Dataset Information

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

ABSTRACT: BACKGROUND:This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC). METHODS:Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined. RESULTS:Phase-I: no DLTs observed; nintedanib MTD in both groups was 200?mg bid. Phase-II: patients (N?=?93) were randomised to nintedanib (n?=?62) or sorafenib (n?=?31); TTP was 5.5 vs. 4.6 months (HR?=?1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR?=?0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR?=?1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ? 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]). CONCLUSIONS:Nintedanib may have similar efficacy to sorafenib in aHCC.

SUBMITTER: Palmer DH

PROVIDER: S-EPMC5943284 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

Palmer D H DH Ma Y T YT Peck-Radosavljevic M M Ross P P Graham J J Fartoux L L Deptala A A Studeny M M Schnell D D Hocke J J Loembé A-B AB Meyer T T

British journal of cancer 20180322 9

<h4>Background</h4>This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC).<h4>Methods</h4>Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomi ...[more]

PMID: 29563636

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Project description:Background:Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC). Patients and Methods:For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5-6, an Eastern Cooperative Oncology Group performance score ?2, and an ALT/AST ?2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory. Results:The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib (n = 63) or sorafenib (n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73-2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59-1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome. Conclusions:Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.

Project description:BackgroundSapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years.ResultsIn total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters.ConclusionsThe addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria.Trial registrationClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.

Project description:Promising clinical data and significant antigen-sparing have been demonstrated for a pandemic H5N1 influenza split-virion vaccine adjuvanted with AS03A, an ?-tocopherol-containing oil-in-water emulsion-based Adjuvant System. Although studies using this formulation have been reported, there have been no data for Japanese populations. This study therefore aimed to assess the immunogenicity and tolerability of a prepandemic (H5N1) influenza vaccine adjuvanted with AS03A in Japanese adults.This open-label, single-group study was conducted at two centres in Japan in healthy Japanese males and females aged 20-64 years (n = 100). Subjects received two doses of vaccine, containing 3.75 ?g haemagglutinin of the A/Indonesia/5/2005-like IBCDC-RG2 Clade 2.1 (H5N1) strain adjuvanted with AS03A, 21 days apart. The primary endpoint evaluated the humoral immune response in terms of H5N1 haemagglutination inhibition (HI) antibody titres against the vaccine strain (Clade 2.1) 21 days after the second dose. Ninety five percent confidence intervals for geometric mean titres, seroprotection, seroconversion and seropositivity rates were calculated. Secondary and exploratory endpoints included the assessment of the humoral response in terms of neutralising antibody titres, the response against additional H5N1 strains (Clade 1 and Clade 2.2), as well as the evaluation of safety and reactogenicity.Robust immune responses were elicited after two doses of the prepandemic influenza vaccine adjuvanted with AS03A. Overall, vaccine HI seroconversion rates and seroprotection rates were 91% 21 days after the second vaccination. This fulfilled all regulatory acceptance criteria for the vaccine-homologous HI antibody level. A substantial cross-reactive humoral immune response was also observed against the virus strains A/turkey/Turkey/1/2005 (Clade 2.2) and A/Vietnam/1194/2004 (Clade 1) after the second vaccine administration. A marked post-vaccination response in terms of neutralising antibody titres was demonstrated and persistence of the immune response was observed 6 months after the first dose. The vaccine was generally well tolerated and there were no serious adverse events reported.The H5N1 candidate vaccine adjuvanted with AS03A elicited a strong and persistent immune response against the vaccine strain A/Indonesia/5/2005 in Japanese adults. Vaccination with this formulation demonstrated a clinically acceptable reactogenicity profile and did not raise any safety concerns in this population.Clinicaltrials.gov NCT00742885.

Project description:Background: Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza.Methods: In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ?20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480.Findings: Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02-1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4-16] vs 11 days [5-25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0-6] vs 3 days [0-14], p=0·14). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine [20%] of 46 vs 20 [38%] of 52, p=0·041), the most frequent of which were acute respiratory distress syndrome (one [2%] vs two [4%] patients) and stroke (one [2%] vs two [4%] patients).Interpretation: Although there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention.Funding: National Institute of Allergy and Infectious Diseases, US National Institutes of Health.

Project description:BackgroundFibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements.MethodsIn this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed.FindingsBetween Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related.InterpretationThese data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements.FundingIncyte Corporation.

Dataset Information

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

Publications

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

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