A phase 1 study of AR-42 in patients with advanced solid tumors, including nervous system tumors.

Valencia, Hugo; Newton, Herbert B.; Hade, Erinn M.; Sborov, Douglas W.; Cavaliere, Robert; Poi, Ming; Phelps, Mitch A.; Wang, Jiang; Coss, Christopher C.; Khountham, Soun; Monk, Paul; Olencki, Thomas; Shapiro, Charles L.; Piekarz, Richard; Hofmeister, Craig C.; Grever, Michael R.; Welling, D. Bradley; Mortazavi, Amir

doi:10.1200/jco.2016.34.15_suppl.2558

Cited by 4 publications

(5 citation statements)

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“…Combined, OSU09102 (NCT01129193), the first-in-human trial, and OSU11130 (NCT01798901) included a total of 57 patients with relapsed or refractory malignancies. Summaries of the patient demographics and disease characteristics were previously published, and a subset of patient features are also presented in Supplemental Table 2 [ 2 , 4 , 5 , 17 ]. Anthropometric measurements were not available for one patient.…”

Section: Resultsmentioning

confidence: 99%

“…Overall, REC-2282 has demonstrated acceptable safety in these early phase studies, and promising clinical activity has been observed in some patients, especially in those with schwanomas [ 3 , 30 ]. Notably, REC-2282 was also discovered through novel in silico screening to have high activity in NF2-driven tumors [ 5 ], which has motivated investigators to further explore this area clinically.…”

Section: Discussionmentioning

confidence: 99%

“…The details of trial design concerning the clinical trials included in our analysis have been previously described [ 2 , 4 , 5 , 17 ]. These studies were approved by The Ohio State University Institutional Review Board and conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, REC-2282 has shown promising activity in preclinical models of neurofibromatosis type 2 (NF2) [ 3 ]. Interestingly, from the first-in-human (FIH) study, the median progression-free survival for solid tumors was 3.6 months compared to 9.1 months in patients with NF2 and meningiomas [ 4 , 5 ]. In agreement with these clinical findings, an informatics-based artificial intelligence (AI) approach independently suggested REC-2282 would be effective in NF2 [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Population Pharmacokinetic Analysis from First-in-Human Data for HDAC Inhibitor, REC-2282 (AR-42), in Patients with Solid Tumors and Hematologic Malignancies: A Case Study for Evaluating Flat vs. Body Size Normalized Dosing

Liva

Chen

Mortazavi

et al. 2021

Eur J Drug Metab Pharmacokinet

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Background and Objectives REC-2282 is a novel histone deacetylase inhibitor that has shown antitumor activity in in vitro and in vivo models of malignancy. The aims of this study were to characterize the population pharmacokinetics of REC-2282 (AR-42) from the first-in-human (NCT01129193) and phase I acute myeloid leukemia trials (NCT01798901) and to evaluate potential sources of variability. Additionally, we sought to understand alternate body size descriptors as sources of inter-individual variability (IIV), which was significant for dose-normalized maximum observed concentration and area under the concentration-time curve (AUC). Methods Datasets from two clinical trials were combined, and population pharmacokinetic analysis was performed using NONMEM and R softwares; patient demographics were tested as covariates.Results A successful population pharmacokinetic model was constructed. The pharmacokinetics of REC-2282 were best described by a two-compartment model with one transit compartment for absorption, first-order elimination and a proportional error model. Fat-free mass (FFM) was retained as a single covariate on clearance (CL), though it explained < 3% of the observed variability on CL. Tumor type and formulation were retained as covariates on lag time, and a majority of variability, attributed to absorption, remained unexplained. Computed tomography (CT)-derived lean body weight estimates were lower than estimated lean body weight and fat-free mass measures in most patients. Analysis of dose-normalized AUC vs. body size descriptors suggests flat dosing is most appropriate for REC-2282. Conclusions FFM was identified as a significant covariate on CL; however, it explained only a very small portion of the IIV; major factors contributing significantly to REC-2282 pharmacokinetic variability remain unidentified.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Population Pharmacokinetic Analysis from First-in-Human Data for HDAC Inhibitor, REC-2282 (AR-42), in Patients with Solid Tumors and Hematologic Malignancies: A Case Study for Evaluating Flat vs. Body Size Normalized Dosing

Liva

Chen

Mortazavi

et al. 2021

Eur J Drug Metab Pharmacokinet

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“…Alternate treatment options for NF2 tumours include inhibitors of the epidermal growth factor receptor (EGFR) [22], inhibitors of the vascular endothelial growth factor (VEG-F) [23–25], inhibitors of mTORC1 [26], an inhibitor of platelet-derived growth factor (PDGF) [27], and an inhibitor of histone deacetylase (HDAC) [28]. However, such treatments have resulted in mixed and sometimes limited success in human trials [29]. Current phase II clinical trials explore better treatment options through inhibition of the mTORC1, PDGF-R, VEGF and anti-angiogenic pathways (NCT01419639; NCT00561665; NCT00589784; NCT02104323).…”

Section: Introductionmentioning

confidence: 99%

Nonsteroidal sulfamate derivatives as new therapeutic approaches for Neurofibromatosis 2 (NF2)

Shen

Arellano-Garcia

Menjivar

et al. 2019

BMC Pharmacol Toxicol

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BackgroundNeurofibromatosis 1 and 2, although involving two different tumour suppressor genes (neurofibromin and merlin, respectively), are both cancer predisposition syndromes that disproportionately affect cells of neural crest origin. New therapeutic approaches for both NF1 and NF2 are badly needed. In promising previous work we demonstrated that two non-steroidal analogues of 2-methoxy-oestradiol (2ME2), STX3451(2-(3-bromo-4,5-dimethoxybenzyl)-7-methoxy-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinoline), and STX2895 (7-Ethyl-6-sulfamoyloxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline) reduced tumour cell growth and induced apoptosis in malignant and benign human Neurofibromatosis 1 (NF1) tumour cells. In earlier NF1 mechanism of action studies we found that in addition to their effects on non-classical hormone-sensitive pathways, STX agents acted on the actin- and myosin-cytoskeleton, as well as PI3Kinase and MTOR signaling pathways. Tumour growth in NF2 cells is affected by different inhibitors from those affecting NF1 growth pathways: specifically, NF2 cells are affected by merlin-downstream pathway inhibitors. Because Merlin, the affected tumour suppressor gene in NF2, is also known to be involved in stabilizing membrane-cytoskeletal complexes, as well as in cell proliferation, and apoptosis, we looked for potentially common mechanisms of action in the agents’ effects on NF1 and NF2. We set out to determine whether STX agents could therefore also provide a prospective avenue for treatment of NF2.MethodsSTX3451 and STX2895 were tested in dose-dependent studies for their effects on growth parameters of malignant and benign NF2 human tumour cell lines in vitro. The mechanisms of action of STX3451 and STX2895 were also analysed.ResultsAlthough neither of the agents tested affected cell growth or apoptosis in the NF2 tumour cell lines tested through the same mechanisms by which they affect these parameters in NF1 tumour cell lines, both agents disrupted actin- and myosin-based cytoskeletal structures in NF2 cell lines, with subsequent effects on growth and cell death.ConclusionsBoth STX3451 and STX2895 provide new approaches for inducing cell death and lowering tumour burden in NF2 as well as in NF1, which both have limited treatment options.

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Epigenetic therapy of cancer

Avendaño¹,

Menéndez²

2023

Medicinal Chemistry of Anticancer Drugs

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A phase 1 study of AR-42 in patients with advanced solid tumors, including nervous system tumors.

Cited by 4 publications

References 0 publications

Population Pharmacokinetic Analysis from First-in-Human Data for HDAC Inhibitor, REC-2282 (AR-42), in Patients with Solid Tumors and Hematologic Malignancies: A Case Study for Evaluating Flat vs. Body Size Normalized Dosing

Population Pharmacokinetic Analysis from First-in-Human Data for HDAC Inhibitor, REC-2282 (AR-42), in Patients with Solid Tumors and Hematologic Malignancies: A Case Study for Evaluating Flat vs. Body Size Normalized Dosing

Nonsteroidal sulfamate derivatives as new therapeutic approaches for Neurofibromatosis 2 (NF2)

Epigenetic therapy of cancer

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