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Abstract Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in clinical treatment. The purpose of this study was to establish a rapid and reliable method for the detection of abexinostat concentrations in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. Selective reaction monitoring (SRM) was used for detection with ion transitions at m/z 397.93 → 200.19 for abexinostat and m/z 422.01 → 186.11 for givinostat, respectively. The intra-day and inter-day precision of abexinostat were less than 11.5% and the intra-day and inter-day accuracy ranged from − 10.7% to 9.7% using this method. During the analysis process, the stability of the test sample was reliable. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat.

Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in clinical treatment. The purpose of this study was to establish a rapid and reliable method for the detection of abexinostat concentrations in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. Selective reaction monitoring (SRM) was used for detection with ion transitions at m/z 397.93 → 200.19 for abexinostat and m/z 422.01 → 186.11 for givinostat, respectively. The intra-day and inter-day precision of abexinostat were less than 11.5% and the intra-day and inter-day accuracy ranged from − 10.7% to 9.7% using this method. During the analysis process, the stability of the test sample was reliable. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM PUBLISHER]

Objective: To examine the effect of PCI-24781 (abexinostat) on the blastocyst formation rate in pig somatic cell nuclear transferred (SCNT) embryos and acetylation levels of the histone H3 lysine 9 and histone H4 lysine 12. Results: Treatment with 0.5 nM PCI-24781 for 6 h significantly improved the development of cloned embryos, in comparison to the control group (25.3 vs. 10.5 %, P < 0.05). Furthermore, PCI-24781 treatment led to elevated acetylation of H3K9 and H4K12. TUNEL assay and Hoechst 33342 staining revealed that the percentage of apoptotic cells in blastocysts was significantly lower in PCI-24781-treated SCNT embryos than in untreated embryos. Also, PCI-24781-treated embryos were transferred into three surrogate sows, one of whom became pregnant and two fetuses developed. Conclusion: PCI-24781 improves nuclear reprogramming and the developmental potential of pig SCNT embryos. [ABSTRACT FROM AUTHOR]

BACKGROUND It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas. METHODS Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design. Abexinostat was administered on days 1 through 5 with 75 mg/m2 of doxorubicin administered on day 4 of every 21-day cycle until patients developed disease progression or drug intolerance or reached a cumulative lifetime doxorubicin dose of 450 mg/m2. Granulocyte-colony-stimulating factor (G-CSF) support was provided at physician discretion on arm A and was provided to all participants in arm B. From 3 to 6 participants initially received abexinostat 30 mg/m2 twice daily, and subsequent cohorts were administered doses of 15 mg/m2, 45 mg/m2, or 60 mg/m2 twice daily. All patients without progressive disease after receiving a cumulative lifetime doxorubicin dose of 450 mg/m2 were given the option to continue with abexinostat as a single agent until they developed disease progression. RESULTS In total, 22 participants (10 who had previously experienced tumor growth after doxorubicin therapy) were enrolled (6 in arm A, 14 in arm B), 20 were evaluable for dose-limiting toxicity (DLT), and 17 were evaluable for radiologic response. In arm A, participants received abexinostat 15 mg/m2 or 30 mg/m2 twice daily. DLTs of grade 3 and 4 neutropenia were observed in 2 of 3 participants who received abexinostat 30 mg/m2 twice daily. Neither of those patients received G-CSF prophylaxis. In arm B, participants received abexinostat at doses of 30 mg/m2, 45 mg/m2, or 60 mg/m2 twice daily, all with mandated G-CSF support. Two DLTs were observed at the 60 mg/m2 twice-daily dose (grade 3 infection, grade 4 thrombocytopenia). The pharmacokinetics of abexinostat were not affected by doxorubicin. HDAC activity, as measured by histone acetylation in peripheral blood mononuclear cells, was maximally inhibited at the abexinostat 30 mg/m2 twice-daily dose. Of the 17 participants who were evaluable for radiologic response, 1 patient had a partial response, 9 patients had stable disease, and 7 patients had progressive disease as their best response; and 8 patients completed ≥5 cycles. Three of those participants had stable disease as their most recent disease status when the current report was written. Four participants who continued on monotherapy remained in stable disease for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study-related deaths were observed. CONCLUSIONS The maximum tolerated dose for abexinostat was 45 mg/m2 twice daily administered on days 1 through 5 when patients received doxorubicin 75 mg/m2 on day 4 of a 3-week cycle and G-CSF support was mandated. Toxicities were manageable, and tumor responses were observed. Additional studies are needed to further define the specific contributions of HDAC inhibition in patients who receive doxorubicin for the treatment of metastatic sarcoma. Cancer 2015;121:1223-1230. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background We determined the safety, pharmacokinetics, pharmacodynamics, and antitumour activity of abexinostat in B-cell lymphoma or chronic lymphocytic leukaemia. Patients and methods Thirty-five patients received oral abexinostat 30, 45, or 60 mg/m bid in a 3 + 3 design in three 21-day schedules: 14 days on treatment in schedule 1 (D1-14); 10 days in schedule 2 (D1-5 and D8-12); and 12 days in schedule 3 (D1-4, D8-11, and D15-18). Safety, tumour response, plasma concentration, and histone H3 acetylation were measured. Results Two dose-limiting toxicities occurred in each schedule (one grade 3 febrile neutropenia; five grade 4 thrombocytopenia) at 60 mg/m bid (maximal tolerated dose). The recommended dose was 45 mg/m bid; schedule 1 was considered optimal. Non-haematological drug-related toxicities included grade 1 or 2 diarrhoea (43 %), nausea (23 %), and vomiting (11 %); haematological toxicities included thrombocytopenia (31 % grade 3, and 26 % grade 4), which remained manageable and reversible on withdrawal. Of 29 evaluable patients, there were 2 complete and 6 partial responses; median duration of response was 14.6 months (range 3-16.5 months) (1 cycle is equivalent to 0.75 months). There was no evidence for nonlinear pharmacokinetics. There was a correlation between dose and histone acetylation. Conclusion Abexinostat has manageable toxicity and induced some durable complete and partial responses in B-cell lymphoma or chronic lymphocytic leukaemia. Our results suggest most favourable responses in patients with follicular lymphoma, though further research would be needed to confirm this finding. [ABSTRACT FROM AUTHOR]

Background In the clinical development of oncology drugs, the recommended dose is usually determined using a 3 + 3 dose-escalation study design. However, this phase I design does not always adequately describe dose-toxicity relationships. Methods 125 patients, with either solid tumours or lymphoma, were included in the study and 1217 platelet counts were available over three treatment cycles. The data was used to build a population pharmacokinetic/pharmacodynamic (PKPD) model using a sequential modeling approach. Model-derived Recommended Doses (MDRD) of abexinostat (a Histone Deacetylase Inhibitor) were determined from simulations of different administration schedules, and the higher bound for the probability of reaching these MDRD with a 3 + 3 design were obtained. Results The PKPD model developed adequately described platelet kinetics in both patient populations with the inclusion of two platelet baseline counts and a disease progression component for patients with lymphoma. Simulation results demonstrated that abexinostat administration during the first 4 days of each week in a 3-week cycle led to a higher MDRD compared to the other administration schedules tested, with a maximum probability of 40 % of reaching these MDRDs using a 3 + 3 design. Conclusions The PKPD model was able to predict thrombocytopenia following abexinostat administration in both patient populations. A model-based approach to determine the recommended dose in phase I trials is preferable due to the imprecision of the 3 + 3 design. [ABSTRACT FROM AUTHOR]

Purpose: A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the thrombocytopenia (dose-limiting toxicity) of abexinostat, a new histone deacetylase inhibitor. An optimal administration schedule of the drug was determined using a simulation-based approach. Methods: Early PK and PK/PD data were analysed using a sequential population modeling approach (NONMEM 7), allowing for the description of a PK profile and platelet-count decrease after abexinostat administration with various administration schedules. Simulations of platelet count with several administration schedules over 3-week treatment cycles (ASC) and over a day (ASD) were computed to define the optimal schedule that limits the depth of thrombocytopenia. Results: An intermediate PK/PD model accurately described the data. The administration of abexinostat during the first 4 days of each week in a 3-week cycle resulted in fewer adverse events (with no influence of ASD on platelet count profiles), and corresponded to the optimal treatment schedule. This administration schedule was clinically evaluated in a phase I clinical trial and allowed for the definition of a new maximum tolerated dose (MTD), leading to a nearly 30% higher dose-intensity than that of another previously tested schedule. Lastly, a final model was built using all of the available data. Conclusions: The final model, characterizing the dose-effect and the dose-toxicity relationships, provides a useful modeling tool for clinical drug development. [ABSTRACT FROM AUTHOR]

Hydroxamate-based histone deacetylase inhibitors (Hb-HDACIs), such as vorinostat, belinostat and panobinostat, have been previously shown to have a wide range of activity in hematologic malignancies such as cutaneous T-cell lymphoma and multiple myeloma. Recent data show that they synergize with a variety of cytotoxic and molecular targeted agents in many different solid tumors, including breast, prostate, pancreatic, lung and ovarian cancer. Hb-HDACIs have a quite good toxicity profile and are now being tested in phase I and II clinical trials in solid tumors with promising results in selected neoplasms, such as hepatocarcinoma. This review will focus on their clinical activity and safety in patients with advanced solid neoplasms. [ABSTRACT FROM AUTHOR]