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EMERGE Clinical Trial Phase 2A Domatinostat Dose Escalation

2021 Year in Review - Gastrointestinal Cancer

The dose-escalation phase of the EMERGE clinical trial results show that 200 mg domatinostat twice daily is safe and efficacious.

Domatinostat is an oral class I selective histone deacetylase inhibitor that has immunomodulatory effects on cancer cells and strengthens antitumor immune responses in the body.1 It has been shown to increase the number of cytotoxic CD8+ T-cells (CTLs) in tumors with low levels of CTLs, as well as in tumors with high CTL levels.1 Combined with PD-L1 inhibitors, it has demonstrated increased tumor response rates and survival in preclinical models.1 The Epigenetic Modulation of the immunE Response in GastrointEstinal Cancers (EMERGE) clinical trial is an interventional multicenter phase 2 clinical trial that is evaluating the efficacy of domatinostat plus avelumab, an anti–PD-L1 monoclonal antibody, in adults with previously treated, advanced, inoperable, or metastatic gastroesophageal or colorectal adenocarcinoma. The phase 2A study was performed as a domatinostat dose escalation. Domatinostat was dosed at 3 rates: 100 mg once daily, 200 mg once daily, and 200 mg twice daily in combination with avelumab 10 mg/kg every 2 weeks. The end point was to recommend a safe and tolerable domatinostat dose for use in the main study phase.

Cartwright presented the phase 2A study results at the European Society for Medical Oncology Congress 2021. There were 13 patients enrolled and no dose-limiting toxicities were found. At least 1 treatment-related adverse event (TRAE) was experienced by 12 patients, but most were grades 1 to 2. One patient had a rise in alkaline phosphatase considered to be a grade 3 TRAE. Fatigue was the most common TRAE, followed by anorexia, nausea, and anemia. Immune-related AEs were seldom encountered; 2 patients developed hypothyroidism, 1 patient had an increase in aspartate aminotransferase, and 1 patient had a maculopapular rash. Serious AEs were experienced by 3 patients, but none were treatment related. No patient discontinued treatment because of AEs, but 6 had treatment delayed. The median duration of treatment during the phase 2A study was 3.6 months, with 7 patients achieving stable disease and 1 of the 7 patients having a partial response.

Final evaluation determined that up to 200 mg domatinostat twice daily in combination with 10 mg/kg avelumab is safe, and the recommended study dose is 200 mg domatinostat twice daily.

Source: Cartwright E. EMERGE: a phase 2 trial assessing the efficacy of domatinostat plus avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal cancers – phase 2A dose finding. Poster presented at ESMO Congress 2021; September 16, 2021; Virtual meeting.

Reference

  1. Bretz AC, Parnitzke U, Kronthaler K, et al. Domatinostat favors the immunotherapy response by modulating the tumor immune microenvironment (TIME). J Immunother Cancer. 2019;7:294.
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