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02.03.2023 | Clinical Trial Report

Phase 1 study of belinostat and adavosertib in patients with relapsed or refractory myeloid malignancies

verfasst von: Danielle Shafer, Amanda B. Kagan, Michelle A. Rudek, Maciej Kmieciak, Mary Beth Tombes, Ellen Shrader, Dipankar Bandyopadhyay, Daniel Hudson, Heidi Sankala, Caryn Weir, Jeffrey E. Lancet, Steven Grant

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2023

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Abstract

Purpose

Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models.

Experimental design

This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1–5 and 8–12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy.

Results

Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m²) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination.

Conclusions

The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population.

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Titel: Phase 1 study of belinostat and adavosertib in patients with relapsed or refractory myeloid malignancies
verfasst von: Danielle Shafer
Amanda B. Kagan
Michelle A. Rudek
Maciej Kmieciak
Mary Beth Tombes
Ellen Shrader
Dipankar Bandyopadhyay
Daniel Hudson
Heidi Sankala
Caryn Weir
Jeffrey E. Lancet
Steven Grant
Publikationsdatum: 02.03.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 3/2023
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-023-04511-0

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Phase 1 study of belinostat and adavosertib in patients with relapsed or refractory myeloid malignancies