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Joint adolescent–adult early phase clinical trials to improve access to new drugs for adolescents with cancer: proposals from the multi-stakeholder platform—ACCELERATE

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      Most cited references 27

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      PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.

      Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma. In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).
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        Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

        Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant. Copyright © 2014 Elsevier Inc. All rights reserved.
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          Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors.

          The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed. Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed. Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin. GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted. ©2011 AACR.
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            Author and article information

            Affiliations
            [1 ]Department of Oncology for Children and Adolescents, Gustave Roussy Cancer Campus, Villejuif, France
            [2 ]Paediatric and Adolescent Drug Development Team, Oak Centre for Children & Young People, The Royal Marsden Hospital & The Institute of Cancer Research, London, UK
            [3 ]Create for Chloe and UK Representative for aPODD, European Medicines Agency, London, UK
            [4 ]Product Development Scientific Support Department, European Medicines Agency, London, UK
            [5 ]Gritstone Oncology, Inc., Emeryville, USA
            [6 ]Imagine for Margo, Fourqueux, France
            [7 ]Novartis AG, Basel, Switzerland
            [8 ]Belgium Federal Agency for Medicines and Health Products, EUROSTATION, Brussels, Belgium
            [9 ]Centre for English Language Teaching, University of York, York, UK
            [10 ]Pharmaceuticals Division, PDOA, Oncology, F. Hoffmann-La Roche Ltd, Basel, Switzerland
            [11 ]Universitair Ziekenhuis Antwerpen, Edegem, Belgium
            [12 ]Jeunes Solidarité Cancer, Paris, France
            [13 ]aPODD Foundation, City Point, London, UK
            [14 ]Pediatric Oncology Department, University Hospital Brno, School of Medicine Masaryk University Brno, Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, ICRC Brno, St. Anna University Hospital Brno, Czech Republic
            [15 ]Boehringer Ingelheim, Pharma GmbH&Co KG, TA Oncology, Biberach, Germany
            [16 ]Regulatory Strategy Oncology, Pfizer Italia, Milano, Italy
            [17 ]Centre Léon Bérard and University Claude Bernard Lyon 1, Lyon
            [18 ]Drug Development Department (DITEP), Gustave Roussy, Villejuif and University Paris-Sud, Orsay, France
            [19 ]Adult Drug Development Unit, The Royal Marsden Hospital and The Institute of Cancer Research, London, UK
            [20 ]Paediatric Haematology/Oncology, Clinical Research/Paediatric Drug Development, University Childreńs Hospital III Hufelandstraße, Essen, Germany
            [21 ]Department of Clinical Research, Gustave Roussy, Villejuif and Paris-Sud University, Le Kremlin-Bicêtre, France
            Author notes
            Journal
            Ann Oncol
            Ann. Oncol
            annonc
            Annals of Oncology
            Oxford University Press
            0923-7534
            1569-8041
            March 2018
            16 January 2018
            16 January 2018
            : 29
            : 3
            : 766-771
            29351570 5889024 10.1093/annonc/mdy002 mdy002
            © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

            Counts
            Pages: 6
            Product
            Funding
            Funded by: Oak Foundation 10.13039/100001275
            Award ID: OCay-04-169
            Award ID: LO1605, 1413
            Categories
            Industry Corner: Perspectives and Controversies

            Oncology & Radiotherapy

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