Search

Histone deacetylase (HDAC) inhibitors are emerging as promising treatments for hematological malignancies, with potential applications extending to solid tumors in the future. Given their wide-ranging biological effects, there is a pressing need for a thorough understanding of the toxicities linked to HDAC inhibition. In this study, a pharmacovigilance analysis was conducted using the FDA Adverse Event Reporting System database. Suspected adverse events linked to HDAC inhibitors were detected through various statistical methodologies, including reporting odds ratio, proportional reporting ratio, information component, and Empirical Bayes Geometric Mean. Our study findings have illuminated that, among the total reported cases examined, gastrointestinal disorders accounted for 13% patients of the cohort, while lymphatic system disorders comprised 8% cases of the cohort, all of which manifested as adverse events induced by HDAC inhibitors. Importantly, the usage of HDAC inhibitors was found to be associated with incidents of atrial fibrillation, heart failure, respiratory failure, hepatic dysfunction, and acute kidney injury. Romidepsin and belinostat demonstrated more pronounced signals of adverse events compared to panobinostat and vorinostat, emphasizing the need for vigilant monitoring of adverse events in this particular population. Furthermore, atrial fibrillation (clinical priority score of 7 points) emerged as the paramount medical event warranting utmost clinical attention. Eventually, multiple adverse events were observe to emerge within the initial and second months following the initiation of treatment. Vigilant monitoring and supportive care strategies are critical in addressing the toxicities associated with HDAC inhibitors, particularly those concerning cardiotoxicity, respiratory toxicity, renal toxicity, and hepatotoxicity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Belinostat is an intravenous histone deacetylase inhibitor with approval for T-cell lymphomas. Adavosertib is a first in class oral Wee1 inhibitor. Preclinical studies of the combination demonstrated synergy in various human acute myeloid leukemia (AML) lines as well as AML xenograft mouse models., Experimental Design: This was a phase 1 dose-escalation study of belinostat and adavosertib in patients with relapsed/refractory AML and myelodysplastic syndrome (MDS). Patients received both drugs on days 1-5 and 8-12 of a 21-day cycle. Safety and toxicity were monitored throughout the study. Plasma levels of both drugs were measured for pharmacokinetic analysis. Response was determined by standard criteria including bone marrow biopsy., Results: Twenty patients were enrolled and treated at 4 dose levels. A grade 4 cytokine release syndrome at dose level 4 (adavosertib 225 mg/day; belinostat 1000 mg/m 2 ) qualified as a dose-limiting toxicity event. The most common non-hematologic treatment-related adverse events were nausea, vomiting, diarrhea, dysgeusia, and fatigue. No responses were seen. The study was terminated prior to maximum tolerated dose/recommended phase 2 dose determination., Conclusions: The combination of belinostat and adavosertib at the tested dose levels was feasible but without efficacy signals in the relapsed/refractory MDS/AML population., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Panobinostat is an oral pan histone-deacetylase inhibitor used in the treatment of relapsed and refractory multiple myeloma. Previously published studies of panobinostat demonstrated synergy with bortezomib but included few patients exposed to newer agent combinations (ie, panobinostat plus daratumumab or carfilzomib). Here, we report outcomes of panobinostat-based combinations at an academic medical center among patients whose disease had been heavily pretreated with modern agents. We retrospectively analyzed 105 patients with myeloma treated with panobinostat at The Mount Sinai Hospital in New York City between October 2012 and October 2021. These patients had a median age of 65 (range 37-87) and had received a median of 6 prior lines of therapy while in 53% the disease was classified as triple class refractory and in 54% the disease had high-risk cytogenetics. Panobinostat was most commonly utilized at 20 mg (64.8%) as part of a triplet (61.0%) or quadruplet (30.5%). Aside from steroids, panobinostat was most commonly administered in combination with lenalidomide, pomalidomide, carfilzomib, and daratumumab in descending order of frequency. Among the 101 response-evaluable patients, the overall response rate was 24.8%, clinical benefit rate (≥minimal response) was 36.6%, and median progression-free survival was 3.4 months. Median overall survival was 19.1 months. The most common toxicities ≥grade 3 were hematologic, primarily neutropenia (34.3%), thrombocytopenia (27.6%), and anemia (19.1%). Panobinostat-based combinations produced modest response rates in patients with heavily pretreated multiple myeloma, over half of whom had triple-class refractory disease. Panobinostat warrants continued investigation as a tolerable oral option for recapturing responses in patients whose disease has progressed after receipt of standard-of-care therapies., Competing Interests: Conflicts of interest Tarek H. Mouhieddine received advisory board fees from Legend Biotech. Joshua Richter received speaking fees from Celgene/Bristol Myers Squibb, Sanofi, and Janssen, and advisory board fees from Celgene/Bristol Myers Squibb, Janssen, Celgene/Bristol Myers Squibb, Karyopharm, Sanofi, X4 Pharmaceuticals, Oncopeptides, Adaptive Biotechnologies, Secura Bio, Astrazeneca, and Takeda, and consulting fees from Celgene/Bristol Myers Squibb, Secura Bio, and Oncopeptides., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cancer cachexia is mainly characterized by wasting of skeletal muscles and fat and body weight loss, along with severe complications of major organs like liver, heart, brain and bone. There can be diminishing performance of these major organs as cancer cachexia progresses, one such drastic effect on the cardiac system. In the present study, differential effect of histone deacetylase inhibitors (HDACi) on cardiac complications associated with cancer cachexia is studied. Two models were used to induce cancer cachexia: B16F1 induced metastatic cancer cachexia and Lewis lung carcinoma cell - induced cancer cachexia. Potential of Class I HDACi entinostat, Class II HDACi MC1568, and nonspecific HDACi sodium butyrate on cardiac complications were evaluated using the cardiac hypertrophy markers, hemodynamic markers, and cardiac markers along with histopathological evaluation of heart sections by Periodic acid-Schiff staining, Masson's trichrome staining, Picro-sirius red staining, and haematoxylin and eosin staining. Immunohistochemistry evaluation by vimentin and caspase 3 protein expression was evaluated. Entinostat showed promising results by attenuating the cardiac complications, and MC1568 treatment further exacerbated the cardiac complications, while non-conclusive effect were recorded after treatment with sodium butyrate. This study will be helpful in evaluating other HDACi for potential in cardiac complications associated with cancer cachexia.

Older patients with acute myeloid leukaemia (AML) account for nearly half of those with the disease. Because they are perceived to be unfit for, unwilling to receive, or unlikely to benefit from conventional chemotherapy they represent an important unmet need. Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy. We report the only randomised study of low-dose cytosine arabinoside (LDAC) combined with tosedostat (LDAC-T) versus LDAC in untreated older patients not suitable for intensive treatment. A total of 243 patients were randomised 1:1 as part of the 'Pick-a-Winner' LI-1 trial. There was a statistically non-significant increase in the complete remission (CR) rate with the addition of tosedostat, LDAC-T 19% versus LDAC 12% [odds ratio (OR) 0·61, 95% confidence interval (CI) 0·30-1·23; P = 0·17]. For overall response (CR+CR with incomplete recovery of counts), there was little evidence of a benefit to the addition of tosedostat (25% vs. 18%; OR 0·68, 95% CI 0·37-1·27; P = 0·22). However, overall survival (OS) showed no difference (2-year OS 16% vs. 12%, hazard ratio 0·97, 95% CI 0·73-1·28; P = 0·8). Exploratory analyses failed to identify any subgroup benefitting from tosedostat. Despite promising pre-clinical, early non-randomised clinical data with acceptable toxicity and an improvement in response, we did not find evidence that the addition of tosedostat to LDAC produced a survival benefit in this group of patients with AML. International Standard Randomised Controlled Trial Number: ISRCTN40571019., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m 2 bortezomib and 1000 mg/m 2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.

Purpose: Effective second-line chemotherapy options are limited in treating advanced biliary tract cancers (BTCs). Resminostat is an oral histone deacetylase inhibitor. Such inhibitors increase sensitivity to fluorouracil, the active form of S-1. In the phase I study, addition of resminostat to S-1 was suggested to have promising efficacy for pre-treated BTCs. This study investigated the efficacy and safety of resminostat plus S-1 in second-line therapy for BTCs., Methods: Patients were randomly assigned to receive resminostat or placebo (200 mg orally per day; days 1-5 and 8-12) and S-1 group (80-120 mg orally per day by body surface area; days 1-14) over a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), response rate (RR), disease control rate (DCR), and safety., Results: Among 101 patients enrolled, 50 received resminostat+S-1 and 51 received placebo+S-1. Median PFS was 2.9 months for resminostat+S-1 vs. 3.0 months for placebo+S-1 (HR: 1.154, 95% CI: 0.759-1.757, p = 0.502); median OS was 7.8 months vs. 7.5 months, respectively (HR: 1.049, 95% CI: 0.653-1.684, p = 0.834); the RR and DCR were 6.0% vs. 9.8% and 70.0% vs. 78.4%, respectively. Treatment-related adverse events (TrAEs) of grade ≥ 3 occurring more frequently (≥10% difference) in the resminostat+S-1 than in the placebo+S-1 comprised platelet count decreased (18.0% vs. 2.0%) and decreased appetite (16.0% vs. 2.0%)., Conclusions: Resminostat plus S-1 therapy improved neither PFS nor OS for patients with pre-treated BTCs. Addition of resminostat to S-1 was associated with higher incidence of TrAEs, but these were manageable (JapicCTI-183883)., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Epigenetic changes associated with aging have been linked to functional and cognitive deficits in the adult CNS. Histone acetylation is involved in the control of the transcription of plasticity and regeneration-associated genes. The intrinsic axon growth capacity in the CNS is negatively regulated by phosphatase and tensin homolog (Pten). Inhibition of Pten is an effective method to stimulate axon growth following an injury to the optic nerve, corticospinal tract (CST), and rubrospinal tract (RST). Our laboratory has previously demonstrated that the deletion of Pten in aged animals diminishes the regenerative capacity in rubrospinal neurons. We hypothesize that changes in the chromatin structure might contribute to this age-associated decline. Here, we assessed whether Trichostatin A (TSA), a histone deacetylases (HDACs) inhibitor, reverses the decline in regeneration in aged Pten f/f mice. We demonstrate that HDAC inhibition induces changes in the expression of GAP43 in both young and aged Pten f/f mice. The regenerative capacity of the RST did not improve significantly in young mice, neither their motor function on the horizontal ladder or cylinder test after TSA treatment for 7 days. Interestingly, TSA treatment in the aged mice worsened their motor function deficits, suggesting that the systemic treatment with TSA might have an overall adverse effect on motor recovery after SCI in aged animals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic., Methods: We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction., Results: Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m 2 /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m 2 in patients with normal liver function, compared to 542, 505 and 444 mL/min/m 2 in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease., Conclusion: While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy., Methods: This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed., Results: Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks)., Conclusions: Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

Histone deacetylase inhibitors (HDACIs) have demonstrated effectiveness against lymphomas and myelomas in clinical practice. However, common to all currently approved broad-acting HDACIs (panHDACIs) is dose-limiting thrombocytopenia, which has prevented wider use in cancer therapy. Using CD34 + hematopoietic stem cells (HSCs), we show that megakaryocyte (MK) cell maturation and differentiation are impaired by panHDACIs, correlating to clinical thrombocytopenia. Importantly, we demonstrate that inhibitors of class II histone deacetylases (HDACs), including LMK235 and tubacin at clinically relevant concentrations, do not affect MK maturation. Furthermore, we show that HDACI-induced impairment of MK differentiation is associated with reduction of protein levels of the transcription factor GATA-1, but not tubulin hyperacetylation. Finally, we report that panHDACIs trigger a rapid loss of GATA-1 protein via a proteasome-dependent pathway. Our data support the notion that specifically targeting class II HDACs in cancer treatment is a potential strategy that would offer a safer alternative than current panHDACIs., (Copyright © 2019 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

This open-label, single-arm phase II study examined efficacy, safety, pharmacokinetics, and biomarkers of histone deacetylase (HDAC) inhibitor resminostat in patients with relapsed or refractory Hodgkin lymphoma. Thirty-seven heavily pretreated patients received 600 (19 patients) or 800 mg (18 patients) oral resminostat daily for the initial 5 days of 14-day treatment cycles. Objective response rate (ORR) (primary) was 34% reaching disease control in 54% patients. Most patients (69%) showed reduced tumor size and reduced [ 18 F]-FDG uptake in target lesions (71%). Median progression-free survival (PFS) was 2.3 months (95%CI [1.3; 3.3]) and median overall survival (OS) was 12.5 months (95%CI [9.6; 18.6]). Patients who responded or stabilized under resminostat had a 10-month longer OS than patients who progressed. Efficacy assessment, pharmacodynamics, and exploratory biomarker results followed plasma levels, showed target engagement and epigenetic modulations. Common drug-related adverse events (AEs) were nausea, vomiting, anemia, thrombocytopenia, and fatigue, mainly grade 1 or 2.

Histone deacetylases (HDACs) are expressed at increased levels in cells of various malignancies, and the use of HDAC inhibitors has improved outcomes in patients with haematological malignancies (T-cell lymphomas and multiple myeloma). However, they are not as effective in solid tumours. Five agents are currently approved under various jurisdictions, namely belinostat, chidamide, panobinostat, romidepsin and vorinostat. These agents are associated with a range of class-related and agent-specific serious and/or severe adverse effects, notably myelosuppression, diarrhoea and various cardiac effects. Among the cardiac effects are ST-T segment abnormalities and QTc interval prolongation of the electrocardiogram, isolated cases of atrial fibrillation and, in rare instances, ventricular tachyarrhythmias. In order to improve the safety profile of this class of drugs as well as their efficacy in indications already approved and to further widen their indications, a large number of newer HDAC inhibitors with varying degrees of HDAC isoform selectivity have been synthesised and are currently under clinical development. Preliminary evidence from early studies suggests that they may be effective in non-haematological cancers as well when used in combination with other therapeutic modalities, but that they too appear to be associated with the above class-related adverse effects. As the database accumulates, the safety, efficacy and risk/benefit of the newer agents and their indications will become clearer.

Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC)., Experimental Design: In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP)., Results: Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 months with monotherapy versus 2.8/11.8 months with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p < 0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9 months for monotherapy versus 2.8/13.1 months for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 10 3 /mm 3 )., Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.

This is a phase II study of panobinostat, an oral pan-HDAC inhibitor, combined with rituximab in patients with relapsed diffuse large B cell lymphoma. Panobinostat was administered orally 3 times a week every other week on a 28-day cycle. Rituximab was administered weekly during the first cycle, then on Day 1 of cycles 2 to 6. Patients without disease progression after 6 cycles continued panobinostat monotherapy for up to 6 additional cycles in the absence of disease progression. Eighteen eligible subjects were enrolled, and 18 were evaluable for response. The overall response rate was 11% (90% CI [2%-34%]) with 2 subjects having a partial response. The duration of response in these subjects was 51 and 60 days. Five additional subjects had stable disease with 3 subjects having tumor reduction between 27 and 44%, not meeting criteria for partial response. One subject with stable disease remained on therapy a total of 12 cycles. The most common toxicities while on study were thrombocytopenia (14 patients, 78%); fatigue (11, 61%); anemia (10, 56%); diarrhea (8, 44%); and nausea, lymphopenia, anorexia, and hypophosphatemia (5 each, 28% of patients), the majority of which was grade 2 or less. These data indicate that the combination of panobinostat with rituximab is able to induce responses in a limited number of subjects with relapsed diffuse large B cell lymphoma., (Copyright © 2018 John Wiley & Sons, Ltd.)

Purpose: Belinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide., Methods: The PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelosuppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data., Results: Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle., Conclusions: This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.

Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drug‑resistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)‑induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSA‑resistant cells (PANC‑1‑TSA) had higher proliferative activity than non‑resistant cells (PANC‑1). This over‑proliferative activity induced by TSA may be associated with abnormal activation of JAK2/STAT3 signaling, which can be strengthened by interleukin‑6 (IL‑6), a STAT3‑upstream inducer, resulting in enhanced expression of STAT3-downstream target genes including c‑Myc, c‑Src, HIF‑1α, and CCND1. In addition, increased expression of Bcl‑2 mRNA and decreased expression of Bax mRNA in PANC‑1‑TSA cells indicated that TSA induced the inhibition of mitochondrial-dependent apoptosis in PCCs. Tyrphostin B42 treatment evidently antagonized the activation of IL‑6/JAK2/STAT3 in a dose‑dependent manner. As a result, tyrphostin B42 inhibited the over‑proliferative activity of PANC‑1‑TSA cells, and downregulated the expression of IL‑6/JAK2/STAT3‑downstream target genes. Moreover, tyrphostin B42 induced the apoptosis of PCCs by regulating the expression of mitochondrial‑related genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated TSA‑mediated resistance in PCCs by antagonizing the IL‑6/JAK2/STAT3 signaling.

Quercetin, a flavonol, displays anti-inflammatory and anti-cancer properties. This study aimed to investigate whether a diet containing 0.1% or 1% quercetin (LQ and HQ, respectively) enhances the anti-tumor effects of trichostatin A (TSA) and prevents muscle wasting induced by TSA. The positive control group received quercetin intraperitoneally (IQ). Three weeks after injecting A549 cells, nude mice were given TSA alone or in combination with quercetin administered orally or intraperitoneally for 16 weeks. Tumor volumes as well as body, muscle and epididymal fat weights were determined during or after the experiment. Quercetin given as a diet supplement dose-dependently enhanced the anti-tumor potency of TSA (p < 0.05). The enhancing effect of HQ was similar to that of IQ. HQ also significantly increased the expression of p53, a tumor suppressor, in tumor tissues compared with the TSA alone group. In addition, TSA-induced loss of gastrocnemius muscle weight was inhibited by oral quercetin in a dose dependent manner; the efficiencies of LQ and HQ were similar to or better than IQ. Moreover, both LQ and HQ decreased TSA-induced activation of Forkhead box O1 (FOXO1), a crucial transcription factor that regulates muscle wasting associated genes. Consistently, LQ and HQ suppressed muscle wasting associated proteins atrophy gene-1 and muscle ring-finger protein-1 expression as well as increased the myosin heavy chain level in the gastrocnemius muscles. Besides, quercetin attenuated TSA-increased oxidative damage and proinflammatory cytokines (p < 0.05). These findings demonstrate that a diet containing 0.1% or 1% quercetin enhances the antitumor effect of TSA and prevents TSA-induced muscle wasting.

Suberoylanilide hydroxamic acid (SAHA) is a histone deacetylase inhibitor, which has been widely utilized throughout the cancer research field. SAHA-induced radiosensitization in normal human fibroblasts AG1522 and lung carcinoma cells A549 were evaluated with a combination of γ-rays, proton, and carbon ion exposure. Growth delay was observed in both cell lines during SAHA treatment; 2 μM SAHA treatment decreased clonogenicity and induced cell cycle block in G1 phase but 0.2 μM SAHA treatment did not show either of them. Low LET (Linear Energy Transfer) irradiated A549 cells showed radiosensitization effects on cell killing in cycling and G1 phase with 0.2 or 2 μM SAHA pretreatment. In contrast, minimal sensitization was observed in normal human cells after low and high LET radiation exposure. The potentially lethal damage repair was not affected by SAHA treatment. SAHA treatment reduced the rate of γ-H2AX foci disappearance and suppressed RAD51 and RPA (Replication Protein A) focus formation. Suppression of DNA double strand break repair by SAHA did not result in the differences of SAHA-induced radiosensitization between human cancer cells and normal cells. In conclusion, our results suggest SAHA treatment will sensitize cancer cells to low and high LET radiation with minimum effects to normal cells., Competing Interests: The authors declare no conflict of interest.

The current therapy for high-risk myelodysplastic syndrome (MDS) involves repeated cycles of the DNA demethylating agent 5-azacitidine (5-Aza), but combination treatments have been proposed to improve patient outcomes. We performed a phase Ib study to investigate the safety and tolerability of 5-Aza (75 mg/m 2 ) combined with the histone deacetylase inhibitor panobinostat (PAN) in adult Japanese patients with MDS or chronic myelomonocytic leukemia (CMML). Eleven patients were enrolled; five received 20 mg PAN + 5-Aza and six received 30 mg PAN + 5-Aza. All patients in the 20 mg PAN cohort had MDS, while two in the 30 mg PAN cohort had MDS and three had CMML. All patients experienced ≥1 adverse event (AE) related to the study treatment, and five discontinued the study treatment because of AEs. One patient in each group exhibited dose-limiting toxicities: lung infection (PAN 20 mg + 5-Aza) and cellulitis (PAN 30 mg + 5-Aza). PAN exposure increased with ascending doses, and combination therapy did not affect PAN plasma trough concentrations. In summary, 20 or 30 mg PAN combined with 5-Aza was safe and tolerable in adult Japanese patients with CMML or MDS. Study registration ClinicalTrials.gov Identifier: NCT01613976.

Background: Methylated gene markers have shown promise in predicting breast cancer outcomes and treatment response. We evaluated whether baseline and changes in tissue and serum methylation levels would predict pathological complete response (pCR) in patients with HER2-negative early breast cancer undergoing preoperative chemotherapy., Methods: The TBCRC008 trial investigated pCR following 12 weeks of preoperative carboplatin and albumin-bound paclitaxel + vorinostat/placebo (n = 62). We measured methylation of a 10-gene panel by quantitative multiplex methylation-specific polymerase chain reaction and expressed results as cumulative methylation index (CMI). We evaluated association between CMI level [baseline, day 15 (D15), and change] and pCR using univariate and multivariable logistic regression models controlling for treatment and hormone receptor (HR) status, and performed exploratory subgroup analyses., Results: In univariate analysis, one log unit increase in tissue CMI levels at D15 was associated with 40% lower chance of obtaining pCR (odds ratio, OR 0.60, 95% CI 0.37-0.97; p = 0.037). Subgroup analyses suggested a significant association between tissue D15 CMI levels and pCR in vorinostat-treated [OR 0.44 (0.20, 0.93), p = 0.03], but not placebo-treated patients., Conclusion: In this study investigating the predictive roles of tissue and serum CMI levels in patients with early breast cancer for the first time, we demonstrate that high D15 tissue CMI levels may predict poor response. Larger studies and improved analytical procedures to detect methylated gene markers in early stage breast cancer are needed. TBCRC008 is registered on ClinicalTrials.gov (NCT00616967).

Purpose: To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials., Methods: We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1-14), or schedule B: weekly ixabepilone + vorinostat (days 1-7; 15-21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed., Results: The schedule A MTD was vorinostat 300 mg daily (days 1-14), ixabepilone 32 mg/m 2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1-7; 15-21), ixabepilone 16 mg/m 2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m 2 , respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months., Conclusions: We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.

Purpose: This study compared the efficacy and safety of suberoylanilide hydroxamic acid (SAHA) and mitomycin C (MMC) up to 4 months in the prevention of corneal haze induced by photorefractive keratectomy (PRK) in rabbits in vivo., Methods: Corneal haze in rabbits was produced with -9.00 diopter PRK. A single application of SAHA (25 μM) or MMC (0.02%) was applied topically immediately after PRK. Effects of the two drugs were analyzed by slit-lamp microscope, specular microscope, TUNEL assay, and immunofluorescence., Results: Single topical adjunct use of SAHA (25 μM) or MMC (0.02%) after PRK attenuated more than 95% corneal haze and myofibroblast formation (P < .001). SAHA did not reduce keratocyte density, cause keratocyte apoptosis, or increase immune cell infiltration compared to MMC (P < .01 or .001). Furthermore, SAHA dosing did not compromise corneal endothelial phenotype, density, or function in rabbit eyes, whereas MMC application did (P < .01 or .001)., Conclusions: SAHA and MMC significantly decreased corneal haze after PRK in rabbits in vivo. SAHA exhibited significantly reduced short- and long-term damage to the corneal endothelium compared to MMC in rabbits. SAHA is an effective and potentially safer alternative to MMC for the prevention of corneal haze after PRK. Clinical trials are warranted. [J Refract Surg. 2017;33(12):834-839.]., (Copyright 2017, SLACK Incorporated.)

Panobinostat (Farydak) is an orally active hydroxamic acid-derived histone deacetylase inhibitor used for the treatment of relapsed or refractory multiple myeloma. Based on recombinant cytochrome P450 (P450) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was mediated primarily by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also an in vitro reversible and time-dependent inhibitor of CYP3A4/5 and a reversible inhibitor of CYP2D6 and CYP2C19. Based on a previous clinical drug-drug interaction study with ketoconazole (KTZ), the contribution of CYP3A4 in vivo was estimated to be ∼40%. Using clinical pharmacokinetic (PK) data from several trials, including the KTZ drug-drug interaction (DDI) study, a physiologically based pharmacokinetic (PBPK) model was built to predict panobinostat PK after single and multiple doses (within 2-fold of observed values for most trials) and the clinical DDI with KTZ (predicted and observed area under the curve ratios of 1.8). The model was then applied to predict the drug interaction with the strong CYP3A4 inducer rifampin (RIF) and the sensitive CYP3A4 substrate midazolam (MDZ) in lieu of clinical trials. Panobinostat exposure was predicted to decrease in the presence of RIF (65%) and inconsequentially increase MDZ exposure (4%). Additionally, PBPK modeling was used to examine the effects of stomach pH on the absorption of panobinostat in humans and determined that absorption of panobinostat is not expected to be affected by increases in stomach pH. The results from these studies were incorporated into the Food and Drug Administration-approved product label, providing guidance for panobinostat dosing recommendations when it is combined with other drugs., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML. Experimental Design: We compared outcomes in 259 adults with AML ( n = 217) and MDS ( n = 42) randomized to receive either AZA monotherapy (75 mg/m 2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients. Results: Co-administration of VOR did not increase the overall response rate ( P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A ( P = 0.0001), IDH1 ( P = 0.004), and TP53 ( P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment. Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430-40. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. As mutation of TP53 in HNSCC occurs in 60% to 80% of non-HPV-associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA sequencing, and apoptosis analyses were performed to dissect molecular mechanisms. Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated HR through activation of CDK1, and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival. Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC. Clin Cancer Res; 23(21); 6541-54. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 ( P = .028) and GVHD biomarkers (Reg3, P = .041; ST2, P = .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568., (© 2017 by The American Society of Hematology.)

Background: Patients with relapsed or relapsed/refractory multiple myeloma (RRMM) face poor treatment options by the time third-line therapy is required, despite advances in overall survival in recent years. Treatment free interval (TFI) and opportunities to maintain quality of life (QoL) have been cited as additional measures of efficacy that can be utilized in personalized treatment decisions., Methods: The clinical health outcomes data from PANORAMA-1, the pivotal phase-3 trial comparing panobinostat-bortezomib-dexamethasone (PAN-BTZ-DEX) with placebo (PBO)-BTZ-DEX in RRMM patients treated with 1 to 3 prior regimens, retrospectively assessed TFI as a health outcome measure and metric of patient treatment experience relevant to the RRMM population., Results: PAN-BTZ-DEX shows promise for prolonged TFI (mean TFI, 7.49 months; 95% CI, 6.02 to 8.71) compared to PBO-BTZ-DEX (mean TFI, 3.86 months; 95% CI, 3.08 to 4.60) for heavily pre-treated advanced RRMM patients), due to the short duration of therapy and extended progression free-survival. Further, QoL during the TFI was similar to baseline., Conclusions: PAN-BTZ-DEX provides a treatment regimen with prolonged TFI benefits previously not available for RRMM patients. TFI has not been traditionally measured in clinical trials, but should be assessed in prospective data collection given its value to payers, providers, and patients.

Purpose: To determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure, distant intracranial failure, and overall survival rates., Materials and Methods: In this multicenter study, patients with 1 to 4 NSCLC brain metastases, each ≤2 cm, were enrolled in a phase 1, 3 + 3 dose escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any Common Terminology Criteria for Adverse Events version 3.0 grade 3 to 5 acute nonhematologic adverse event related to vorinostat or SRS occurring within 30 days., Results: From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. Because no DLTs were observed, the MTD was established as 400 mg. Acute adverse events were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n=2), nausea (n=1), and fatigue (n=2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier overall survival was 13 months. There were no local failures. One patient (8%) at the 400-mg dose level with a 2.0-cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months after SRS., Conclusions: The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew before completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Histone deacetylase (HDAC) inhibitor abexinostat is under investigation for the treatment of various cancers. Epigenetic changes including aberrant HDAC activity are associated with cancers, including myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). In this phase 1 dose-escalation study, 17 patients with relapsed/refractory higher-risk MDS, AML, or ALL received oral abexinostat (60, 80 [starting dose], 100, or 120 mg) twice daily (bid) on Days 1-14 of 21-day cycles. The most common treatment-related grade ≥3 adverse events were thrombocytopenia (29%) and neutropenia (24%), none of which led to discontinuation. Maximum-tolerated dose was not reached. Of 12 evaluable patients, best response was stable disease in 1 patient. This study was closed due to limited clinical benefit. Future development of oral abexinostat 100 mg bid in patients with MDS, AML, or ALL should focus on combination regimens. ISRCTN registry: 99680465.

Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein, we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The bromodomain inhibitor JQ1 attenuated CD4 + FOXP3 + T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC. Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852-67. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 783 ., (©2017 American Association for Cancer Research.)

Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation. Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle. Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307-15. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism. Experimental Design: We used EGFR -mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR. Results: EGFR -mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion-positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR -mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR -T790M mutations. Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR -mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139-49. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Purpose: Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial., Methods: Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients., Results: Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC., Conclusion: Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

Objective: To determine the long-term effects of vorinostat on safety and virological parameters in HIV-infected individuals on suppressive antiretroviral therapy (ART)., Design: Prospective longitudinal observational extended follow-up of 20 HIV-infected individuals on ART previously enrolled in a clinical trial of daily vorinostat 400 mg for 14 days. Extended follow-up included visits at 6, 12, 18 and 24 months postenrolment in the initial clinical trial., Methods: Cell-associated unspliced HIV RNA, total HIV DNA and plasma HIV RNA were quantified by PCR, and CD4 and CD8 T cells quantified by flow cytometry. Changes over time in each parameter were assessed using the Wilcoxon matched pair signed-rank test and generalized estimating equations for trend modelling., Results: We recorded a total of 31 adverse events (26 grade 1 and five grade 2) in all study participants (n = 20). There were no significant changes in the number of CD4 or CD8 T cells or plasma HIV RNA over time. In 12 participants for whom baseline samples were available, there were no significant changes in total HIV DNA, cell-associated unspliced HIV RNA, plasma RNA or CD4 and CD8 T cells at 6, 12, 18 or 24 months., Conclusion: Extended follow-up for 24 months did not reveal any long-term toxicity or changes in markers of HIV persistence or transcription in participants on ART who had received 14 days of vorinostat.

Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-containing histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concentrations required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between October 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, respectively. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses observed in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large B-cell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less dose-intense week-on-week-off schedule is warranted. ( Trial registered at: EudraCT-2009-013691-47 )., (Copyright© Ferrata Storti Foundation.)

Purpose: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser., Materials and Methods: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA., Results: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss., Conclusion: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m 2 . In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m 2 ) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1-5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m 2 of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8-5.7) months with docetaxel group and 4.1 (1.5-5.4) months with DR group (hazard ratio [HR]: 1.354, 95% CI: 0.835-2.195; p = 0.209). Grade ≥ 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.

Peripheral T-cell lymphoma is a heterogenous non-Hodgkin Lymphoma with historically poor outcomes. Currently, response rates remain poor with traditional chemotherapy and many of those responding to initial therapy will relapse. Belinostat (Beleodaq, Spectrum Pharmaceuticals) is a histone deacetylase inhibitor (HDACi) approved for use in relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat is metabolized hepatically through cytochrome P-450 enzymes 3A4, 2C9, and 2A6; however, no empiric dosage adjustments of belinostat are recommended during concurrent use of inhibitors or inducers of these enzymes. Belinostat's efficacy has been evaluated in a clinical trial showing an overall response rate (ORR) of 25.8% and a median duration of response of 8.4 months. Belinostat is generally well tolerated, with the most common adverse reactions (>25%) being nausea, vomiting, fatigue, pyrexia, and anemia in patients with relapsed or refractory PTCL. Belinostat is a safe and effective treatment option for relapsed and refractory peripheral T-cell lymphoma, with many future applications currently being investigated.

Umbilical cord blood is a valuable source of hematopoietic stem cells. While cytokine stimulation can induce ex vivo hematopoietic cell proliferation, attempts have been made to use epigenetic-modifying agents to facilitate stem cell expansion through the modulation of cellular epigenetic status. However, the potential global effect of these modifying agents on epigenome raises concerns about the functional normality of the expanded cells. We studied the ex vivo expansion of cord blood hematopoietic stem and progenitor cells (HSPCs) by histone deacetylase (HDAC) inhibitors, trichostatin A and valproic acid. Treatment with HDAC inhibitors resulted in mild expansion of the total hematopoietic cell number when compared with cytokine stimulated sample. Nevertheless, we observed 20-30-fold expansion of the CD34 + CD38 - HSPC population. Strikingly, cord blood cells cultured with HDAC inhibitors exhibited aberrant expression of leukemia-associated genes, including CDKN1C, CEBPα, HOXA9, MN1, and DLK1. Our results thus suggest that the expansion of HSPCs by this approach may provoke a pre-leukemic cell state. We propose that the alteration of epigenome by HDAC inhibitors readily expands cord blood HSPC population through the re-activation of the leukemia gene transcription. The present study provides an assessment of the leukemogenic potential of HSCs expanded ex vivo using HDAC inhibitors for clinical applications.

Background: Panobinostat (a pan histone deacetylase inhibitor) is approved in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma who have received two or more previous lines of therapy. We aimed to improve the safety of this combination and investigate efficacy by incorporating low-dose thalidomide, using sub-cutaneous weekly bortezomib, and determining the maximum tolerated dose of panobinostat in this regimen., Methods: We did a phase 1/2, multicentre, open-label trial (MUK six) at four hospitals in the UK, enrolling patients with relapsed, or relapsed and refractory, multiple myeloma aged at least 18 years, with an Eastern Cooperative Oncology Group performance status of 2 or less who had previously received 1-4 lines of therapy. Exclusion criteria included any antimyeloma treatment within 28 days of study drugs (except dexamethasone 160 mg >48 h before treatment). We used a rolling six escalation design to determine the maximum tolerated dose of panobinostat, and allocated patients to receive subcutaneous bortezomib 1·3 mg/m 2 , and oral thalidomide 100 mg, dexamethasone 20 mg, and panobinostat 10, 15, or 20 mg (escalated to 20 mg according to the escalation schedule). Treatment was given during a 21-day cycle (bortezomib on days 1 and 8; thalidomide every day; dexamethasone on days 1, 2, 8, and 9; and panobinostat on days 1, 3, 5, 8, 10, and 12) for 16 cycles in the absence of disease progression or unacceptable toxicity. Patients were permitted to come off study for autologous stem cell transplantation. The primary objective was to determine the maximum tolerated dose and recommended dose of panobinostat, and to estimate the proportion of patients with an overall response that was equal to a partial response or greater within 16 cycles of treatment at the recommended panobinostat dose in the modified intention-to-treat population. We assessed safety in all patients who received a trial drug (ie, bortezomib, thalidomide, dexamethasone, or panobinostat). This trial is registered at ClinicalTrials.gov, number NCT02145715, and with the ISRCTN registry, number ISRCTN59395590 and is closed to recruitment., Findings: Between Jan 31, 2013, and Oct 30, 2014, we enrolled 57 eligible patients who received at least one dose of trial medication or any drug. One dose-limiting toxicity was reported (grade 3 hyponatremia at the 20 mg dose), therefore the maximum tolerated dose was not reached, and 20 mg was deemed to be the recommended dose. 46 patients were treated with panobinostat 20 mg (the intention-to-treat population). 42 patients (91%, 80% CI 83·4-96·2) of 46 achieved the primary endpoint of an overall response that was equal to a partial response or greater. Most adverse events were grade 1-2 with few occurrences of grade 3-4 diarrhoea or fatigue. The most common adverse events of grade 3 or worse in the safety population (n=57) were reduced neutrophil count (15 [26%]), hypophosphatemia (11 [19%]), and decreased platelet count (8 [14%]). 46 serious adverse events were reported in 27 patients; of 14 suspected to be related to the trial medication, seven (50%) were gastrointestinal disorders., Interpretation: Panobinostat 20 mg in combination with bortezomib, thalidomide, and dexamethasone is an efficacious and well tolerated regimen for patients with relapsed multiple myeloma., Funding: Novartis and Myeloma UK., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients., Patients and Methods: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined., Results: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6)., Conclusions: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma., Methods: In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40-240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1-21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, number NCT01583283., Findings: Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1-21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1-2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhoea (grade 1-2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% [95% CI 38-71]) of 38 patients had an overall response., Interpretation: The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma., Funding: Acetylon Pharmaceuticals., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Epigenetic alterations by histone/protein deacetylases (HDACs) are one of the many mechanisms that cancer cells use to alter gene expression and promote growth. HDAC inhibitors have proven to be effective in the treatment of specific malignancies, particularly in combination with other anticancer agents. We conducted a phase I trial of panobinostat in patients with unresectable stage III or IV melanoma. Patients were treated with oral panobinostat at a dose of 30 mg daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose interruption. Due to this, a second treatment arm was opened and the dose was changed to 30 mg oral panobinostat three times a week every other week (Arm B). Six patients were treated on Arm A and 10 patients were enrolled to Arm B with nine patients treated. In nine patients treated on Arm B, the response rate was 0% (90% confidence interval [CI]: 0-28%) and the disease-control rate was 22% (90% CI: 4-55%). Among all 15 patients treated, the overall response rate was 0% (90% CI: 0-17%) and the disease-control rate was 27% (90% CI: 10-51%). There was a high rate of toxicity associated with treatment. Correlative studies suggest the presence of immune modifications after HDAC inhibition. Panobinostat is not active as a single agent in the treatment of melanoma. Further exploration of this agent in combination with other therapies may be warranted., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial., Methods: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m 2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308., Findings: Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50)., Interpretation: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this., Funding: Novartis Pharmaceuticals., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study determined the anti-neoplastic activity and nephrotoxicity of epigenetic inhibitors in vitro. The therapeutic efficacy of epigenetic inhibitors was determined in human prostate cancer cells (PC-3 and LNCaP) using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-Aza) and the histone deacetylase inhibitor trichostatin A (TSA). Cells were also treated with carbamazepine (CBZ), an anti-convulsant with histone deacetylase inhibitor-like properties. 5-Aza, TSA or CBZ alone did not decrease MTT staining in PC-3 or LNCaP cells after 48 h. In contrast, docetaxel, a frontline chemotherapeutic induced concentration-dependent decreases in MTT staining. Pretreatment with 5-Aza or TSA increased docetaxel-induced cytotoxicity in LNCaP cells, but not PC-3 cells. TSA pretreatment also increased cisplatin-induced toxicity in LNCaP cells. Carfilzomib (CFZ), a protease inhibitor approved for the treatment of multiple myeloma had minimal effect on LNCaP cell viability, but reduced MTT staining 50% in PC-3 cells compared to control, and pretreatment with 5-Aza further enhanced toxicity. Treatment of normal rat kidney (NRK) and human embryonic kidney 293 (HEK293) cells with the same concentrations of epigenetic inhibitors used in prostate cancer cells significantly decreased MTT staining in all cell lines after 48 h. Interestingly, we found that the toxicity of epigenetic inhibitors to kidney cells was dependent on both the compound and the stage of cell growth. The effect of 5-Aza and TSA on DNA methyltransferase and histone deacetylase activity, respectively, was confirmed by assessing the methylation and acetylation of the CDK inhibitor p21. Collectively, these data show that combinatorial treatment with epigenetic inhibitors alters the efficacy of chemotherapeutics in cancer cells in a compound- and cell-specific manner; however, this treatment also has the potential to induce nephrotoxic cell injury., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (-78%) and perivascular epithelioid tumor (-54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma.

Recent advances in diffuse large B-cell lymphomas (DLBCL) have underscored the importance of tumor microenvironment in escaping host anti-tumor responses. One mechanism is loss of major histocompatibility Class II antigens (MHCII) associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHCII is controlled by CIITA which in turn is regulated by histone acetylation. In this study, we hypothesized that HDAC inhibition with belinostat increases MHCII, CIITA expression, TIL and improves patient outcomes. Primary objective was evaluation of toxicity and response. Twenty-two patients were enrolled for the study. Belinostat was well tolerated with mild toxicity. Two partial responses were observed at 5, 13 months after registration for an overall response rate (ORR) (95% CI) of 10.5% (1.3-33.1%), and three patients had stable disease for 4.7, 42.3+, and 68.4 + months with minimum 3-year follow-up. Included correlative studies support the hypothesis and serve as the basis for SWOG S0806 combining vorinostat with R-CHOP.

Hydroxychloroquine (HCQ) enhances the anti-cancer activity of the histone deacetylase inhibitor, vorinostat (VOR), in pre-clinical models and early phase clinical studies of metastatic colorectal cancer (mCRC). Mechanisms could include autophagy inhibition, accumulation of ubiquitinated proteins, and subsequent tumor cell apoptosis. There is growing evidence that autophagy inhibition could lead to improved anti-cancer immunity. To date, effects of autophagy on immunity have not been reported in cancer patients. To address this, we expanded an ongoing clinical study to include patients with advanced, refractory mCRC to evaluate further the clinical efficacy and immune effects of VOR plus HCQ. Refractory mCRC patients received VOR 400 milligrams orally with HCQ 600 milligrams orally daily, in a 3-week cycle. The primary endpoint was median progression-free survival (mPFS). Secondary endpoints include median overall survival (mOS), adverse events (AE), pharmacodynamic of inhibition of autophagy in primary tumors, immune cell analyses, and cytokine levels. Twenty patients were enrolled (19 evaluable for survival) with a mPFS of 2.8 months and mOS of 6.7 months. Treatment-related grade 3-4 AEs occurred in 8 patients (40%), with fatigue, nausea/vomiting, and anemia being the most common. Treatment significantly reduced CD4+CD25hiFoxp3+ regulatory and PD-1+ (exhausted) CD4+ and CD8+ T cells and decreased CD45RO-CD62L+ (naive) T cells, consistent with improved anti-tumor immunity. On-study tumor biopsies showed increases in lysosomal protease cathepsin D and p62 accumulation, consistent with autophagy inhibition. Taken together, VOR plus HCQ is active, safe and well tolerated in refractory CRC patients, resulting in potentially improved anti-tumor immunity and inhibition of autophagy.

Introduction: New treatment options for patients with metastatic Soft Tissue Sarcoma are urgently needed. Preclinical studies suggested activity of vorinostat, a histone deacetylase inhibitor., Methods: A multi-centre, open-label, non-randomised phase II trial to investigate the efficacy and safety of vorinostat in patients with locally advanced or metastatic Soft Tissue Sarcoma failing 1st-line anthracycline-based chemotherapy was initiated. Patients were treated with vorinostat 400 mg po qd for 28 d followed by a treatment-free period of 7 d, representing a treatment cycle of 5 weeks. Restaging was performed every three cycles or at clinical progression., Results: Between 06/10 and 09/13, 40 Soft Tissue Sarcoma patients were treated with vorinostat at seven participating centres. Patients had received 1 (n=8, 20%), 2 (n=10, 25%) or ≥3 (n=22, 55%) previous lines of chemotherapy. Best response after three cycles of treatment was stable disease (n=9, 23%). Median progression-free survival and overall survival were 3.2 and 12.3 months, respectively. Six patients showed long-lasting disease stabilisation for up to ten cycles. Statistical analyses failed to identify baseline predictive markers in this subgroup. Major toxicities (grade ≥III) included haematological toxicity (n=6, 15%) gastrointestinal disorders (n=5, 13%), fatigue (n=4, 10%), musculoskeletal pain (n=4, 10%), and pneumonia (n=2, 5%)., Conclusion: In a heavily pre-treated patient population, objective response to vorinostat was low. However, a small subgroup of patients had long-lasting disease stabilisation. Further studies aiming to identify predictive markers for treatment response as well as exploration of combination regimens are warranted., Trial Registration: NCT00918489 (ClinicalTrials.gov) EudraCT-number: 2008-008513-19., (Copyright © 2016 Elsevier Ltd. All rights reserved.)