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1. Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib

Author

Sandrine Mansard, Philippe Saiag, Hervé Maillard, Amine Denden, Caroline Robert, Laurent Mortier, S. Dalac-Rat, Charlée Nardin, Olivier Dereure, Thierry Lesimple, Laurent Machet, Eve-Marie Neidhardt, Florent Grange, Alexandra Szenik, Caroline Dutriaux, Christophe Bedane, Céleste Lebbé, Jean-Jacques Grob, HAL UVSQ, Équipe, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Université de Lille, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Léon Bérard [Lyon], Centre Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Francois Rabelais [Tours], Service de Dermatologie [CHU Limoges], CHU Limoges, Service de dermatologie [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Novartis Pharma S.A.S., CHU Bordeaux [Bordeaux], Amgen, Bristol-Myers Squibb, BMS, Pfizer, Merck, Novartis, Roche, Sanofi, Meso Scale Diagnostics, MSD, Novartis Pharma, Les Laboratories Pierre Fabre, This work was supported by Novartis Pharma S.A.S. , France., Philippe Saiag has received personal fees from Amgen, Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, Sanofi and Novartis, he has received non-financial support from Bristol-Myers Squibb, MSD, Roche-Genentech and Novartis, and has received a funding grant from Roche-Genentech., Céléste Lebbe has received honoraria from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte, has acted as a consultant or has served as a member of an advisory board for BMS, and has received travel grant support from BMS and MSD., Jean-Jacques Grob has received honoraria from BMS, MSD, Merck, Pfizer, Incyte, Novartis, Roche, Amgen and Pierre Fabre, has received travel grant support from BMS, MSD and Roche, and has acted as a consultant and advisor for BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer and Incyte., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, Male, Proto-Oncogene Proteins B-raf, Oncology, Cancer Research, medicine.medical_specialty, Pyridones, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pyrimidinones, 030204 cardiovascular system & hematology, Regression tree, 03 medical and health sciences, BRAF V600-mutation, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Trametinib, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Oximes, medicine, Humans, Prospective Studies, Stage (cooking), Prospective cohort study, education, neoplasms, Melanoma, Aged, Neoplasm Staging, education.field_of_study, Proportional hazards model, business.industry, Dabrafenib, Imidazoles, Middle Aged, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Mutation, Disease Progression, Female, business, Brain metastasis, medicine.drug
Abstract

International audience; Background: BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. Methods: Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan–Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. Results: Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33–8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with

Published
2021
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2. Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆

Author

S. Dalle, M.-T. Leccia, Florence Granel-Brocard, Olivier Dereure, E. Maubec, C. Dutriaux, Henri Montaudié, Y. Di Filippo, Céleste Lebbé, W. Lefevre, J. De Quatrebarbes, Sophie Dalac, B. Oriano, Clara Allayous, Marie Beylot-Barry, D. Legoupil, Philippe Saiag, J.-P. Arnnault, P.-E. Stoebner, Thierry Lesimple, Laurent Mortier, Alain Dupuy, F. Aubin, A. Stephan, F. Brunet-Possenti, J.-J. Grob, Centre Hospitalier Universitaire de Nice (CHU Nice), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CHU Grenoble, Université Grenoble Alpes (UGA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de dermatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, Service de dermatologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Service de Dermatologie et Allergologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Dermatologie [Rennes] = Dermatology [Rennes], CHU Pontchaillou [Rennes], Service de Dermatologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre d'épidémiologie Clinique [Hôtel-Dieu], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Hôtel Dieu, Université Nice Sophia Antipolis (... - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, body mass index, [SDV.CAN]Life Sciences [q-bio]/Cancer, Systemic therapy, Targeted therapy, systemic therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, melanoma, Humans, Prospective Studies, Adverse effect, Aged, Retrospective Studies, 2. Zero hunger, business.industry, Retrospective cohort study, Hematology, targeted therapy, Progression-Free Survival, clinical outcomes, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cohort, immunotherapy, Underweight, medicine.symptom, business, Body mass index, Obesity paradox, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Background: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy.Patients and methods: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out.Results: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI.Conclusion: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Published
2020
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3. Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover

Author

Céleste Lebbé, Armin Schueler, Richard Isaacs, Giorgio Massimini, Willem Kruit, Brigitte Dreno, Virginia Ferraresi, Caroline Robert, Luc Thomas, Enrique Espinosa, Carmen Loquai, Paul Vasey, Joseph Kerger, Bernard Guillot, Jean-Jacques Grob, Robert M. Conry, Caroline Dutriaux, Claus Garbe, Filippo de Braud, Thierry Lesimple, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Saint Louis (CIC-1427), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service de dermatologie Hôpital Saint-André Bordeaux, CHU Bordeaux [Bordeaux], Centre Eugène Marquis (CRLCC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), IRCCS Istituto Nazionale dei Tumori [Milano], Università degli Studi di Milano [Milano] (UNIMI), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), University Medical Center [Mainz], IFO - Istituto Nazionale Tumori Regina Elena [Roma] (IRE), Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University of Alabama at Birmingham [ Birmingham] (UAB), Palmerston North Hospital [Palmerston North], Hospital Universitario La Paz, Merck [Darmstadt], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Medical Oncology, Herrada, Anthony, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Milano = University of Milan (UNIMI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Cancer Research, Gastroenterology, pimasertib, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Clinical endpoint, 030212 general & internal medicine, Malignant melanoma, Hazard ratio, Progression-free survival, Sciences bio-médicales et agricoles, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Dacarbazine, Oncology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, medicine.symptom, Pimasertib, medicine.drug, Quality of life, medicine.medical_specialty, Nausea, malignant melanoma, dacarbazine, [SDV.CAN]Life Sciences [q-bio]/Cancer, N-(2 3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide, Neutropenia, N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide, lcsh:RC254-282, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Adverse effect, business.industry, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, adverse events, Cancérologie, quality of life, Adverse events, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, business, progression-free survival, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg, oral twice-daily) or DTIC (1000 mg/m2, intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS), secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively, hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42&ndash, 0.83, p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00&ndash, 4.98, p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively, HR 0.89, 95% CI 0.61&ndash, 1.30), 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade &ge, 3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068

Published
2020
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4. Increased thyroid uptake on 18F-FDG PET/CT is associated with the development of permanent hypothyroidism in stage IV melanoma patients treated with anti-PD-1 antibodies

Author

Anne Devillers, Florence Le Jeune, Lise Boussemart, Thierry Lesimple, Eva Jali, Pandora James, Alain Dupuy, Xavier Palard-Novello, Julien Edeline, Antoine Girard, Alexandra Frelau, Malbec, Odile, CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and CHU Pontchaillou [Rennes]

Subjects
Male, Cancer Research, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Thyroid Gland, Standardized uptake value, Kaplan-Meier Estimate, Metastatic melanoma, Gastroenterology, Anti-PD-1 antibodies, 03 medical and health sciences, Immune checkpoint inhibitors, 0302 clinical medicine, Hypothyroidism, Fluorodeoxyglucose F18, Immune-related adverse events, Positron Emission Tomography Computed Tomography, Internal medicine, medicine, Humans, Immunology and Allergy, Cutoff, Molecular Targeted Therapy, Melanoma, Aged, Neoplasm Staging, Thyroid, Thyroid uptake, Receiver operating characteristic, biology, medicine.diagnostic_test, business.industry, 18F-FDG PET/CT, Middle Aged, Prognosis, Thyroid disorder, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, ROC Curve, Oncology, Positron emission tomography, biology.protein, Female, Antibody, business, 030215 immunology
Abstract

International audience; Purpose To determine performances of 2-deoxy-2-(18F)fluoro-d-glucose (18F-FDG) positron emission tomography (PET) to detect the development of permanent thyroid dysfunction (PTD), and to evaluate the prognostic value of early increased thyroid uptake in stage IV melanoma patients treated with anti-programmed death 1 (anti-PD-1) antibodies. Methods Twenty-nine patients were retrospectively enrolled. PTD was defined as symptomatic thyroid disorder requiring long-term specific treatment. On the first PET performed during follow-up, maximal standardized uptake value of the thyroid (SUVmax-Th) and SUVmax-Th/SUVmax-blood-pool ratio (Th/B) were measured. Areas under ROC curves (AUC) of these parameters for the diagnostic of PTD were compared. Cutoff values were defined to maximize the Youden's index. Survival analyses were performed according to the Kaplan-Meier method and compared using the log-rank method between patients with and without enhanced thyroid uptake according to cutoff values defined with the Hothorn and Lausen method. Results Four patients presented PTD. Median SUVmax-Th and Th/B were, respectively, 2.11 and 1.00. The median followup period was 21.7 months. AUC were 1.0 (CI 95% 0.88-1.0) for both parameters. Optimal cutoff values were, respectively, SUVmax-Th > 4.1 and Th/B > 2.0, both conferring sensitivities of 100% (CI 95% 40-100%) and specificities of 100% (CI 95% 86-100%). The median progression-free survival and overall survival were 11.3 months and 33.5 months, respectively. Using optimized cutoffs, there was no statistically significant difference of survival. Conclusion SUVmax-Th > 4.1 and Th/B > 2.0 provided perfect diagnostic performances to detect patients that developed PTD. No significant survival difference was found between patients with and without increased thyroid uptake.

Published
2020
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5. Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Preexisting Autoimmune Disease: A Nationwide Multicenter Cohort Study

Author

François-Xavier Danlos, Club Rhumatismes et Inflammations, Catherine Dubos, Thierry Lesimple, Gilles Gonzales, Julie De Quatrebarbes, Laurent Misery, Florence Brunet-Possenti, Marie Kostine, Emmanuel Nowak, Mickaël Lambert, Elisa Funck-Brentano, Laurent Chiche, Stéphanie Martinez, Sandrine Mansard, Hélène Doubre, Marie Marcq, Camille Scalbert, Yohann Loriot, Olivier Lambotte, Sarah Maanaoui, Gwenaelle Le Garff, Marie Beylot-Barry, Christos Chouaid, Jean-Bernard Auliac, Anne Pham-Ledard, Emilie Routier, Damien Giacchero, Bertille Bonniaud, Hervé Vallerand, Gilles Quere, C. Stavris, Florian Guisier, François Aubin, Chantal Decroisette, Nathalie Beneton, Ouidad Zehou, Alice Tison, Caroline Robert, Christophe Roge, R. Veillon, Groupe de cancérologie cutanée, François Skowron, Catherine Michel, Divi Cornec, Ioana Carpiuc, Nora Kramkimel, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Ambroise Paré , Assistance Publique - Hôpitaux de Paris (AP - HP), Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Oncologie génito-urinaire, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Eugène Marquis (CRLCC), Hopital d'Aix en Provence, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CHI Créteil, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen [Fondation Ambroise Paré - Marseille], Centre Hospitalier Le Mans (CH Le Mans), CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Hôpital Foch [Suresnes], Centre Hospitalier de Valence (CH DE VALENCE), Centre hospitalier de Valence, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Henri Mondor, CH Morlaix, CHU Bordeaux [Bordeaux], Hôpital Cochin [AP-HP], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), CH, Mantes-La-Jolie, Centre hospitalier Les Chanaux [Mâcon], Hôpital de St Brieuc, Clinique des Cèdres, Service de Médecine Respiratoire [CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), CHD Vendee (La Roche Sur Yon), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Lymphocyte B et Auto-immunité (LBAI), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, autoimmune disease, Inflammatory bowel disease, Autoimmune Diseases, immune checkpoint inhibitors, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Rheumatology, Internal medicine, Psoriasis, Neoplasms, medicine, Immunology and Allergy, Humans, cancer, Progression-free survival, Survival rate, Aged, Retrospective Studies, Autoimmune disease, Aged, 80 and over, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Symptom Flare Up, Progression-Free Survival, 3. Good health, Discontinuation, Survival Rate, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Rheumatoid arthritis, immune-related adverse events, Female, immunotherapy, business, Immunosuppressive Agents
Abstract

Objective Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. Methods A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. Results The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. Conclusion Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

Published
2019
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6. Impact of radiotherapy administered simultaneously with systemic treatment in patients with melanoma brain metastases within MelBase, a French multicentric prospective cohort

Author

Stéphane Dalle, Raphaël Porcher, Thierry Lesimple, Marie-Thérèse Leccia, Jean-Philippe Lacour, Sophie Dalac, D. Legoupil, Pauline Tétu, Sameh Mohamed, A. Ballon, Florence Brunet-Possenti, Céleste Lebbé, Clara Allayous, Laurent Mortier, François Aubin, Julie De Quatrebarbes, Pierre-Emmanuel Stoebner, Caroline Dutriaux, Bastien Oriano, Brigitte Dréno, Bernard Guillot, Philippe Saiag, Marie Beylot-Barry, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Diagnostic et de Thérapeutique, Hôpital de l’Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Hôpital Ambroise Paré [AP-HP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre Eugène Marquis (CRLCC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and CCSD, Accord Elsevier

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, genetic structures, Propensity score, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Systemic therapy, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Humans, Prospective Studies, cardiovascular diseases, Stage (cooking), Prospective cohort study, Melanoma, Aged, Proportional Hazards Models, Radiotherapy, Brain Neoplasms, business.industry, MESH: Brain Neoplasms/radiotherapy, Melanoma/drug therapy, Melanoma/radiotherapy, Middle Aged, Brain metastases, medicine.disease, equipment and supplies, Advanced melanoma, Combined Modality Therapy, Confidence interval, 3. Good health, Radiation therapy, 030104 developmental biology, 030220 oncology & carcinogenesis, Propensity score matching, cardiovascular system, Female, Immunotherapy, business, circulatory and respiratory physiology
Abstract

International audience; Background: Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy.Patients and methods: Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias.Results: Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4-0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively.Conclusion: This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy.

Published
2019
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7. Interactions between glioma and pregnancy: insight from a 52-case multicenter series

Author

Guillaume Gauchotte, Mélanie Pagès, Fabrice Chrétien, Thierry Lesimple, M. Lopes, Stéphanie Cartalat-Carel, Philippe Menei, Catherine Miquel, Patrick Beauchesne, Philippe Colin, Luc Taillandier, Johan Pallud, Marc Zanello, Jean Stecken, Marc Debouverie, Denys Fontaine, Luc Bauchet, Didier Frappaz, Catherine Oppenheim, Emmanuel Jouanneau, Sophie Peeters, Pascale Varlet, Elisabeth Moyal, Jean-Sébastien Guillamo, Laurence Bozec, Christophe Deroulers, Olivier De Witte, Jean-Yves Delattre, Laurent Capelle, Hugues Duffau, Hospices Civils de Lyon (HCL), Service de Neurophysiologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Neurophysiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, medicine.medical_specialty, Malignancy, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Glioma, medicine, Humans, Retrospective Studies, [PHYS]Physics [physics], Brain Neoplasms, Vaginal delivery, Obstetrics, business.industry, Pregnancy Outcome, Retrospective cohort study, General Medicine, medicine.disease, Survival Analysis, 3. Good health, Surgery, Natural history, Tumor progression, 030220 oncology & carcinogenesis, Disease Progression, Gestation, Female, business, Pregnancy Complications, Neoplastic, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

OBJECTIVEThe goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk.METHODSIn this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma.RESULTSFor gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal.CONCLUSIONSWhen a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management.■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

Published
2018
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8. Sorafenib in metastatic uveal melanoma: efficacy, toxicity and health-related quality of life in a multicentre phase II study

Author

Thierry Lesimple, Natacha Heutte, Antoine Thyss, Florence Joly, C. Delcambre, E. M. Neidhart-Berard, Frédéric Mouriaux, L. Peyro Saint Paul, C. Dutriaux, A. D. Pham, Vincent Servois, Nicolas Penel, Jean-Jacques Parienti, S. Piperno-Neumann, Université de Rennes 1 - Faculté de Médecine (UR1 Médecine), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pontchaillou [Rennes], Hôpital du Saint-Sacrement [CHU Québec] (HSS), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Institut Curie [Paris], Centre Eugène Marquis (CRLCC), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Bordeaux [Bordeaux], Centre Léon Bérard [Lyon], Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Département de radiothérapie oncologique [Paris], [DGOS/PHRC09₀6-005], Université de Rennes - Faculté de Médecine (UR Médecine), Université de Rennes (UR), Université de Lille-UNICANCER, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CHU de Québec, Department of Radiology and Nuclear Medicine, CRLCC Eugène Marquis (CRLCC), Santé publique : épidémiologie et qualité des soins-EA 2694 (CERIM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, UNICANCER-Université Lille Nord de France (COMUE), Department of Medical Oncology, Institut Curie, Paris 75248, France, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Radiology, Centre Hospitalier Universitaire [Rennes], Centre d’études des transformations des activités physiques et sportives (CETAPS), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut de Recherche Interdisciplinaire Homme et Société (IRIHS), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), and Department of Medical Oncology

Subjects
Male, Uveal Neoplasms, 0301 basic medicine, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Phases of clinical research, 0302 clinical medicine, Quality of life, Medicine, renal-cell carcinoma, ComputingMilieux_MISCELLANEOUS, eye metastasis, cancer-treatment, Cervical cancer, b-raf, Sorafenib, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, targeted therapy, inhibition, 3. Good health, uveal, 030220 oncology & carcinogenesis, Toxicity, Female, Liver cancer, medicine.drug, Niacinamide, medicine.medical_specialty, proliferation, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, survival, Disease-Free Survival, 03 medical and health sciences, Internal medicine, melanoma, Humans, Adverse effect, Aged, clinical-trials, therapy, business.industry, Phenylurea Compounds, medicine.disease, Clinical trial, 030104 developmental biology, quality of life, Clinical Study, fatigue, progression, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Background: The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma. Methods: A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL. Results: Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%-47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%-79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue. Conclusions: Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

Published
2016
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9. Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study

Author

P.A. Ascierto, Jamila Louahed, Ralf Gutzmer, Dirk Schadendorf, Lev V. Demidov, Armando Santoro, N. Vanhoutte, Jochen Utikal, Carmen Loquai, P M De Sousa Alves, Paola Queirolo, Frederic Lehmann, Axel Hauschild, B. Dréno, V G Brichard, Marc Gillet, Erwin S. Schultz, B. Salaun, Jean-Jacques Grob, Licia Rivoltini, Thierry Lesimple, Silvija Jarnjak, Ruggero Ridolfi, Alberto Testori, Evgeny Levchenko, Skin Cancer Center Hannover, Hannover Medical School [Hannover] (MHH), Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Petrov Research Insitut of Oncology, Division of Melanoma and Muscolocutaneous sarcoma, European Institute of Oncology, Skin Cancer Unit of the German Cancer Research Center Heidelberg, University Mannheim, Istituto Nazionale per lo studio e la cura dei Tumori, Naples, Italy, Cancer Research Center, Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunoterapia e Terapia Cellulare Somatica, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Department of Dermatology, University Hospital Essen, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Johannes Gutenberg - Universität Mainz (JGU), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Schleswig-Holstein University Hospitals, Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Surgical oncology Centre Eugènes Marquis, Centre Eugènes Marquis, GSK Vaccines - Belgium, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Bernardo, Elizabeth, and Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS

Subjects
safety, Cancer Research, medicine.drug_class, medicine.medical_treatment, Medizin, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, immunogenicity, Immunostimulant, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer immunotherapy, medicine, 030304 developmental biology, Original Research, PRAME antigen, 0303 health sciences, PRAME, cancer immunotherapy, business.industry, Melanoma, Immunogenicity, Cancer, medicine.disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Immunology, Chills, medicine.symptom, business, metastatic melanoma
Abstract

Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results.

Published
2016
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10. Immunologic and Clinical Effects of Injecting Mature Peptide- Loaded Dendritic Cells by Intralymphatic and Intranodal Routes in Metastatic Melanoma Patients

Author

Louis Toujas, Irène Philip, André Carsin, Mohamed Chokri, Thierry Lesimple, Virginie Vignard, Gilles Clapisson, Delphine Monnier, Véronique Quillien, Henri Adamski, Nathalie Labarrière, Claudia Lefeuvre, Brigitte Collet, Brigitte Birebent, Eve-Marie Neidhard, Centre Eugène Marquis (CRLCC), Centre Léon Bérard [Lyon], Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), CHU Pontchaillou [Rennes], Etablissement français du sang [Rennes] (EFS Bretagne), IDM (Immuno-Designed Molecules), IDM S.A., and LABARRIERE, Nathalie

Subjects
Male, Cancer Research, Pathology, Skin Neoplasms, medicine.medical_treatment, Immunotherapy, Adoptive, 0302 clinical medicine, Melanoma, Aged, 80 and over, 0303 health sciences, Immunity, Cellular, biology, Middle Aged, 3. Good health, Neoplasm Proteins, Lymphatic system, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Lymphatic Metastasis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cancer Vaccines, Disease-Free Survival, 03 medical and health sciences, MART-1 Antigen, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Immunity, Antigens, Neoplasm, medicine, Humans, 030304 developmental biology, Aged, business.industry, Injections, Intralymphatic, Immunotherapy, Dendritic cell, Dendritic Cells, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Survival Analysis, Immunology, Antibody Formation, biology.protein, business, Peptides, CD8, Keyhole limpet hemocyanin
Abstract

Purpose: A phase I/II trial was conducted to evaluate clinical and immunologic responses after intralymphatic and intranodal injections of mature dendritic cells.Experimental Design: Fourteen patients with a metastatic melanoma received matured dendritic cells, loaded with Melan-A/MART-1 and/or NA17-A peptides and keyhole limpet hemocyanin. The cells were matured overnight with Ribomunyl, a toll-like receptor ligand, and IFN-γ, which ensured the production of high levels of interleukin-12p70. Dendritic cells were injected at monthly intervals, first into an afferent lymphatic and then twice intranodally. Immunologic responses were monitored by tetramer staining of circulating CD8+ lymphocytes and delayed-type hypersensitivity tests.Results: Dendritic cell vaccination induced delayed-type hypersensitivity reactivity toward NA17-A-pulsed, keyhole limpet hemocyanin–pulsed, and Melan-A-pulsed dendritic cells in 6 of 10, 4 of 11, and 3 of 9 patients, respectively. Four of the 12 patients analyzed by tetramer staining showed a significantly increased frequency of Melan-A-specific T cells, including one patient vaccinated only with NA17-A-pulsed dendritic cells. Furthermore, 2 of the 12 analyzed patients had a significant increase of NA17-A-specific T cells, including one immunized after an optional additional treatment course. No objective clinical response was observed. Two patients were stabilized at 4 and 10 months and three patients are still alive at 30, 39, and 48 months.Conclusions: Injections into the lymphatic system of mature peptide-loaded dendritic cells with potential TH1 polarization capacities did not result in marked clinical results, despite immunologic responses in some patients. This highlights the need to improve our understanding of dendritic cell physiology.

Published
2006
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11. Radiation-induced spinal cord glioma subsequent to treatment of Hodgkin's disease: case report and review.: Radiation-induced spinal cord glioma subsequent to treatment of Hodgkin's disease: case report and review

Author

Laurent Riffaud, Thierry Lesimple, Marc Bernard, Xavier Morandi, Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], CHU Pontchaillou [Rennes], Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Département d'oncologie médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Service de neurologie [Rennes], Université de Rennes (UR), Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)

Subjects
Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, MESH: Neoplasms, Radiation-Induced, Neoplasms, Radiation-Induced, medicine.medical_treatment, Central nervous system, Spinal Cord Glioma, MESH: Magnetic Resonance Imaging, Central nervous system disease, Meningioma, MESH: Glioma, MESH: Spinal Cord, 03 medical and health sciences, 0302 clinical medicine, Glioma, Humans, Medicine, Spinal Cord Neoplasms, neoplasms, MESH: Humans, business.industry, MESH: Adult, MESH: Spinal Cord Neoplasms, medicine.disease, Spinal cord, Hodgkin Disease, Magnetic Resonance Imaging, MESH: Hodgkin Disease, MESH: Male, nervous system diseases, 3. Good health, Radiation therapy, medicine.anatomical_structure, Spinal Cord, Neurology, Oncology, 030220 oncology & carcinogenesis, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Neurology (clinical), Sarcoma, Tomography, X-Ray Computed, business, MESH: Tomography, X-Ray Computed, 030217 neurology & neurosurgery
Abstract

article clinique; Radiation-induced neoplasms of the central nervous system generally present as meningioma or sarcoma. Spinal cord glioma after radiation therapy is rare and half of the cases documented occurred after treatment of Hodgkin's disease.A 39-year-old male presented with a 1-month history of gradually worsening neck ache and paraparesis. The patient had been treated for stage IB Hodgkin's disease 9 years previously with combined therapy: MOPP-ABV and a 40-Gray mediastinal radiotherapy from T1 to T10. Magnetic resonance imaging disclosed an intramedullary lesion from C6 to T2 and histopathological examination from biopsy demonstrated a malignant glioma. Despite chemotherapy and additional radiotherapy, the patient's neurological status worsened and he died 11 months after initial presentation.We suggest a strategy aimed solely at obtaining a tissue diagnosis to differentiate myelitis from tumor, and, in the event of tumor, confirming the strong likelihood of a high histopathological grade. The very limited survival associated with these tumors regardless of therapy advocates palliative therapies without attempting complete resection.

Published
2006
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