Abstract
Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.
Highlights
Epigenetic changes such as DNA methylation and post-translational histone acetylation play a critical role in the development of cancer due to their ability to alter the accessibility of transcription factors to DNA and chromatin structure [1]
Current treatments for patients with advanced metastatic solid tumors tend to be only palliative, which represents an area of unmet need
Concomitant chemoradiotherapy is an established treatment modality for solid tumors, for loco-regional disease control [19]; the main drawback of chemotherapy when combined with radiotherapy is the possible amplification of radiation-induced acute and late toxicity to normal tissues
Summary
Epigenetic changes such as DNA methylation and post-translational histone acetylation play a critical role in the development of cancer due to their ability to alter the accessibility of transcription factors to DNA and chromatin structure [1]. Histone deacetylases (HDACs) enzymatically remove acetyl groups from histones and serve as key regulators of gene expression. Tumorigenesis is linked to aberrant activity of HDACs such as deacetylation of the tumor suppressor gene p53, leading to its decreased transcription [2], and HDAC-mediated upregulation of oncogenes such as BCL2 [3]. Panobinostat in combination with bortezomib and dexamethasone has been approved for the treatment of multiple myeloma. These agents have been evaluated as single agents in a variety of solid tumors but have shown limited or no activity [4,5,6,7,8,9,10,11]. Due to the broad specificity and moderate activity of the existing HDACIs observed in these studies, a combinatorial approach has been suggested
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