A Phase II Exploratory Study of PXD-101 (Belinostat) Followed by Zevalin in Patients with Relapsed Aggressive High-Risk Lymphoma

Abstract

Objective: Aggressive lymphomas (aNHL) including diffuse large B-cell lymphoma (DLBCL) have poor outcomes in relapsed refractory patients. Prior studies have demonstrated that loss of major histocompatibility complex class II (MHCII) expression in DLBCL is associated with poor survival. The objective of this single-arm phase II study was to evaluate if PXD-101 would increase MHCII expression, synergize with Zevalin, and improve clinical outcomes. Methods: This was a single-center open-label phase II trial (NCT01686165) geared toward heavily pretreated patients with CD20-positive aNHL. The primary endpoint was overall response rate (ORR) in aNHL patients treated with 2 cycles of PXD-101 followed by restaging CT and 1 cycle of Zevalin. Results: Five patients were enrolled, and all were heavily pretreated. Therapy was well tolerated, with nausea and vomiting being the most frequent adverse events. All patients progressed after receiving therapy; the study did not achieve the required ORR to proceed to the next stage. Conclusion: The pleotropic effects of histone deacetylase inhibition and lack of clinical biomarkers have precluded a priori identification of responding patients. Thus, while we report a negative trial of PXD-101 in combination with Zevalin, this study highlights the importance of a clinically feasible biomarker.

Immunoepigenetics Combination Therapies: An Overview of the Role of HDACs in Cancer Immunotherapy

“…With a recruitment group of five white participants, the therapy was well tolerated with nausea and vomiting being the most frequent adverse events. Although all patients progressed after receiving therapy, the study did not achieve the required overall response rate (ORR) to proceed to the next stage [146].…”

Small Molecules Targeting HATs, HDACs, and BRDs in Cancer Therapy

“…SIRT proteins belong NAD-dependent deacetylases that act as intracellular regulators and are thought to have ADP-ribosyltransferase activity ( 93 ). It has been reported that ( 94 – 97 ) SIRT1 and SIRT2 as deacetylases modulate the acetylation of p53, thereby regulating p53 target genes and cancer cell progression ( 81 , 98 ). JQ-101, which inhibits SIRT1-mediated H4K16 and p53 acetylation, thereby inducing A549 cell senescence and inhibiting tumor growth and invasiveness, similar phenomenon and mechanism has been detected in SIRT1 specific inhibitor EX527 treated glioma cells ( 82 , 99 ).…”

“…In addition, many compounds are still in pre-clinical development, such as abexinostat, AR-42, chidamide, CHR-3996, CI-994, CUDC-101, CUDC-907, entinostat (MS-275), givinostat, MGCD0103, mocetinostat, phenylbutyrate, pivanex, pracinostat, quisinostat, ricolinostat, valproic acid (VPA). Some confer added benefits in combination with other drugs and are undergoing phase I/II clinical trials ( Table 1 ) ( 62 , 65 , 94 – 97 , 102 – 104 , 106 – 109 , 112 – 120 , 123 – 130 , 132 – 135 , 139 – 143 , 175 , 176 ).…”

HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis

“…In addition to these HDACIs approved for clinical use, there are many clinical trials of HDACIs in other diseases 34–67 (Table 1). SAHA was used in a phase II clinical trial to treat human immunodeficiency virus (HIV)–infected individuals 42 and in phase I/II clinical trials of sickle cell disease 36 with promising results.…”