Fimepinostat (CUDC‐907) in patients with relapsed/refractory diffuse large B cell and high‐grade B‐cell lymphoma: report of a phase 2 trial and exploratory biomarker analyses

• Published in: British journal of haematology Vol. 195; no. 2; pp. 201 - 209
• Main Authors: Landsburg, Daniel J., Barta, Stefan K., Ramchandren, Radhakrishnan, Batlevi, Connie, Iyer, Swaminathan, Kelly, Kevin, Micallef, Ivana N., Smith, Sonali M., Stevens, Don A., Alvarez, Mariano, Califano, Andrea, Shen, Yao, Bosker, Gideon, Parker, Jefferson, Soikes, Raul, Martinez, Elizabeth, Roemeling, Reinhard, Martell, Robert E., Oki, Yasuhiro
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2021
• Subjects: B-cell lymphoma; biomarker; Biomarkers; Biomarkers, Tumor - analysis; Clinical trials; Copy number; diffuse large B‐cell lymphoma; Female; Gene rearrangement; Hematology; Histone deacetylase; histone deacetylase inhibitor; Histone Deacetylase Inhibitors - administration & dosage; Histone Deacetylase Inhibitors - therapeutic use; Humans; Kinases; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Non-Hodgkin - drug therapy; Lymphoma, Non-Hodgkin - genetics; Male; Middle Aged; Morpholines - administration & dosage; Morpholines - therapeutic use; MYC; Myc protein; Patients; phosphatidylinositol 3‐kinase inhibitor; Phosphoinositide-3 Kinase Inhibitors - administration & dosage; Phosphoinositide-3 Kinase Inhibitors - therapeutic use; Predictive Value of Tests; Proteins; Proto-Oncogene Proteins c-myc - genetics; Pyrimidines - administration & dosage; Pyrimidines - therapeutic use; Recurrence; Safety; Treatment Outcome; phosphatidylinositol 3-kinase inhibitor; diffuse large B-cell lymphoma; biomarker; MYC; histone deacetylase inhibitor
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.17730

Summary Fimepinostat (CUDC‐907), a first‐in‐class oral small‐molecule inhibitor of histone deacetylase and phosphatidylinositol 3‐kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high‐grade B‐cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/or MYC gene rearrangement/copy number gain (MYC‐altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end‐point of overall response (OR) rate for patients with MYC‐IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC‐altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC‐altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three‐protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC‐altered R/R DLBCL/HGBL treated with single‐agent fimepinostat. Combination therapies and/or biomarker‐based patient selection strategies may lead to higher response rates in future clinical trials.