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Melanoma: HELP
Articles by Marc S. Ernstoff
Based on 49 articles published since 2009
(Why 49 articles?)
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Between 2009 and 2019, M. Ernstoff wrote the following 49 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Melanoma, Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Ernstoff, Marc / Fields, Ryan C / Fleming, Martin D / Gonzalez, Rene / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Sosman, Jeff / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. · ·J Natl Compr Canc Netw · Pubmed #27059193.

ABSTRACT: This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

2 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

3 Editorial Is pediatric melanoma always malignant? 2013

Coit, Daniel G / Ernstoff, Marc S / Busam, Klaus J. ·Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. ·Cancer · Pubmed #24022827.

ABSTRACT: -- No abstract --

4 Editorial Been there, not done that--melanoma in the age of molecular therapy. 2011

Ernstoff, Marc S. · ·N Engl J Med · Pubmed #21639809.

ABSTRACT: -- No abstract --

5 Review ESMO / ASCO Recommendations for a Global Curriculum in Medical Oncology Edition 2016. 2016

Dittrich, Christian / Kosty, Michael / Jezdic, Svetlana / Pyle, Doug / Berardi, Rossana / Bergh, Jonas / El-Saghir, Nagi / Lotz, Jean-Pierre / Österlund, Pia / Pavlidis, Nicholas / Purkalne, Gunta / Awada, Ahmad / Banerjee, Susana / Bhatia, Smita / Bogaerts, Jan / Buckner, Jan / Cardoso, Fatima / Casali, Paolo / Chu, Edward / Close, Julia Lee / Coiffier, Bertrand / Connolly, Roisin / Coupland, Sarah / De Petris, Luigi / De Santis, Maria / de Vries, Elisabeth G E / Dizon, Don S / Duff, Jennifer / Duska, Linda R / Eniu, Alexandru / Ernstoff, Marc / Felip, Enriqueta / Fey, Martin F / Gilbert, Jill / Girard, Nicolas / Glaudemans, Andor W J M / Gopalan, Priya K / Grothey, Axel / Hahn, Stephen M / Hanna, Diana / Herold, Christian / Herrstedt, Jørn / Homicsko, Krisztian / Jones, Dennie V / Jost, Lorenz / Keilholz, Ulrich / Khan, Saad / Kiss, Alexander / Köhne, Claus-Henning / Kunstfeld, Rainer / Lenz, Heinz-Josef / Lichtman, Stuart / Licitra, Lisa / Lion, Thomas / Litière, Saskia / Liu, Lifang / Loehrer, Patrick J / Markham, Merry Jennifer / Markman, Ben / Mayerhoefer, Marius / Meran, Johannes G / Michielin, Olivier / Moser, Elizabeth Charlotte / Mountzios, Giannis / Moynihan, Timothy / Nielsen, Torsten / Ohe, Yuichiro / Öberg, Kjell / Palumbo, Antonio / Peccatori, Fedro Alessandro / Pfeilstöcker, Michael / Raut, Chandrajit / Remick, Scot C / Robson, Mark / Rutkowski, Piotr / Salgado, Roberto / Schapira, Lidia / Schernhammer, Eva / Schlumberger, Martin / Schmoll, Hans-Joachim / Schnipper, Lowell / Sessa, Cristiana / Shapiro, Charles L / Steele, Julie / Sternberg, Cora N / Stiefel, Friedrich / Strasser, Florian / Stupp, Roger / Sullivan, Richard / Tabernero, Josep / Travado, Luzia / Verheij, Marcel / Voest, Emile / Vokes, Everett / Von Roenn, Jamie / Weber, Jeffrey S / Wildiers, Hans / Yarden, Yosef. ·3rd Medical Department , Centre for Oncology and Haematology, Kaiser Franz Josef-Spital , Vienna , Austria. · Division of Hematology/Oncology , Scripps Green Cancer Center, Scripps Clinic , La Jolla, California , USA. · European Society for Medical Oncology (ESMO) , Lugano , Switzerland. · American Society of Clinical Oncology (ASCO) , Alexandria, Virginia , USA. · Department of Medical Oncology , Università Politecnica delle Marche, Ospedali Riuniti Ancona , Ancona , Italy. · The Strategic Research Programme in Cancer, Karolinska Institutet and University Hospital , Stockholm , Sweden. · Department of Internal Medicine , NK Basile Cancer Institute, American University of Beirut Medical Center , Beirut , Lebanon. · Department of Medical Oncology and Cellular Therapy, Medical Oncology Department , Tenon Assistance Publique-Hôpitaux de Paris , Paris , France. · Department of Oncology , HUCH Helsinki University Central Hospital and University of Helsinki , Helsinki, Finland. · Department of Medical Oncology , University of Ioannina , Ioannina , Greece. · Clinic of Oncology , Pauls Stradins Clinical University Hospital , Riga , Latvia. · Medical Oncology Clinic , Jules Bordet Institute, Université Libre de Bruxelles , Brussels , Belgium. · The Royal Marsden NHS Foundation Trust , London , UK. · Division of Pediatric Hematology/Oncology, Department of Pediatrics , Institute of Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, UAB Comprehensive Cancer Center , Birmingham, Alabama , USA. · The European Organisation for Research and Treatment of Cancer (EORTC) , Brussels , Belgium. · Department of Oncology , Cancer Practice-Mayo Clinic Cancer Center , Rochester, Minnesota , USA. · Breast Unit , Champalimaud Clinical Center , Lisbon , Portugal. · Medical Oncology Unit 2 (Adult Mesenchymal Tumours and Rare Cancers) , Fondazione IRCCS Istituto Nazionale Tumori , Milan , Italy. · University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania , USA. · UF Department of Medicine Division of Hematology/Oncology, UF Hematology/Oncology Fellowship Program, Gainesville, Florida, USA; Medical Service, Malcom Randall VA Medical Center, Gainesville, Florida, USA. · Department of Hematology , University Claude Bernard Lyon 1, Centre Hospitalier Lyon-Sud , Lyon , France. · Breast and Ovarian Cancer Program , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore, Maryland , USA. · Pathology, Molecular and Clinical Cancer Medicine , University of Liverpool , Liverpool , UK. · Department of Oncology , Radiumhemmet, Karolinska Institutet and University Hospital , Stockholm , Sweden. · University of Warwick, Cancer Research Centre , Coventry , UK. · Department of Medical Oncology , University Medical Center Groningen, University of Groningen , Groningen , The Netherlands. · The Oncology Sexual Health Clinic, Harvard Medical School, Department of Medicine , Massachusetts General Hospital , Boston, Massachusetts , USA. · Department of Medicine , University of Florida , Gainesville, Florida , USA. · Division of Gynecologic Oncology , University of Virginia School of Medicine , Charlottesville, Virginia , USA. · Department of Breast Tumors , Cancer Institute "Ion Chiricuta" , Cluj-Napoca , Romania. · Department of Medicine , Roswell Park Cancer Institute , Buffalo, New York , USA. · Medical Oncology Department , Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona , Spain. · Inselspital and University Hospital of Bern , Bern , Switzerland. · Vanderbilt University School of Medicine , Nashville, Tennessee , USA. · Department of Respiratory Medicine, Thoracic Oncology , Institute of Oncology, Hospices Civils de Lyon , Lyon , France. · Department of Nuclear Medicine & Molecular Imaging , University of Groningen, University Medical Center Groningen , Groningen , The Netherlands. · Department of Medicine , University of Florida and Section of Medicine, Malcom Randall VA Medical Center , Gainesville, Florida , USA. · Mayo Clinic Rochester , Rochester, Minnesota , USA. · Division of Radiation Oncology , The University of Texas MD Anderson Cancer Center , Houston, Texas , USA. · Division of Medical Oncology , University of Southern California, Hoag Family Cancer Institute , Newport Beach, California , USA. · Department of Biomedical Imaging and Image-guided Therapy , Medical University Vienna, Vienna General Hospital , Vienna , Austria. · Department of Oncology , Odense University Hospital, University of Southern Denmark , Odense , Denmark. · Department of Oncology , University Hospital of Lausanne , Lausanne , Switzerland. · Department of Medicine, Division of Hematology/Oncology/Stem Cell Transplant, University of Florida, Gainesville, Florida, USA; Section of Hematology and Oncology, Malcom Randall VA Medical Center, Gainesville, Florida, USA. · Cantonal Hospital Baselland , Bruderholz , Switzerland. · Charité Comprehensive Cancer Center , Berlin , Germany. · Hematology and Oncology, Internal Medicine , UT Southwestern Medical Center , Dallas, Texas , USA. · Department of Psychosomatic Division , University Hospital Basel , Basel , Switzerland. · University Clinic for Internal Medicine-Oncology and Hematology, Klinikum Oldenburg , Oldenburg , Germany. · Clinic of Dermatology/Vienna General Hospital, Medical University Vienna , Vienna , Austria. · Department of Medical Oncology , Norris Comprehensive Cancer Center, University of Southern California , Los Angeles, California , USA. · Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College , New York, New York , USA. · Istituto Nazionale Tumori , Milan , Italy. · Division for Molecular Microbiology, Children'sCancer Research Institute (CCRI), Vienna, Austria; LabDia Laboratoriumsdiagnostik GmbH, Vienna, Austria. · Department of Statistics , The European Organisation for Research and Treatment of Cancer (EORTC) , Brussels , Belgium. · Indiana University Melvin and Bren Simon Cancer Center, Indiana University School of Medicine , Indianapolis, Indiana , USA. · Division of Hematology & Oncology , University of Florida College of Medicine , Gainesville, Florida , USA. · Monash Cancer Centre, Monash Health , Melbourne , Australia. · Department of Biomedical Imaging and Image-guided Therapy , Medical University of Vienna, Vienna General Hospital , Vienna , Austria. · Internal Department, Krankenhaus Barmherzige Brüder , Vienna , Austria. · Department of Oncology , CHUV , Lausanne , Switzerland. · Champalimaud Foundation , Lisbon , Portugal. · University of Athens School of Medicine , Athens , Greece. · Department of Medical Oncology , Mayo Clinic , Rochester, Minnesota , USA. · University of British Columbia , Vancouver, British Columbia , Canada. · Department of Thoracic Oncology , National Cancer Center Hospital , Tokyo , Japan. · Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden; Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. · University of Torino , Torino , Italy. · Fertility & Procreation Unit, Gynecologic Oncology Department , European Institute of Oncology , Milan , Italy. · Hanusch Hospital , Vienna , Austria. · Division of Surgical Oncology, Department of Surgery , Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital , Boston, Massachusetts , USA. · Department of Medicine , Maine Medical Center Cancer Institute , Scarborough, Maine , USA. · Clinical Genetics Service, Department of Medicine , Memorial Sloan Kettering Cancer Center , New York, New York , USA. · Department of Soft Tissue/Bone Sarcoma and Melanoma , Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw , Poland. · Breast Cancer Translational Research Laboratory, Jules Bordet Institute, Brussels, Belgium; Department of Pathology, TCRU, GZA Antwerp, Antwerp, Belgium. · Harvard Medical School , Massachusetts General Hospital , Boston, Massachusetts , USA. · Department of Epidemiology , Center for Public Health, Medical University of Vienna , Vienna , Austria. · Department of Nuclear Medicine and Endocrine Oncology , Institut Gustave Roussy, Université Paris-Sud , Villejuif , France. · Division Clinical Oncology Research , University Clinic Halle (Saale), Martin-Luther-University, Halle-Wittenberg , Halle , Germany. · Department of Medicine , Beth Israel Deaconess Medical Center , Boston, Massachusetts , USA. · Oncology Institute of Southern Switzerland , Bellinzona , Switzerland. · Dubin Breast Center, Division of Hematology/Medical Oncology , Tisch Cancer Center, Mount Sinai Health System , New York, New York , USA. · Anatomic Pathology, Scripps Clinic Department of Pathology , Scripps Green Hospital , La Jolla, California , USA. · Department of Medical Oncology , San Camillo Forlanini Hospital , Rome , Italy. · Psychiatric Liaison Service, Department of Psychiatry , University Hospital of Lausanne-CHUV , Lausanne , Switzerland. · Oncological Palliative Medicine, Clinic Oncology/Hematology, Department Internal Medicine & Palliative Centre , Cantonal Hospital St.Gallen , St. Gallen , Switzerland. · University Hospital Zürich , Zürich , Switzerland. · Institute of Cancer Policy, Conflict & Health Research Program, London , UK. · Psycho-Oncology Service, Clinical Centre of the Champalimaud Centre for the Unknown, Champalimaud Foundation , Lisbon , Portugal. · Department of Radiation Oncology , The Netherlands Cancer Institute , Amsterdam , The Netherlands. · The Netherlands Cancer Institute , Amsterdam , The Netherlands. · Department of Medicine , University of Chicago Medical Center , Chicago, Illinois , USA. · Education, Science, and Professional Development, American Society of Clinical Oncology (ASCO) , Alexandria, Virginia , USA. · Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center , New York, New York , USA. · Department of General Medical Oncology , University Hospitals Leuven , Leuven , Belgium. ·ESMO Open · Pubmed #27843641.

ABSTRACT: The European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) are publishing a new edition of the ESMO/ASCO Global Curriculum (GC) thanks to contribution of 64 ESMO-appointed and 32 ASCO-appointed authors. First published in 2004 and updated in 2010, the GC edition 2016 answers to the need for updated recommendations for the training of physicians in medical oncology by defining the standard to be fulfilled to qualify as medical oncologists. At times of internationalisation of healthcare and increased mobility of patients and physicians, the GC aims to provide state-of-the-art cancer care to all patients wherever they live. Recent progress in the field of cancer research has indeed resulted in diagnostic and therapeutic innovations such as targeted therapies as a standard therapeutic approach or personalised cancer medicine apart from the revival of immunotherapy, requiring specialised training for medical oncology trainees. Thus, several new chapters on technical contents such as molecular pathology, translational research or molecular imaging and on conceptual attitudes towards human principles like genetic counselling or survivorship have been integrated in the GC. The GC edition 2016 consists of 12 sections with 17 subsections, 44 chapters and 35 subchapters, respectively. Besides renewal in its contents, the GC underwent a principal formal change taking into consideration modern didactic principles. It is presented in a template-based format that subcategorises the detailed outcome requirements into learning objectives, awareness, knowledge and skills. Consecutive steps will be those of harmonising and implementing teaching and assessment strategies.

6 Review Primary melanoma of the spinal cord: a case report, molecular footprint, and review of the literature. 2011

Fuld, Alexander D / Speck, Maren E / Harris, Brent T / Simmons, Nathan E / Corless, Christopher L / Tsongalis, Gregory J / Pastel, David A / Hartford, Alan C / Ernstoff, Marc S. ·Dartmouth Hitchcock Medical Center and Dartmouth Medical School, Lebanon, NH, USA. ·J Clin Oncol · Pubmed #21444862.

ABSTRACT: -- No abstract --

7 Clinical Trial NCI 8628: A randomized phase 2 study of ziv-aflibercept and high-dose interleukin 2 or high-dose interleukin 2 alone for inoperable stage III or IV melanoma. 2018

Tarhini, Ahmad A / Frankel, Paul / Ruel, Christopher / Ernstoff, Marc S / Kuzel, Timothy M / Logan, Theodore F / Khushalani, Nikhil I / Tawbi, Hussein A / Margolin, Kim A / Awasthi, Sanjay / Butterfield, Lisa H / McDermott, David / Chen, Alice / Lara, Primo N / Kirkwood, John M. ·University of Pittsburgh Medical Center Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania. · Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center, Cleveland, Ohio. · City of Hope National Medical Center, Duarte, California. · Roswell Park Comprehensive Cancer Center, Buffalo, New York. · Rush University Medical Center, Chicago, Illinois. · Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana. · Moffitt Cancer Center, Tampa, Florida. · The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. · Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. · Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland. · University of California at Davis Comprehensive Cancer Center, Sacramento, California. ·Cancer · Pubmed #30303516.

ABSTRACT: BACKGROUND: Interleukin 2 (IL-2) is a growth factor for T and natural killer cells, promotes proinflammatory cytokines, and can lead to durable responses in patients with melanoma. Vascular endothelial growth factor (VEGF) promotes angiogenesis and modulates host innate and adaptive immunity. High VEGF levels were found to be associated with nonresponse to IL-2. Ziv-aflibercept may deplete VEGF and thereby enhance antitumor T-cell responses, thus supporting a combination immunotherapeutic strategy with IL-2. METHODS: NCI 8628 was a phase 2 trial of ziv-aflibercept and IL-2 (arm A) versus IL-2 alone (arm B) randomized at 2:1, respectively. Eligible patients had inoperable American Joint Committee on Cancer stage III or stage IV melanoma. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 89 patients were enrolled and 84 patients were treated. The median follow-up was 41.4 months. Among treated patients (55 patients in arm A and 29 patients in arm B), PFS was significantly improved in favor of arm A, with a median of 6.9 months (95% confidence interval [95% CI], 4.1-8.7 months) versus 2.3 months (95% CI, 1.6-3.5 months) (P<.001). No significant difference was noted with regard to overall survival, with a median of 26.9 months (95% CI, 14.4-63.6 months) for arm A and 24.2 months (95% CI, 11.3-36.4 months) for arm B. The response rate (according to Response Evaluation Criteria In Solid Tumors [RECIST]) was 22% in arm A (4 complete responses [CRs] and 8 partial responses [PRs]) and 17% in arm B (1 CR and 4 PRs). Stable disease or PR or CR was noted in 65% of patients in arm A and 48% of patients in arm B. The combination was found to be superior to monotherapy in patients with high and low levels of serum VEGF and VEGF receptor 2. Adverse events were consistent with the expected profiles of monotherapy with IL-2 and ziv-aflibercept. CONCLUSIONS: Ziv-aflibercept and IL-2 were found to significantly improve PFS compared with IL-2 alone, thereby meeting the primary endpoint of the current study. These findings support further study of immunotherapeutic combination strategies involving VEGF inhibitors.

8 Clinical Trial Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. 2018

Tawbi, Hussein A / Forsyth, Peter A / Algazi, Alain / Hamid, Omid / Hodi, F Stephen / Moschos, Stergios J / Khushalani, Nikhil I / Lewis, Karl / Lao, Christopher D / Postow, Michael A / Atkins, Michael B / Ernstoff, Marc S / Reardon, David A / Puzanov, Igor / Kudchadkar, Ragini R / Thomas, Reena P / Tarhini, Ahmad / Pavlick, Anna C / Jiang, Joel / Avila, Alexandre / Demelo, Sheena / Margolin, Kim. ·From the University of Texas M.D. Anderson Cancer Center, Houston (H.A.T.) · Moffitt Cancer Center and Research Institute, Tampa, FL (P.A.F., N.I.K.) · University of California-San Francisco, San Francisco (A. Algazi), the Angeles Clinic and Research Institute, Los Angeles (O.H.), Stanford University Hospital, Palo Alto (R.P.T.), and the Department of Medical Oncology, City of Hope, Duarte (K.M.) - all in California · Dana-Farber Cancer Institute, Boston (F.S.H., D.A.R.) · University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill (S.J.M.) · University of Colorado Comprehensive Cancer Center, Aurora (K.L.) · University of Michigan, Ann Arbor (C.D.L.) · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (M.A.P.), Roswell Park Cancer Institute, Buffalo (M.S.E., I.P.), and New York University, Lake Success (A.C.P.) - all in New York · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · Winship Cancer Institute of Emory University, Atlanta (R.R.K.) · University of Pittsburgh Medical Center, Pittsburgh (A.T.) · Bristol-Myers Squibb, Princeton, NJ (J.J., A. Avila, S.D.) · and Cleveland Clinic-Taussig Cancer Institute, Cleveland (A.T.). ·N Engl J Med · Pubmed #30134131.

ABSTRACT: BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases. METHODS: In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response. RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases. CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058 .).

9 Clinical Trial A multi-center phase II study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma. 2018

Clark, Joseph I / Singh, Jatinder / Ernstoff, Marc S / Lao, Christopher D / Flaherty, Lawrence E / Logan, Theodore F / Curti, Brendan / Agarwala, Sanjiv S / Taback, Bret / Cranmer, Lee / Lutzky, Jose / Luna, Theresa L / Aung, Sandra / Lawson, David H. ·Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL, 60153, USA. jclark@lumc.edu. · Primary Biostatistical Solutions, Victoria, BC, Canada. · Roswell Park Cancer Institute, Buffalo, NY, USA. · University of Michigan, Ann Arbor, MI, USA. · The Karmanos Cancer Institute, Detroit, MI, USA. · Indiana University, Indianapolis, IN, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. · St. Luke's Hospital and Health Network, Bethlehem, PA, USA. · Columbia University/Herbert Irving Comprehensive Cancer Center, New York, NY, USA. · Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA. · Mt. Sinai Comprehensive Cancer Center, Miami Beach, FL, USA. · Prometheus Laboratories Inc, San Diego, CA, USA. · Nektar Inc, San Diego, CA, USA. · Emory Winship Cancer Institute at Emory University, Atlanta, GA, USA. ·J Immunother Cancer · Pubmed #30053905.

ABSTRACT: BACKGROUND: Preclinical studies suggest that BRAF inhibitors enhance anti-tumor immunity and antigen presentation. Combination BRAF inhibition with immunotherapy is an appealing therapeutic approach. We sequenced vemurafenib with HD IL-2 in patients with BRAF-mutated metastatic melanoma to improve long term outcomes. METHODS: Eligible patients were HD IL-2 eligible with metastatic BRAF V600 mutated melanoma. Cohort 1 was treatment naïve and received vemurafenib 960 mg BID for 6 weeks before HD IL-2. Cohort 2 received vemurafenib for 7-18 weeks before enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 h days 1-5 and days 15-19. The primary objective was to assess complete responses (CR) at 10 weeks ±3 (assessment 1) and 26 weeks ±3 (assessment 2) from the start of HD IL-2. RESULTS: Fifty-three patients were enrolled, (cohort 1, n = 38; cohort 2, n = 15). Of these, 39 underwent assessment 1 and 15 assessment 2. The CR rate at assessment 1 was 10% (95% CI 3-24) for both cohorts combined, and 27% (95% CI 8-55) at assessment 2. Three-year survival was 30 and 27% for cohort 1 and cohort 2, respectively. No unexpected toxicities occurred. A shift in the melanoma treatment landscape during this trial adversely affected accrual, leading to early trial closure. CONCLUSIONS: Vemurafenib in sequence with HD IL-2 did not change the known toxicity profile for either agent. Lower than expected response rates to vemurafenib were observed. Overall response rates and durability of responses appear similar to that observed with HD IL-2 alone. TRIAL REGISTRATION: NCTN, NCT01683188. Registered 11 September 2012, http://www.clinicaltrials.gov/NCT01683188.

10 Clinical Trial Phase I Trial of ALT-803, A Novel Recombinant IL15 Complex, in Patients with Advanced Solid Tumors. 2018

Margolin, Kim / Morishima, Chihiro / Velcheti, Vamsidhar / Miller, Jeffrey S / Lee, Sylvia M / Silk, Ann W / Holtan, Shernan G / Lacroix, Andreanne M / Fling, Steven P / Kaiser, Judith C / Egan, Jack O / Jones, Monica / Rhode, Peter R / Rock, Amy D / Cheever, Martin A / Wong, Hing C / Ernstoff, Marc S. ·City of Hope National Medical Center, Duarte, California. kmargolin@coh.org. · University of Washington, Seattle, Washington. · Cancer Immunotherapy Trials Network, Fred Hutchinson Cancer Research Center, Seattle, Washington. · Cleveland Clinic, Cleveland, Ohio. · University of Minnesota, Minneapolis, Minnesota. · Seattle Cancer Care Alliance, Seattle, Washington. · Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey. · Altor BioScience, a Nantworks Company, Miramar, Florida. · Roswell Park Cancer Center, Buffalo, New York. ·Clin Cancer Res · Pubmed #30045932.

ABSTRACT:

11 Clinical Trial Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. 2016

Hodi, F Stephen / Chesney, Jason / Pavlick, Anna C / Robert, Caroline / Grossmann, Kenneth F / McDermott, David F / Linette, Gerald P / Meyer, Nicolas / Giguere, Jeffrey K / Agarwala, Sanjiv S / Shaheen, Montaser / Ernstoff, Marc S / Minor, David R / Salama, April K / Taylor, Matthew H / Ott, Patrick A / Horak, Christine / Gagnier, Paul / Jiang, Joel / Wolchok, Jedd D / Postow, Michael A. ·Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu. · University of Louisville, Louisville, KY, USA. · New York University, New York, NY, USA. · Gustave Roussy, INSERM U981, Paris, France. · Huntsman Cancer Institute, Salt Lake City, UT, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Washington University School of Medicine, St Louis, MO, USA. · Institut Universitaire du Cancer, Toulouse, France. · Greenville Health System Cancer Institute, Greenville, SC, USA. · St Luke's Cancer Center and Temple University, Bethlehem, PA, USA. · University of New Mexico, Albuquerque, NM, USA. · Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA. · California Pacific Center for Melanoma Research, San Francisco, CA, USA. · Duke University Medical Center, Durham, NC, USA. · Oregon Health & Science University, Portland, OR, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Bristol-Myers Squibb, Princeton, NJ, USA. · Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA. ·Lancet Oncol · Pubmed #27622997.

ABSTRACT: BACKGROUND: Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. METHODS: In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF FINDINGS: Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. INTERPRETATION: Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. FUNDING: Bristol-Myers Squibb.

12 Clinical Trial Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697). 2015

Lawson, David H / Lee, Sandra / Zhao, Fengmin / Tarhini, Ahmad A / Margolin, Kim A / Ernstoff, Marc S / Atkins, Michael B / Cohen, Gary I / Whiteside, Theresa L / Butterfield, Lisa H / Kirkwood, John M. ·David H. Lawson, Winship Cancer Institute of Emory University, Atlanta, GA · Sandra Lee and Fengmin Zhao, Dana-Farber Cancer Institute · Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA · Ahmad A. Tarhini, Theresa L. Whiteside, Lisa H. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, PA · Kim A. Margolin, Seattle Cancer Care Alliance, Seattle, WA · Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH · and Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD. ·J Clin Oncol · Pubmed #26351350.

ABSTRACT: PURPOSE: We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma. PATIENTS AND METHODS: Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2-positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2-negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population. RESULTS: A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. When survival in HLA-A2-positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups. CONCLUSION: Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.

13 Clinical Trial A phase I, dose-escalation study of cyclical weekly oral temozolomide and weekly PEG-interferon alpha-2b in patients with refractory or advanced solid tumours. 2013

Coker, Shodeinde A / Dandamudi, Uday B / Beelen, Andrew P / Crosby, Nancy A / Fisher, Jan L / Obrocea, Michael / Ernstoff, Marc S / Lewis, Lionel D. · ·J Chemother · Pubmed #24093213.

ABSTRACT: BACKGROUND: Temozolomide (TMZ) is an oral alkylating agent used in the treatment of central nervous system neoplasms and metastatic melanoma. Preclinical and clinical data suggested that combining TMZ with interferon alpha-2b (IFN-alpha-2b) may result in increased anti-tumour efficacy. METHODS: This was a phase I, dose-escalation study to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of cyclical oral TMZ (days 1-7 and 15-21) in combination with pegylated IFN-alpha-2b (PEG-IFN-alpha-2b) in patients with advanced solid tumours. RESULTS: We treated 19 patients (10 female and nine male), median age 58 years (range: 41-79 years). Ten patients tolerated TMZ at 100 mg/m² on days 1-7 and 15-21 plus PEG-IFN-alpha-2b at 1.5 mcg/kg/week on 28-day cycles which was the MTD of the combination. The pharmacokinetic parameters of PEG-IFN-alpha-2b were not altered by TMZ, at the MTD. CONCLUSION: The MTD of cyclical oral TMZ was 100 mg/m² on days 1-7 and 15-21 when combined with weekly subcutaneous PEG-IFNα-2b at 1.5 mcg/kg/week on 28 days cycles. The PK of PEG-IFN-alpha-2b appeared consistent with those when it is used as monotherapy.

14 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute · Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital · Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA · Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR · Philip Friedlander, Mount Sinai Medical Center, New York, NY · Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO · Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Thomas F. Gajewski, University of Chicago, Chicago, IL · Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA · Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX · Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: PURPOSE: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. RESULTS: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

15 Clinical Trial Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma. 2013

Poklepovic, Andrew / Youssefian, Leena E / Winning, Mary / Birdsell, Christine A / Crosby, Nancy A / Ramakrishnan, Viswanathan / Ernstoff, Marc S / Roberts, John D. ·Massey Cancer Center and the Division of Hematology, Oncology & Palliative Care, Virginia Commonwealth University, Richmond, VA 23298-0037, USA. ·Invest New Drugs · Pubmed #23315028.

ABSTRACT: PURPOSE: Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. EXPERIMENTAL DESIGN: Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. RESULTS: Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. CONCLUSIONS: Bortezomib 1.6 mg/m(2) and dacarbazine 580 mg/m(2) administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

16 Clinical Trial Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. 2012

Margolin, Kim / Ernstoff, Marc S / Hamid, Omid / Lawrence, Donald / McDermott, David / Puzanov, Igor / Wolchok, Jedd D / Clark, Joseph I / Sznol, Mario / Logan, Theodore F / Richards, Jon / Michener, Tracy / Balogh, Agnes / Heller, Kevin N / Hodi, F Stephen. ·University of Washington, Seattle, WA 98109, USA. kmargoli@seattlecca.org ·Lancet Oncol · Pubmed #22456429.

ABSTRACT: BACKGROUND: Brain metastases commonly develop in patients with melanoma and are a frequent cause of death of patients with this disease. Ipilimumab improves survival in patients with advanced melanoma. We aimed to investigate the safety and activity of this drug specifically in patients with brain metastases. METHODS: Between July 31, 2008, and June 3, 2009, we enrolled patients with melanoma and brain metastases from ten US centres who were older than 16 years into two parallel cohorts. Patients in cohort A were neurologically asymptomatic and were not receiving corticosteroid treatment at study entry; those in cohort B were symptomatic and on a stable dose of corticosteroids. Patients were to receive four doses of 10 mg/kg intravenous ipilimumab, one every 3 weeks. Individuals who were clinically stable at week 24 were eligible to receive 10 mg/kg intravenous ipilimumab every 12 weeks. The primary endpoint was the proportion of patients with disease control, defined as complete response, partial response, or stable disease after 12 weeks, assessed with modified WHO criteria. Analyses of safety and efficacy included all treated patients. This trial is registered with ClinicalTrials.gov, number NCT00623766. FINDINGS: We enrolled 72 patients: 51 into cohort A and 21 into cohort B. After 12 weeks, nine patients in cohort A exhibited disease control (18%, 95% CI 8-31), as did one patient in cohort B (5%, 0·1-24). When the brain alone was assessed, 12 patients in cohort A (24%, 13-38) and two in cohort B (10%, 1-30) achieved disease control. We noted disease control outside of the brain in 14 patients (27%, 16-42) in cohort A and in one individual (5%, 0·1-24) in cohort B. The most common grade 3 adverse events in cohort A were diarrhoea (six patients [12%]) and fatigue (six [12%]); in cohort B, they were dehydration (two individuals [10%]), hyperglycaemia (two [10%]), and increased concentrations of serum aspartate aminotransferase (two [10%]). One patient in each cohort had grade 4 confusion. The most common grade 3 immune-related adverse events were diarrhoea (six patients [12%]) and rash (one [2%]) in cohort A, and rash (one individual [5%]) and increased concentrations of serum aspartate aminotransferase (two [10%]) in cohort B. One patient in cohort A died of drug-related complications of immune-related colitis. INTERPRETATION: Ipilimumab has activity in some patients with advanced melanoma and brain metastases, particularly when metastases are small and asymptomatic. The drug has no unexpected toxic effects in this population. FUNDING: Bristol-Myers Squibb.

17 Clinical Trial A phase 1 study of a vaccine targeting preferentially expressed antigen in melanoma and prostate-specific membrane antigen in patients with advanced solid tumors. 2011

Weber, Jeffrey S / Vogelzang, Nicholas J / Ernstoff, Marc S / Goodman, Oscar B / Cranmer, Lee D / Marshall, John L / Miles, Sabrina / Rosario, Dar / Diamond, David C / Qiu, Zhiyong / Obrocea, Mihail / Bot, Adrian. ·Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL 33612. jeffrey.weber@moffitt.org ·J Immunother · Pubmed #21760528.

ABSTRACT: Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications.

18 Clinical Trial Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. 2011

Bedikian, A Y / DeConti, R C / Conry, R / Agarwala, S / Papadopoulos, N / Kim, K B / Ernstoff, M. ·Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. abedikia@mdanderson.org ·Ann Oncol · Pubmed #20855467.

ABSTRACT: BACKGROUND: Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin(®)) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS: In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA-paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS: No significant difference in OS was noted between patients in the DHA-paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA-paclitaxel. CONCLUSIONS: DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted.

19 Clinical Trial Clinical electron paramagnetic resonance (EPR) oximetry using India ink. 2010

Williams, Benjamin B / Khan, Nadeem / Zaki, Bassem / Hartford, Alan / Ernstoff, Marc S / Swartz, Harold M. ·EPR Center for Viable Systems, Department of Radiology, Dartmouth Medical School, 703 Vail, Hanover, NH 03755, USA. ben.williams@dartmouth.edu ·Adv Exp Med Biol · Pubmed #20204785.

ABSTRACT: Electron paramagnetic resonance (EPR) oximetry can be used to provide direct absolute measurements of pO(2) in living tissue using India ink as an O(2) reporter. In vivo measurements are made using low frequency (1.2 GHz) EPR spectroscopy and surface loop resonators, which enable measurements to be made at superficial sites through a non-invasive (after placing the ink in the tissues) and repeatable measurement procedure. Ongoing EPR oximetry studies in human subjects include measurement of subcutaneous pO(2) in the feet of healthy volunteers to develop procedures that could be used in the treatment of peripheral vascular disease and oximetry in tumors during courses of radiation and chemotherapy, to follow pO(2) so oxygen-dependent therapies can be optimized. In each case, we aim to provide quantitative measurements of tissue pO(2) which will aid physicians in the characterization of disease status and the effects of therapeutic measures, so that treatments can be applied with optimal effectiveness by taking into account the oxygen-dependent aspects of the therapy. The overall goal is to enhance clinical outcomes. Oximetry measurements of subcutaneous tissue on dorsal and plantar foot surfaces have been made in 9 volunteers, with measurements ongoing for each and the longest set of measurements carried out successfully over the last 5 years. Tumor oximetry measurements have been performed in tumor tissues of 10 patients during courses of radiation and chemotherapy. Tumor types include melanoma, basal cell, soft tissue sarcoma, and lymphoma, and measurement sites have ranged from the feet to the scalp. These studies demonstrate the feasibility of EPR oximetry in a clinical setting and the potential for more widespread use in the treatment of these and other oxygen-dependent diseases.

20 Clinical Trial Cytokine working group study of lymphodepleting chemotherapy, interleukin-2, and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma: clinical outcomes and peripheral-blood cell recovery. 2010

Gunturu, Krishna S / Meehan, Kenneth R / Mackenzie, Todd A / Crocenzi, Todd S / McDermott, David / Usherwood, Edward J / Margolin, Kim A / Crosby, Nancy A / Atkins, Michael B / Turk, Mary Jo / Ahonen, Cory / Fuse, Shinichiro / Clark, Joseph I / Fisher, Jan L / Noelle, Randolph J / Ernstoff, Marc S. ·Section of Hematology/Oncology, Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756, USA. ·J Clin Oncol · Pubmed #20124177.

ABSTRACT: PURPOSE: Recovery of lymphocyte populations after lymphocyte depletion is implicated in therapeutic immune pathways in animal models and in patients with cancer. We sought to evaluate the effects of chemotherapy-induced lymphodepletion followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) and high-dose interleukin-2 (IL-2) therapy on clinical response and the recovery of lymphocyte subcompartments in patients with metastatic melanoma. PATIENTS AND METHODS: This was a two-stage phase II trial design. Patients with measurable metastatic melanoma were treated with intravenous cyclophosphamide (60 mg/kg, days 1 and 2) and fludarabine (25 mg/m(2), day 3 through 7) followed by two 5-day courses of intravenous high-dose bolus IL-2 (600,000 U/kg; days 8 through 12 and 21 through 25). GM-CSF (250 microg/m(2)/d beginning day 8) was given until granulocyte recovery. Lymphocyte recovery profiles were determined by flow cytometric phenotyping at regular intervals, and clinical outcome was assessed by Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: The trial was stopped at the end of stage 1 with four of 18 objective responses noted. Twelve patients had detailed lymphocyte subcompartments evaluated. After lymphodepletion, we observed an induction of regulatory cells (CD4+ T regulatory cells; CD8+ T suppressor cells) and of T memory cells (CD8+ T central memory cells; T effector memory RA+ cells). Expansion of circulating melanoma-specific CD8(+) cells was observed in one of four HLA-A2-positive patients. CONCLUSION: Chemotherapy-induced lymphodepletion modulates the homeostatic repopulation of the lymphocyte compartment and influences recovering lymphocyte subpopulations. Clinical activity seems similar to standard high-dose aldesleukin alone.

21 Article Combination of pembrolizumab and imatinib in a patient with double KIT mutant melanoma: A case report. 2019

Abdou, Yara / Kapoor, Ankita / Hamad, Lamya / Ernstoff, Marc S. ·Roswell Park Comprehensive Cancer Center, Buffalo. · Rochester General Hospital, Rochester, NY. ·Medicine (Baltimore) · Pubmed #31689840.

ABSTRACT: RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations. PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I. INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression. LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.

22 Article Perspectives in melanoma: meeting report from the Melanoma Bridge (November 29th-1 December 1st, 2018, Naples, Italy). 2019

Ascierto, Paolo A / Agarwala, Sanjiv S / Botti, Gerardo / Budillon, Alfredo / Davies, Michael A / Dummer, Reinhard / Ernstoff, Marc / Ferrone, Soldano / Formenti, Silvia / Gajewski, Thomas F / Garbe, Claus / Hamid, Omid / Lo, Roger S / Luke, Jason J / Michielin, Oliver / Palmieri, Giuseppe / Zitvogel, Laurence / Marincola, Francesco M / Masucci, Giuseppe / Caracò, Corrado / Thurin, Magdalena / Puzanov, Igor. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · Medical Oncology and Hematology, St. Luke's University Hospital and Temple University, Bethlehem, PA, USA. · Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Experimental Pharmacology Unit, Department of Translational Research, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Department of Melanoma Medical Oncology, Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Department of Dermatology, University of Zurich Hospital, Zurich, Switzerland. · Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. · Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA. · Department of Pathology and Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine, Chicago, IL, USA. · Division of Dermatologic Oncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany. · The Angeles Clinic, Experimental Therapeutics Cedars Sinai Foundation, Los Angeles, CA, USA. · Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · University of Chicago Medical Center, Chicago, IL, USA. · Oncology Department, UNIL-CHUV, Lausanne, Switzerland. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. · Institut de Cancérologie, Gustave Roussy Cancer Campus, Villejuif, Paris, France. · Refuge Biotechnologies, Menlo Park, CA, USA. · Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. · Division of Surgery of Melanoma and Skin Cancer, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Naples, Italy. · Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, 9609 Medical Center Drive, Bethesda, MD, 20892-7420, USA. thurinm@mail.nih.gov. · Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. ·J Transl Med · Pubmed #31331337.

ABSTRACT: Diagnosis of melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges in melanoma. Recent studies have shown that immune checkpoint blockade that represents a forefront in cancer therapy, provide responses but they are not universal. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers they have yet to be fully characterized and implemented clinically. For example, advancements in sequencing and the understanding of the tumor microenvironment in melanoma have led to the use of genome sequencing and gene expression for development of multi-marker assays that show association with inflammatory state of the tumor and potential to predict response to immunotherapy. As such, melanoma serves as a model system for understanding cancer immunity and patient response to immunotherapy, either alone or in combination with other treatment modalities. Overall, the aim for the translational and clinical studies is to achieve incremental improvements through the development and identification of optimal treatment regimens, which increasingly involve doublet as well as triplet combinations, as well as through development of biomarkers to improve immune response. These and other topics in the management of melanoma were the focus of discussions at the fourth Melanoma Bridge meeting (November 29th-December 1st, 2018, Naples, Italy), which is summarised in this report.

23 Article Small and Isolated Immunohistochemistry-positive Cells in Melanoma Sentinel Lymph Nodes Are Associated With Disease-specific and Recurrence-free Survival Comparable to that of Sentinel Lymph Nodes Negative for Melanoma. 2019

LeBlanc, Robert E / Barton, Dorothea T / Li, Zhongze / Angeles, Christina V / Ernstoff, Marc S / Bagley, Eryn / Wimmer, Daniel / Wong, Sandra L / Barth, Richard J / Shirai, Keisuke / Yan, Shaofeng. ·Departments of Pathology and Laboratory Medicine. · Surgery and Dermatology. · Biostatistics Shared Resource, Norris Cotton Cancer Center. · Departments of Surgery. · Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY. · Medicine, Hematology and Oncology Program, Dartmouth Hitchcock Medical Center, Geisel School of Medicine at Dartmouth, Lebanon, NH. · Inform Diagnostics, Irving, TX. ·Am J Surg Pathol · Pubmed #31091203.

ABSTRACT: Although immunohistochemistry (IHC) has improved our ability to detect melanoma metastases in sentinel lymph nodes (SLN), the American Joint Committee on Cancer (AJCC) does not provide a lower threshold for determining if a SLN is positive for metastasis. Existing literature suggests that even a small aggregate or an enlarged, abnormal cell detectable by IHC can be associated with an adverse outcome. In our experience, however, some SLNs contain small solitary cells the size of neighboring lymphocytes demonstrable only by IHC. We sought to determine their clinical significance. A total of 821 patients underwent a SLN biopsy at our institution over a 12-year period. In all, 639 (77.8%) were SLN-negative, 125 (15.2%) were SLN-positive, and 57 (6.9%) had rare IHC-positive cells of undetermined clinical significance with no disease progression over a mean 59-month follow-up. Kaplan-Meier method with pair-wise comparisons revealed no significant difference in disease-specific survival and recurrence-free survival between SLN-negative and rare IHC-positive groups. There were significant differences in survival and recurrence between patients in the rare IHC-positive group and those with melanoma metastases, including those with solitary melanoma cells and those with tumor burdens ≤0.2 mm. While the lower diagnostic threshold for metastatic melanoma on IHC-stained sections needs to be studied further, our data suggest that rare IHC-positive cells lacking cytomorphologic features of overt malignancy are equivocal for melanoma and could impart a similar prognosis as patients with no evidence of SLN involvement.

24 Article A Review of Exosomes and their Role in The Tumor Microenvironment and Host-Tumor "Macroenvironment". 2019

Tung, Kaity H / Ernstoff, Marc S / Allen, Cheryl / Shu, Shin La. ·Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. ·J Immunol Sci · Pubmed #30972385.

ABSTRACT: Tumor-derived exosomes (TEX) are important intercellular messengers that contribute to tumorigenesis and metastasis through a variety of mechanisms such as immunosuppression and metabolic reprogramming that generate a pre-metastatic niche favorable to tumor progression. Our lab has contributed further to the understanding of the miRNA payloads in TEX by demonstrating that human melanoma-derived exosome (HMEX) associated miRNAs contribute to the metabolic reprogramming of normal stroma. This mini-review highlights the role of TEX in the tumor microenvironment (TME) and the hypothesis that exosomes may also generate a host-tumor "macroenvironment" beyond the TME through their miRNA and protein payloads, so to speak "fertilizing the soil for cancer seeding."

25 Article Validation of Melanoma Immune Profile (MIP), a Prognostic Immune Gene Prediction Score for Stage II-III Melanoma. 2019

Gartrell, Robyn D / Marks, Douglas K / Rizk, Emanuelle M / Bogardus, Margaret / Gérard, Camille L / Barker, Luke W / Fu, Yichun / Esancy, Camden L / Li, Gen / Ji, Jiayi / Rui, Shumin / Ernstoff, Marc S / Taback, Bret / Pabla, Sarabjot / Chang, Rui / Lee, Sandra J / Krolewski, John J / Morrison, Carl / Horst, Basil A / Saenger, Yvonne M. ·Columbia University Irving Medical Center, New York, New York. · College of Physician and Surgeons, Columbia University, New York, New York. · Lausanne University Hospital, Lausanne, Switzerland. · Mailman School of Public Health, Columbia University, New York, New York. · Roswell Park Comprehensive Cancer Center, Buffalo, New York. · OmniSeq, Inc., Buffalo, New York. · University of Arizona, Tucson, Arizona. · Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · University of British Columbia, Vancouver, Canada. · Columbia University Irving Medical Center, New York, New York. yms4@cumc.columbia.edu. ·Clin Cancer Res · Pubmed #30647081.

ABSTRACT: PURPOSE: Biomarkers are needed to stratify patients with stage II-III melanoma for clinical trials of adjuvant therapy because, while immunotherapy is protective, it also confers the risk of severe toxicity. We previously defined and validated a 53-immune gene melanoma immune profile (MIP) predictive both of distant metastatic recurrence and of disease-specific survival (DSS). Here, we test MIP on a third independent population. EXPERIMENTAL DESIGN: A retrospective cohort of 78 patients with stage II-III primary melanoma was analyzed using the NanoString assay to measure expression of 53 target genes, and MIP score was calculated. Statistical analysis correlating MIP with DSS, overall survival, distant metastatic recurrence, and distant metastasis-free interval was performed using ROC curves, Kaplan-Meier curves, and standard univariable and multivariable Cox proportional hazards models. RESULTS: MIP significantly distinguished patients with distant metastatic recurrence from those without distant metastatic recurrence using ROC curve analysis (AUC = 0.695; CONCLUSIONS: MIP identifies patients with low risk of death from melanoma and may constitute a clinical tool to stratify patients with stage II-III melanoma for enrollment in clinical trials.

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