Phase I clinical, pharmacokinetic, and pharmacodynamic study of CG200745, a histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13560-e13560
Author(s):  
Kyu-Pyo Kim ◽  
Yong Sang Hong ◽  
Jin-Hee Ahn ◽  
Jae-Lyun Lee ◽  
Kyun-Seop Bae ◽  
...  
Keyword(s):  
Single Dose ◽  
Histone Deacetylase ◽  
Hdac Inhibitor ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Elimination Half ◽  
Solid Malignancies ◽  
Acetylated Histone H4

e13560 Background: The aim of this study was to assess the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and efficacy of single dose of intravenous CG200745, a novel histone deacetylase (HDAC) inhibitor, in patients with advanced solid malignancies. Methods: Two to six patients received Intravenous CG200745 every 3 weeks according to the single dose-escalating 2+4 method. Acetylated histone H4 (Acetyl-H4) was measured in peripheral blood mononuclear cells (PBMCs). Results: Ten patients were treated at one of five doses (1.8-24.0 mg/m2) and received 3 (1-7) cycles of CG200745 (median, range). No dose-limiting toxic effects or QTc prolongations were noted. Dose proportionality was observed for both Cmax and AUC. The elimination half-life and mean residual time was 5.43±0.37(mean±SD) and 4.15±0.50 hrs. An increase in Acetyl-H4 was observed at hour 1 and correlated with dose and Cmax. Acetyl-H4 persisted for 8 hrs in 3 pts and 24 hrs in another 3 pts. Stable disease was seen in 2 pts with colorectal cancer at levels 7.2 and 24 mg/m2. Conclusions: CG200745 can be safely administered at the effective dose levels that inhibit HDAC in PBMCs. As MTD was not reached, this agent is under further investigation for multiple ascending doses.

Phase I Study of Depsipeptide in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Report

2006 ◽  
Vol 24 (22) ◽  
pp. 3678-3685 ◽  
Author(s):  
Maryam Fouladi ◽  
Wayne L. Furman ◽  
Thomas Chin ◽  
Burgess B. Freeman ◽  
Lorina Dudkin ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Independent Manner ◽  
Time Curve ◽  
Peripheral Blood Mononuclear ◽  
Deacetylase Inhibitor ◽  
Recommended Phase Ii Dose

Purpose To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with refractory or recurrent solid tumors. Patients and Methods Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques. Results There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m2 with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed. Conclusion Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.

A first-in-human phase I study of 4SC-201, an oral histone deacetylase (HDAC) inhibitor, in patients with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3530-3530 ◽  
Author(s):  
A. T. Brunetto ◽  
J. E. Ang ◽  
R. Lal ◽  
D. Olmos ◽  
S. Frentzas ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hdac Inhibitor ◽  
Maximum Tolerated Dose ◽  
Individual Variability ◽  
Functional Assay ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Histone H4 Acetylation ◽  
Grade 3 ◽  
Dose Levels

3530 Background: 4SC-201 (former code BYK408740) is a specific, potent, pan-HDAC inhibitor with improved ADME properties. Methods: Patients (pts) with advanced refractory solid tumors were dosed once daily (QD) d1–5 in a 14-day cycle in sequential cohorts of 3–6 pts with 50 or 100% dose increments. Primary objectives were to determine safety, tolerability, pharmacokinetics (PK) and maximum tolerated dose (MTD) of 4SC-201. Pharmacodynamic assessment (histone acetylation and HDAC enzyme activity) and anti-tumor efficacy were secondary objectives. Blood samples for PK and PD were taken on days 1, 5 and 47 of treatment. Results: 18 pts (9M/9F) with a median age of 58.5 yrs (range 40–70) were treated at five dose levels: 3 pts each at 100mg, 200mg, 400mg and 600mg and 6 pts at 800mg. All pts were evaluable for toxicity and received at least 2 treatment cycles. Grade 3 DLT of nausea and vomiting occurred in 1 pt dosed at 800mg. Most common adverse events included nausea, vomiting and fatigue. 8 of 9 pts treated in the 600mg and 800mg cohorts had stable disease during the main phase of the study (4 treatment cycles). A patient with liposarcoma and another with thymoma (marginal response) continued treatment beyond 6 months. PK parameters were dose-proportional with a low inter-individual variability and indicated good bioavailability. The apparent t1/2 of oral 4SC-201 ranged from 2.3 to 4.4 hours. The degree of HDAC inhibition measured in a peripheral blood mononuclear cell functional assay was dose- dependent and increased from 50 to 100 %, although histone H4 acetylation accumulation after dosing did not differ significantly between dose levels. Conclusions: Oral 4SC-201 has favorable disposition and can be safely administered; 600mg QD d1–5 in a 14-day cycle is recommended for phase II evaluation. Safely administered doses modulate target with antitumor activity. [Table: see text]

Phase I and Pharmacokinetic Study of MS-275, a Histone Deacetylase Inhibitor, in Patients With Advanced and Refractory Solid Tumors or Lymphoma

2005 ◽  
Vol 23 (17) ◽  
pp. 3912-3922 ◽  
Author(s):  
Qin C. Ryan ◽  
Donna Headlee ◽  
Milin Acharya ◽  
Alex Sparreboom ◽  
Jane B. Trepel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Histone Deacetylase ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase Inhibition ◽  
Daily Schedule ◽  
Blood Mononuclear Cells

PurposeThe objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275.Patients and MethodsPatients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily × 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2and the dose was escalated in three- to six-patient cohorts based on toxicity assessments.ResultsWith the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for ≥ 3 months.ConclusionThe MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly × 4, repeated every 6 weeks is presently being evaluated.

scholarly journals Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Gilson P. Dorneles ◽  
Maria Carolina R. Boeira ◽  
Lucas L. Schipper ◽  
Ivy R. V. Silva ◽  
Viviane R. Elsner ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Strenuous Exercise ◽  
Low Grade ◽  
Histone H4 ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase 2 ◽  
Histone H4 Acetylation ◽  
Low Grade Inflammation

This study evaluated the response of global histone H4 acetylation (H4ac), histone deacetylase 2 (HDAC2) activity, as well as the production of proinflammatory cytokines and monocyte phenotypes of lean and obese males after exercise. Ten lean and ten obese sedentary men were submitted to one session of strenuous exercise, and peripheral blood mononuclear cells (PBMC) were stimulated in vitro with lipopolysaccharide (LPS). Global H4ac levels, HDAC2 activity in PBMC, and IL-6, IL-8, and TNF-α production were analyzed. Monocyte phenotype was determined in accordance with the expression of CD14 and CD16. At rest, obese individuals presented higher frequency of proinflammatory CD14+CD16+ monocytes. LPS induced a significant augment in global H4ac and in the production of IL-6, IL-8, and TNF-α mainly in obese individuals. After exercise, the increased production of IL-8 and TNF-α and peripheral frequency of CD14+CD16+ were observed in both groups. In addition, exercise also induced a significant hyperacetylation of histone H4 and decreased HDAC2 activity in both nonstimulated and LPS-stimulated PBMC of obese individuals. Our data indicate that the obesity impacts on H4ac levels and that strenuous exercise leads to an enhanced chronic low-grade inflammation profile in obesity via an imbalance on H4ac/HDAC2.

Phase I Trial of Histone Deacetylase Inhibition by Valproic Acid Followed by the Topoisomerase II Inhibitor Epirubicin in Advanced Solid Tumors: A Clinical and Translational Study

2007 ◽  
Vol 25 (15) ◽  
pp. 1979-1985 ◽  
Author(s):  
Pamela Münster ◽  
Douglas Marchion ◽  
Elona Bicaku ◽  
Morgen Schmitt ◽  
Ji Hyun Lee ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Histone Deacetylase ◽  
Topoisomerase Ii ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Median Number ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Histone Deacetylase Inhibition

Purpose To determine the safety, toxicity, and maximum-tolerated dose of a sequence-specific combination of the histone deacetylase inhibitor (HDACi), valproic acid (VPA), and epirubicin in solid tumor malignancies and to define the clinical feasibility of VPA as an HDACi. Patients and Methods Patients were treated with increasing doses of VPA (days 1 through 3) followed by epirubicin (day 3) in 3-week cycles. The study evaluated pharmacokinetic and pharmacodynamic end points, toxicities, and tumor response. Results Forty-eight patients were enrolled, and 44 received at least one cycle of therapy. Patients (median age, 54 years; range, 39 to 78 years) received the following doses of VPA: 15, 30, 45, 60, 75, 90, 100, 120, 140, and 160 mg/kg/d. Dose-limiting toxicities were somnolence (n = 1), confusion (n = 3), and febrile neutropenia (n = 1). No exacerbation of epirubicin-related toxicities was observed. Partial responses were seen across different tumor types in nine patients (22%), and stable disease/minor responses were seen in 16 patients (39%), despite a median number of three prior regimens (range, zero to 10 prior regimens). Patients received a median number of four treatment cycles (range, one to 10 cycles), and treatment was stopped after reaching maximal epirubicin doses rather than progression in 13 (32%) of 41 patients patients. Total and free VPA plasma concentrations increased linearly with dose and correlated with histone acetylation in peripheral-blood mononuclear cells. Conclusion The maximum-tolerated dose and recommended phase II dose was VPA 140 mg/kg/d for 48 hours followed by epirubicin 100 mg/m2. Sustained plasma concentrations of VPA exceeding those required for in vitro synergy were achieved with acceptable toxicity. Noteworthy antitumor activity was observed in heavily pretreated patients and historically anthracycline-resistant tumors.

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

1998 ◽  
Vol 16 (4) ◽  
pp. 1450-1457 ◽  
Author(s):  
R L Schilsky ◽  
J Hohneker ◽  
M J Ratain ◽  
L Janisch ◽  
L Smetzer ◽  
...  
Keyword(s):  
Washout Period ◽  
Mononuclear Cells ◽  
Dihydropyrimidine Dehydrogenase ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Period 2 ◽  
Daily Schedule ◽  
Starting Dose ◽  
Dose Levels

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

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