Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I

Fouliard, Sylvain; Robert, Renata; Jacquet-Bescond, Anne; Rieu, Quentin Chalret du; Balasubramanian, Sriram; Loury, Dana N.; Loriot, Yohann; Hollebecque, Antoine; Kloos, Ioana; Soria, Jean‐Charles; Chenel, Marylore; Depil, Stéphane

doi:10.1016/j.ejca.2013.05.009

Cited by 29 publications

(23 citation statements)

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“…This dosing regimen is consistent with previous work showing a minimum of 6 to 8 hours continuous exposure with HDACi is needed for inducing ROS and apoptosis in tumor cells (30,31); it is also made possible by the unique pharmacokinetic profile of this drug which has a terminal half life of 4 to 5 hours (16,17). This unique dosing regimen also allows for longer recovery time off drug per day, and may account for the better tolerability and enhanced efficacy profile of abexinostat relative to other HDACi agents (18).…”

Section: Discussionmentioning

confidence: 99%

“…The true mean elimination half-life value could therefore not be calculated due to the 4-hour sampling window before the second dose, but it has been previously established as 4 to 5 hours in two other phase I studies with sampling up to 24 hours (16,17). Data from 125 patients have been analyzed and modeled (18,19), and the pharmacokinetics have been shown to be very consistent between the two daily doses. For pharmacodynamic studies, increased levels of acetylated tubulin were observed postdose versus predose in 11 patients treated with 45 mg/m 2 abexinostat twice daily (cohorts 2 and 3 pooled) and significant increases in the 11 patients treated with 60 mg/m 2 abexinostat twice daily, with the mean fold-increase of normalized acetylated tubulin being 1.48 and 1.46, respectively (Fig.…”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

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A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

Evens

Balasubramanian

Vose

et al. 2016

Clinical Cancer Research

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Purpose: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N ¼ 55) with single-agent abexinostat in relapsed/refractory lymphoma.Experimental Design: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m 2 twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/ refractory follicular lymphoma or mantle cell lymphoma.Results: The recommended phase II dose was 45 mg/m 2 twice daily (90 mg/m 2 total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigatorassessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3þ). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with !10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths.Conclusions: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

Evens

Balasubramanian

Vose

et al. 2016

Clinical Cancer Research

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“…The samples were analysed centrally by ELISA with antibodies against acetylated (06-599, Millipore) and total histone H3 (MAB3422, Millipore) (Institut de Recherches Servier, Croissy-sur-Seine, France). Acetylation data were modelled together with data obtained from a phase 1 study in monotherapy in solid tumours [19], using a population pharmacokinetic and pharmacodynamic approach. Simulations were performed at day 1 for 1000 subjects with a body surface area of 1.8 m 2 for the dose levels evaluated.…”

Section: Assessmentsmentioning

confidence: 99%

Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia

et al. 2015

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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(2) 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(2) bid (maximal tolerated dose). The recommended dose was 45 mg/m(2) 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.

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“…Six different clinical interventional trials are now ongoing for PCI-24781, mainly for hematological diseases (NCT01149668, NCT00473577) and for testing the tolerability of the molecule in patients with hematological malignancies (NCT00562224, NCT00724984). A trial is now being recruited for the same drug (NCT01543763) in combination with PZP115891 (a tyrosine kinase inhibitor) (62).…”

Section: Pci-24781mentioning

confidence: 99%

Targeting Histone Deacetylases in Diseases: Where Are We?

Benedetti

Conte

Altucci

2015

Antioxidants & Redox Signaling

100

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Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. Critical Issues: (i) Non-specific (off-target) HDACi effects due to activities unassociated with HDAC inhibition. (ii) Advantages/disadvantages of non-selective or isoformdirected HDACi. (iii) Limited number of response-predictive biomarkers. (iv) Toxicity leading to dysfunction of critical biological processes. Future Directions: Selective HDACi could achieve enhanced clinical utility by reducing or eliminating the serious side effects associated with current first-generation non-selective HDACi. Isoform-selective and pan-HDACi candidates might benefit from the identification of biomarkers, enabling better patient stratification and prediction of response to treatment. Antioxid. Redox Signal. 23, 99-126.Shaping the Epigenome E pigenetic mechanism(s) allow genetically identical cells to adopt different phenotypes regulating transcriptional availability of the genome through differential chromatin marking and packaging (137), creating a network of mutually reinforcing or counteracting signals (192). A key aspect of epigenetics is that chromatin marks can be preserved and/or changed according to environmental, developmental, or pathological needs. These very complex and plastic steps are achieved via the activity of initiators (such as long noncoding RNA), writers (which establish the epigenetic mark, such as histone acetyltransferases), readers (which interpret the epi-mark), and erasers (which remove the epi-mark, such as histone deacetylases, or HDACs) (41, 232). In concert, remodelers (which reposition nucleosomes) and insulators (which build boundaries between epi-domains) create, maintain, and modulate the three-dimensional structure of networking within a cell (223). It is now clear that genetic and epigenetic mechanisms influence each other, cooperating to enable the acquisition of hallmarks of human cancer (89). The frequency of epi-target mutations seen in cancers underlines the relevance of mutations in epigenetic modifiers in cancer (213) and corroborates the concept that deregulation of epigenetic cont...

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Pharmacokinetic/pharmacodynamic modelling-based optimisation of administration schedule for the histone deacetylase inhibitor abexinostat (S78454/PCI-24781) in phase I

Cited by 29 publications

References 18 publications

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma

Phase 1 study of the oral histone deacetylase inhibitor abexinostat in patients with Hodgkin lymphoma, non-Hodgkin lymphoma, or chronic lymphocytic leukaemia

Targeting Histone Deacetylases in Diseases: Where Are We?

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