 2 TEAEs included fatigue, increased alkaline phosphatase, decreased appetite, hematoma, hypokalemia, thrombophlebitis, upper respiratory tract in 1 (10%) patient each. Only 1 TEAE of grade 3 or greater (fatigue, considered possibly drug-related) has occurred to date. Preliminary PK analysis showed plasma levels of APTO-253 were dose proportional. C_max and AUC_0-24h on cycle 1 day 1 (C1D1) were 0.18, 0.07, 0.28 ± 0.15 and 0.77 ± 0.63 µM and 0.08, 0.13, 1.14 ± 0.57, 1.84 ± 0.41 µM*h for dose levels of 20 mg/m², 40 mg/m², 66 mg/m², and 100 mg/m², respectively. Not surprisingly, Fe(253)₃ was detected in the patients’ plasma immediately after dosing and at a significantly higher concentration than the APTO-253 monomer. For example, C_max and AUC_0-24h of Fe(253)₃ on C1D1 of patients in Cohort 66 mg/m² were 3- and 8-fold higher than the monomer at 0.92 ± 0.29 µM and 20.61 ± 9.01 µM*h, respectively. The levels of MYC mRNA in the whole blood, a PD biomarker of APTO-253 and Fe(253)₃ measured by RT-qPCR, were reduced 20-48% at 24 h post-dose as compared to pre-dose in the first 3 cohorts (other samples of Cohort 100 mg/m² in process), suggesting target engagement by the drug.

CONCLUSIONS: APTO-253 has been well-tolerated in patients treated with 20, 40, 66, and 100 mg/m² over multiple cycles. PK analysis revealed APTO-253 monomer rapidly transformed to and co-existed with the Fe(253)₃ complex in peripheral blood and their exposures resulted in suppression of MYC expression in whole blood samples from R/R AML and high-risk MDS patients. Enrollment of patients at the 150 mg/m² dose level is underway and updated clinical data will be presented at the meeting.