Abstract

OPB‑111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two‑stage, 3+3 dose‑escalation clinical trial [dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28‑day cycles] was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB‑111077 in patients with high‑risk AML. A preliminary preclinical analysis evaluated the anti‑proliferative activity of OPB‑111077 in 19 patients with AML with a Vivia Biotech <em>ex vivo</em> PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB‑111077. Dose‑limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment‑emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB‑111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high‑risk AML. A biomarker‑driven design is useful for selecting the study population upfront.

Highlights

  • Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic progenitor cell disorder characterized by immature myeloid cell proliferation and bone marrow failure, exhibiting a spectrum of morphological, immunophenotypic, cytogenetic and molecular characteristics [1].acute myeloid leukemia (AML) is an aggressive disease with a poor prognosis [2,3]

  • This was the starting point to further expand the number of samples reaching statistical significance and converging in population models in order to achieve a better characterization of OPB‐111077

  • The pharmacological profiles revealed a high interpatient variability in the patient samples incubated with OPB‐111077 and in those incubated with decitabine

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Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic progenitor cell disorder characterized by immature myeloid cell proliferation and bone marrow failure, exhibiting a spectrum of morphological, immunophenotypic, cytogenetic and molecular characteristics [1].AML is an aggressive disease with a poor prognosis [2,3]. >50% of patients with AML are MARTÍNEZ-LÓPEZ et al: OPB-111077 IN ACUTE MYELOID LEUKEMIA not candidates for intensive chemotherapy therapy due to their age, performance status and/or associated comorbidities [4]. Two‐thirds of patients with AML who achieve a complete remission (CR) will relapse within the following 18 months [6], and regrettably, there are no safe and effective curative treatments, apart from alloHSCT, which is a rather aggressive therapeutic modality with high treatment‐related morbidity and mortality [5]. Given the significant incidence of relapsed AML and the frequent toxicities associated with standard intensive chemo‐ therapy, an optimal treatment strategy for this population remains unsatisfactory and has yet to be established [4,7]. Several new drugs for the treatment of AML, for elderly patients, have been approved in recent years, such as the FMS‐like tyrosine kinase 3 inhibi‐ tors, venetoclax, glasdegib or Vyxeos, the medical needs of patients with relapsed or refractory (RR) AML continue to be unmet [1,2,8,9]

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