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

• Published in: Cancer chemotherapy and pharmacology 2023-03, Vol.91 (3), p.281-290
• Main Authors: Shafer, Danielle, Kagan, Amanda B., Rudek, Michelle A., Kmieciak, Maciej, Tombes, Mary Beth, Shrader, Ellen, Bandyopadhyay, Dipankar, Hudson, Daniel, Sankala, Heidi, Weir, Caryn, Lancet, Jeffrey E., Grant, Steven
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Animal models; Animals; Biopsy; Bone marrow; Cancer Research; Clinical Trial Report; Design of experiments; Diarrhea; Drug dosages; Drugs; Experimental design; Histone deacetylase; Humans; Hydroxamic Acids - adverse effects; Inhibitors; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - pathology; Lymphocytes T; Lymphoma; Malignancy; Medicine; Medicine & Public Health; Mice; Myelodysplastic syndrome; Myelodysplastic syndromes; Oncology; Pharmacokinetics; Pharmacology/Toxicology; Plasma levels; Pyrimidinones - therapeutic use; Taste disorders; Toxicity; Vomiting; Xenografts; Xenotransplantation
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-023-04511-0

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/m 2 ) 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.