<p>PDF file - 200K, Supplementary Table 1. Comparison of predictive performance for model parameterizations A, (B), and C (with IBW covariate) Supplemental Figure 1. The base structural bevacizumab model consisted of a two compartment model parameterized in terms of clearance from the central compartment and intercompartmental transfer to and from central and peripheral compartments. Supplemental Figure 2. Observed concentration-time data (filled diamonds) with simulations from individual posthoc parameter estimates (dashed lines; ~2 hrs step size) indicate that bevacizumab exhibits bi-exponential decay with a relatively rapid alpha phase and a prolonged beta terminal phase. Supplemental Figure 3. Visual predictive check of observed and model-predicted serum bevacizumab concentrations following 15 mg/kg dosing over a course of three occasions. The shaded region represents the 95% confidence interval of the Monte Carlo model simulations.</p>
Abstract A sensitive method for the determination of depsipeptide (FR901228) in plasma was developed using high performance liquid chromatographic (HPLC) separation with tandem mass spectrometric detection. FR901228 was acidified by potassium acid phthalate (0.05 M, pH 4.0) and extracted with ethyl acetate (5:12, v/v); the supernatant of ethyl acetate extract was evaporated, reconstituted in 250 µL mobile phase, and then separated on a Keystone spherisorb C8, 5µ 2.1 × 100 mm2 column with a mobile phase consisting of methanol–12 mM ammonium acetate (85:15, v/v) at a flow rate of 0.2 mL/min. Detection was achieved by a PE SCIEX API365 LC/MS/MS System at unit (Q1) and low (Q3) resolution in positive multiple reaction monitoring (MRM) mode, monitoring the transition of the FR901228 molecular ion m/z 541.0 to the product ion m/z 272.0, and of the internal standard (IS) (t‐Boc‐D‐glutamic acid 1‐benzyl ester, BGBE) molecular ion m/z 338.0 to the product ion m/z 91.0. The mean recovery for FR901228 was 60% with a lower limit of quantification (LLOQ) of 0.2 ng/mL using 0.5 mL plasma for extraction. This method was validated over a linear range of 1.0–1000 ng/mL, using BGBE as the IS. Results from a 5‐day validation study demonstrated good within‐day and between‐day precision (CV% values were ≤3.5% and ≤5.5%, respectively) and accuracy (range from 99.7% to 112.5%) across the calibration range of 1.0–1000 ng/mL.
8528 Background: Depsipeptide, a histone deacetylase inhibitor, has demonstrated potent antitumor activity against human tumor cell lines (including neuroblastomas) at IC50s < 10nM and in various xenograft models. Methods: A phase I trial of depsipeptide was conducted in children with recurrent or refractory solid tumors to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and pharmacokinetics (PK) of depsipepetide and to assess accumulation of histone acetylation (H3) in peripheral blood mononuclear cells (PBMNC). Depsipeptide was administered as a 4-hour IV infusion weekly × 3 consecutive weeks every 28 days. Dose levels were 10, 13, 17 and 22 mg/m2. PK and histone acetylation studies were conducted in the first course. Results: Of the 24 patients enrolled on this trial, 19 were assessable for toxicity (median age at enrollment: 13, range 2–21 years, 10 male). Three patients experienced DLT: one at 13 mg/m2 had asymptomatic reversible T wave inversions in leads II, III and AVF; one at 22 mg/m2 experienced asymptomatic and reversible sick sinus syndrome and another patient 22 mg/m2 had reversible, asymptomatic T wave inversions in leads II, III and AVF as well as asymptomatic ventricular tachycardia. Six patients have been enrolled at 17 mg/m2; the 6th patient has yet to be evaluated for toxicity. No objective responses have been observed. Two patients with PNET and ependymoma had stable disease for 4 and 5+ courses, respectively. At 17 and 22 mg/m2, the median (range) depsipeptide CL and terminal t1/2 were 12.4 L/hr/m2 (3.5 - 28.9) and 2.2 hrs (1.1 - 3.8), respectively. Median (range) depsipeptide AUC0–24hr at 17 mg/m2 was 1.8 μg-hr/mL (1.1 - 4.8), which is comparable to reported adult exposure at this dosage. Immunostaining in PBMNC demonstrated an accumulation of acetylated H3 between 2–6 hours after the start of the depsipeptide infusion which lasted for up to 20 hours after the end of infusion. Conclusion: Depsipeptide is relatively well-tolerated in children when administered weekly × 3 every 28 days. DLTs include asymptomatic EKG changes, ventricular tachycardia and sick sinus syndrome. Depsipeptide PKs in children are similar to those previously reported in adults.: No significant financial relationships to disclose.
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.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.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/m(2) 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.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.
<div>Abstract<p>Acute lymphoblastic leukemia expressing the gamma delta T-cell receptor (γδ T-ALL) is a poorly understood disease. We studied 200 children with γδ T-ALL from 13 clinical study groups to understand the clinical and genetic features of this disease. We found age and genetic drivers were significantly associated with outcome. γδ T-ALL diagnosed in children under 3 years of age was extremely high-risk and enriched for genetic alterations that result in both <i>LMO2</i> activation and <i>STAG2</i> inactivation. Mechanistically, using patient samples and isogenic cell lines, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer–promoter looping, resulting in deregulation of gene expression associated with T-cell differentiation. High-throughput drug screening identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which can be targeted by poly(ADP-ribose) polymerase inhibition. These data provide a diagnostic framework for classification and risk stratification of pediatric γδ T-ALL.</p><p><b>Significance:</b> Patients with acute lymphoblastic leukemia expressing the gamma delta T-cell receptor under 3 years old or measurable residual disease ≥1% at end of induction showed dismal outcomes and should be classified as having high-risk disease. The STAG2/LMO2 subtype was enriched in this very young age group. STAG2 inactivation may perturb chromatin conformation and cell differentiation and confer vulnerability to poly(ADP-ribose) polymerase inhibition.</p></div>
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
