A phase 1 study to assess the safety, tolerability, and pharmacokinetics of CXD101 in patients with advanced cancer

Abstract

BACKGROUND: In the current study, the authors sought to determine the maximum tolerated dose (MTD) of the novel class 1 selective histone deacetylase inhibitor CXD101 in a dose escalation study in patients with advanced solid tumors or recurrent/refractory lymphoma. METHODS: The authors escalated the dose of CXD101 from 1 mg twice daily orally for 5 days in a 21-day cycle (3+3 design). RESULTS: A total of 39 patients were enrolled, 36 of whom received CXD101. Of the 30 patients in the escalation cohort, 29 were evaluable for determination of the dose-limiting toxicity (DLT). DLTs were noted at doses of 16 mg twice daily (1 of 6 patients), 20 mg twice daily (1 of 6 patients), and 24/25 mg twice daily (2 of 5 patients, both of whom developed neutropenic fever). The MTD was 20 mg twice daily, which achieved maximal plasma concentrations (±standard deviation) of 231 ± 76 nM to 342 ± 126 nM, which was within the biologically active range. Six patients received 20 mg twice daily in an expansion cohort. The most frequent adverse events were fatigue, nausea, and reversible cytopenia. Key grade 3 to 4 adverse events (according to Common Terminology Criteria for Adverse Events criteria [version 4.03]) included thrombocytopenia (11%), neutropenia (17%), and neutropenic fever (2%) across the 133 CXD101 cycles given. The toxicity profile was similar to that of licensing studies with other histone deacetylase inhibitors. In 22 evaluable patients receiving a dose of ≥16 mg twice daily (17 of whom had lymphoma and 5 of whom had solid tumors), 3 partial responses (2 in patients with classic Hodgkin lymphoma after allogenic stem cell transplantation and 1 in a patient with angioimmunoblastic T-cell lymphoma) and 1 complete response (in a patient with follicular lymphoma) were noted (overall response rate of 18%) in addition to 9 patients who achieved durable stable disease. Responses were noted predominantly among patients with lymphoma (tumor reduction noted in 63% of patients on standard computed tomography). CONCLUSIONS: The MTD in the current study was found to be 20 mg twice daily. Encouraging and durable activity was observed in patients with Hodgkin lymphoma, T-cell lymphoma, and follicular lymphoma. Cancer 2019;125:99-108.

Recent Update of HDAC Inhibitors in Lymphoma

“…It has been hypothesized that selectively inhibiting class I HDACs could reduce the toxicity, which is brought by off target inhibition on class II HDACs. Preliminary result shows that, PXD101 has lower toxicity and higher tolerability than other non-selective inhibitor (Eyre et al, 2019).…”

Trends and Challenges in Tumor Anti-Angiogenic Therapies

“…Thus, interfering with this process by means of HDAC inhibitors could represent an alternative target, and current HDAC inhibitors might serve as templates for designing new anti-angiogenic/anti-cancer drugs with more potency and selectivity [283]. Clinical trials are underway to test new HDAC derivates in advanced solid tumors and hematologic malignancies [284]. Moreover, new strategies and clinical trials are emerging using HDAC-inhibitors in combination settings to increase their efficacy in various malignancies [281].…”

Epigenetic targeting in lymphoma

“…Immunohistochemical assessment of the HR23B protein, which shuttles ubiquitinated cargo proteins to the proteasome has been shown to correlate with responses to HDIs in CTCL, 46 although initial data in a mixed population of lymphomas and other malignancies expressing high HR23B levels from a Phase I study of the oral HDI CXD101 has not confirmed a clear association between HR23B expression and response. 26…”

“…85 Epigenetic changes are clearly important in the pathogenesis of HL, 10 and in vitro activity of HDIs has been demonstrated, 44 but relatively few studies have reported efficacy outcomes. Table II 9,26,39,47,97,99 summarises selected published studies. The largest single-agent study examined the oral agent panobinostat in 129 patients with R/R HL after autologous transplant.…”

“…A key issue is therefore an improved understanding of how to target these agents to those patients who will most benefit, mandating the maintenance of translational biology alongside clinical studies in order to better understand their optimal use. Immunohistochemical assessment of the HR23B protein, which shuttles ubiquitinated cargo proteins to the proteasome has been shown to correlate with responses to HDIs in CTCL, 46 although initial data in a mixed population of lymphomas and other malignancies expressing high HR23B levels from a Phase I study of the oral HDI CXD101 has not confirmed a clear association between HR23B expression and response 26 …”