BackgroundSorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child–Pugh A status.MethodsAll patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child–Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients.ResultsThe 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child–Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child–Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively.ConclusionsThere was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia–Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.Electronic supplementary materialThe online version of this article (doi:10.1007/s12072-016-9774-x) contains supplementary material, which is available to authorized users.
IntroductionPain is a major symptom in many medical conditions which can be relieved thanks to analgesics. The goal of this work was to present an indirect comparison of efficacy and tolerability profiles of two analgesics, tramadol and tapentadol, in patients with chronic non-malignant pain.MethodsIn the absence of a head-to-head comparison between these two opioid drugs, model-based meta-analyses were used to characterize the pain intensity time dynamics and evaluate the proportions of most frequent adverse events (constipation, nausea, vomiting, dizziness, and somnolence) and drop-outs (due to adverse event, as well as due to lack of efficacy) in each treatment group. Using these models, the investigational treatments were compared on the basis of Monte Carlo simulation outcomes.ResultsData were extracted from 45 Phase II and Phase III studies representing a total of 81 treatment arms, i.e., approximately 13,000 patients. The pain intensity model shows, that after having adjusted for differences in baseline pain intensity and placebo effects, tramadol 300 mg once daily (qd) was slightly more effective in reducing pain than tapentadol 100–250 mg twice daily (bid), with a 46% change from baseline for the former versus 36% for the latter. From a tolerability standpoint, both drugs showed, as expected, increased risks of adverse events compared to placebo. Yet, tapentadol was associated with slightly lower risks of constipation, and nausea than tramadol.ConclusionOverall, the analysis showed that the benefit–risk profiles of tramadol 300 mg qd and tapentadol 100–250 mg bid were approximately even. The amount of data to characterize dose–response relationships was sufficient only in the tramadol group; public access to tapentadol efficacy and tolerability readouts across a wide dose range in chronic non-malignant pain would allow a comparison of therapeutic indices, a straight quantitation of the benefit–risk ratio. Knowing that their side-effects have been identified as potential hindrance to prescription, a broad and open access to clinical trial data in this indication is encouraged in order to facilitate the evaluation of the opiate analgesics clinical utility.Electronic supplementary materialThe online version of this article (doi:10.1007/s40122-014-0023-5) contains supplementary material, which is available to authorized users.
Nifurtimox (LAMPIT) has been used for decades for the treatment of Chagas disease, a chronic and potentially life‐threatening disease caused by the parasite Trypanosoma cruzi. The pharmacokinetic (PK) information on nifurtimox in humans derived from controlled clinical studies is very limited. The objective was to investigate and compare the population PK of nifurtimox in adult and pediatric patients with Chagas disease to confirm the clinical dosing regimen in children, which was based on allometric approaches using the concept that a dose‐equivalent exposure would reach equivalent antiparasitic efficacy as in adults. The resulting adult model adequately described the PK in adults. Significant predictors of the availability in PK were food intake, tablet formulation (fast‐ vs slow‐dissolution tablet), study, and body weight. As the resulting adult model could not adequately predict the sparse sampled pediatric patient data, these data were analyzed separately to derive exposure estimates for comparison with adult exposure. In the population PK model for pediatric patients, significant covariates were body weight and age. As compared to adults, children aged >2 years were estimated to have 50.6% higher apparent clearance. No hints of dose nonlinearity were observed in a dose range of 30 to 240 mg single dose in adults and 15 to 300 mg 3 times daily (8‐20 mg/kg) in children. Altogether, this study retroactively showed that the current mg/kg dosing regimen in children reached similar exposure as in adults receiving an 8 mg/kg total daily dose.
Antibody-drug conjugates (ADC) represent a promising therapeutic approach for treatment of cancer. We have developed a novel ADC directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer and thus represents a potential therapeutic target for treatment of FGFR2-positive cancer patients with ADC-based therapy. FGFR2-ADC consists of a fully human anti-FGFR2-Ab (BAY 1179470) conjugated via a stable linker to a novel auristatin cytotoxic agent licensed from Seattle Genetics. FGFR2-ADC exhibits low nM to sub-nM potency in vitro in a panel of FGFR2-positive cancer cells lines (SNU-16, MFM-223, NCI-H716) while being inactive against FGFR2-low or -negative cell lines (MDA-MB-231, HEK-293, BaF/3) and highly selective versus a control ADC. FGFR2-ADC is highly efficacious in monotherapy and results in tumor growth inhibition in the gastric cancer xenograft model SNU-16 and tumor regression in the breast cancer xenograft model MFM-223. FGFR2-ADC induces tumor stasis in the colorectal cancer xenograft model NCI-H716 and regrown tumors are sensitive to a second treatment cycle of FGFR2-ADC. FGFR2-ADC shows high efficacy in vivo in monotherapy in patient-derived (PDX) FGFR2-positive murine xenograft models, e.g. in the ovarian cancer model OV30-0511A. FGFR2-ADC is also efficacious in the gastric cancer PDX model GC10-0608 and the breast cancer model MAXF857. The toxophore metabolite of FGFR2-ADC was more than 30-fold enriched in tumors versus other organs (liver, spleen, kidneys) in NCI-H716 tumor-bearing mice. Based on the preclinical efficacy, PK and tolerability data, evaluation of FGFR2-ADC in cancer patients appears warranted. A Phase I study is planned. Citation Format: Anette Sommer, Charlotte Kopitz, Christoph Schatz, Ruprecht Zierz, Joachim Schuhmacher, Sabine Wittemer-Rump, Klaas Prins, Manuela Braun, Frank Reetz, Bertolt Kreft, Hung T. Huynh, Karl Ziegelbauer. Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1684. doi:10.1158/1538-7445.AM2015-1684
BAY 1187982 is an antibody drug conjugate (ADC) directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer. Anti-tumor efficacy of BAY 1187982 has been demonstrated in several FGFR2-positive cancer cell line as well as patient-derived xenograft models. Toxicology findings from repeated dose preclinical safety studies in monkeys indicated effects related to the liver, kidney, heart and coagulation system. To predict the therapeutic index of BAY 1187982 in humans and to support the design of the first-in-human (FIH) study with respect to selection of dose and regimen, preclinical efficacy and toxicity findings were quantified. All available preclinical PK, TK, tumor response and toxicity data from mouse models and monkey studies were used to create a model framework to describe the PK, TK, PK/PD and TK/TD relationship as functions of BAY 1187982 dose, regimen and time. Human PK parameters based on scaling from monkey were used to predict PK profiles in humans for a range of doses and schedules. These sets of predicted exposure models were combined with the PK/PD as well as the TK/TD model to assess the expected efficacy (according to RECIST criteria) and toxicity range in humans, respectively. The dosing schedule leading to the largest therapeutic index and the dose escalation schema for the FIH study were determined. The FIH study is currently under preparation. Citation Format: Sabine Wittemer-Rump, Anette Sommer, Charlotte Kopitz, Hung Huynh, Christoph Schatz, Ruprecht Zierz, Manuela Braun, Kirstin Meyer, Dirk Laurent, Jörg Lippert, Klaas Prins. Pharmacokinetic/pharmacodynamic (PK/PD) and toxicokinetic/toxicodynamic (TK/TD) modeling of preclinical data of FGFR2-ADC (BAY 1187982) to guide dosing in phase 1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1683. doi:10.1158/1538-7445.AM2015-1683
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.