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Melanoma: HELP
Articles by Jose Lutzky
Based on 21 articles published since 2010
(Why 21 articles?)

Between 2010 and 2020, Joe Lutzky wrote the following 21 articles about Melanoma.
+ Citations + Abstracts
1 Guideline An update on the Society for Immunotherapy of Cancer consensus statement on tumor immunotherapy for the treatment of cutaneous melanoma: version 2.0. 2018

Sullivan, Ryan J / Atkins, Michael B / Kirkwood, John M / Agarwala, Sanjiv S / Clark, Joseph I / Ernstoff, Marc S / Fecher, Leslie / Gajewski, Thomas F / Gastman, Brian / Lawson, David H / Lutzky, Jose / McDermott, David F / Margolin, Kim A / Mehnert, Janice M / Pavlick, Anna C / Richards, Jon M / Rubin, Krista M / Sharfman, William / Silverstein, Steven / Slingluff, Craig L / Sondak, Vernon K / Tarhini, Ahmad A / Thompson, John A / Urba, Walter J / White, Richard L / Whitman, Eric D / Hodi, F Stephen / Kaufman, Howard L. ·Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. · Georgetown University, Washington, DC, 20057, USA. · University of Pittsburgh, Pittsburgh, PA, 15213, USA. · St. Luke's Cancer Center and Temple University, Center Valley, PA, 18034, USA. · Loyola University Medical Center, Maywood, IL, 60153, USA. · Roswell Park Cancer Institute, Buffalo, NY, 14263, USA. · University of Michigan, Ann Arbor, MI, 48109, USA. · University of Chicago Medical Center, Chicago, IL, 60637, USA. · Cleveland Clinic, Cleveland, OH, 44195, USA. · Emory Winship Cancer Institute, Atlanta, GA, 30322, USA. · Mt. Sinai Medical Center, Miami Beach, FL, 33140, USA. · Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA. · City of Hope, Duarte, CA, 91010, USA. · Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08901, USA. · New York University Cancer Institute, New York, NY, 10016, USA. · Lutheran General Hospital, Park Ridge, IL, 60068, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21231, USA. · Melanoma Research Foundation, Woodcliff Lake, NJ, 07077, USA. · University of Virginia, Charlottesville, VA, 22908, USA. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. · Cleveland Clinic Taussig Cancer Center, Cleveland, OH, 44195, USA. · Seattle Cancer Care Alliance, Seattle, WA, 98109, USA. · Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA. · Carolinas Medical Center, Charlotte, NC, 28204, USA. · Carol G. Simon Cancer Center, Morristown, NJ, 07046, USA. · Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA. howardkaufman6@gmail.com. ·J Immunother Cancer · Pubmed #29848375.

ABSTRACT: BACKGROUND: Cancer immunotherapy has been firmly established as a standard of care for patients with advanced and metastatic melanoma. Therapeutic outcomes in clinical trials have resulted in the approval of 11 new drugs and/or combination regimens for patients with melanoma. However, prospective data to support evidence-based clinical decisions with respect to the optimal schedule and sequencing of immunotherapy and targeted agents, how best to manage emerging toxicities and when to stop treatment are not yet available. METHODS: To address this knowledge gap, the Society for Immunotherapy of Cancer (SITC) Melanoma Task Force developed a process for consensus recommendations for physicians treating patients with melanoma integrating evidence-based data, where available, with best expert consensus opinion. The initial consensus statement was published in 2013, and version 2.0 of this report is an update based on a recent meeting of the Task Force and extensive subsequent discussions on new agents, contemporary peer-reviewed literature and emerging clinical data. The Academy of Medicine (formerly Institute of Medicine) clinical practice guidelines were used as a basis for consensus development with an updated literature search for important studies published between 1992 and 2017 and supplemented, as appropriate, by recommendations from Task Force participants. RESULTS: The Task Force considered patients with stage II-IV melanoma and here provide consensus recommendations for how they would incorporate the many immunotherapy options into clinical pathways for patients with cutaneous melanoma. CONCLUSION: These clinical guidleines provide physicians and healthcare providers with consensus recommendations for managing melanoma patients electing treatment with tumor immunotherapy.

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 Review New therapeutic options in the medical management of advanced melanoma. 2010

Lutzky, Jose. ·Melanoma Program, Division of Hematology/Oncology, Mount Sinai Comprehensive Cancer Center, Miami Beach, FL, USA. jlutzky@aptiumoncology.com ·Semin Cutan Med Surg · Pubmed #21277538.

ABSTRACT: During the past 3 decades, the incidence, morbidity, and mortality of malignant melanoma have increased dramatically. Advanced melanoma has remained a disease that is for the most part incurable and has challenged all therapeutic efforts to make a dent in its natural history. Recent advances in the understanding of the molecular alterations in melanoma and in the immunologic mechanisms playing a role in this malignancy have brought hope that significant progress can be achieved, as evidenced by early encouraging clinical data. This review will summarize these recent developments and their impact on current clinical practice.

4 Review Velimogene aliplasmid. 2010

Soares, Heloisa P / Lutzky, Jose. ·Department of Medicine, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, USA. ·Expert Opin Biol Ther · Pubmed #20367461.

ABSTRACT: IMPORTANCE OF THE FIELD: Immunotherapy for cancer has been investigated for several decades, achieving limited success. The development of effective new immunotherapeutic agents has reignited interest in the filed. Intralesional injection of plasmids in order to transfect genes capable of stimulating or augmenting immune recognition and destruction of tumors is a relatively new approach. AREAS COVERED IN THIS REVIEW: Our objective is to discuss the role velimogene aliplasmid (Allovectin-7, Vical Incorporated), a plasmid-lipid complex containing the DNA sequences encoding HLA-B7 and beta2 microglobulin, as an immunotherapeutic agent. WHAT THE READER WILL GAIN: Intralesional velimogene aliplasmid induces anti-tumor responses in a proportion of melanoma patients with locoregional and limited distant metastases. Preclinical data and the results of Phase I, II and III clinical trials with this drug are reviewed. The limited data in other malignancies is also reviewed. Velimogene aliplasmid in humans appears safe, with minimal drug-related adverse events. TAKE HOME MESSAGE: Velimogene aliplasmid has activity in melanoma with local and limited distant disease associated with an excellent safety profile. The activity of this approach is also being investigated in other malignancies.

5 Clinical Trial A phase 2 study of glembatumumab vedotin, an antibody-drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma. 2019

Ott, Patrick A / Pavlick, Anna C / Johnson, Douglas B / Hart, Lowell L / Infante, Jeffrey R / Luke, Jason J / Lutzky, Jose / Rothschild, Neal E / Spitler, Lynn E / Cowey, C Lance / Alizadeh, Aaron R / Salama, April K / He, Yi / Hawthorne, Thomas R / Bagley, Rebecca G / Zhang, Joshua / Turner, Christopher D / Hamid, Omid. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, New York University School of Medicine, New York, New York. · Department of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · Florida Cancer Specialists and Research Institute, Fort Myers, Florida. · Tennessee Oncology, PLLC, Nashville, Tennessee. · Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Florida Cancer Specialists, West Palm Beach, Florida. · St. Mary's Medical Center, San Francisco, California. · Northern California Melanoma Center, Baylor University Medical Center, Dallas, Texas. · Northside Hospital Cancer Institute, Decatur, Georgia. · Department of Medical Oncology, Duke University, Durham, North Carolina. · Celldex Therapeutics, Inc, Hampton, New Jersey. · The Angeles Clinic and Research Institute, Los Angeles, California. ·Cancer · Pubmed #30690710.

ABSTRACT: BACKGROUND: Glembatumumab vedotin is an antibody-drug conjugate that produced preliminary clinical activity against advanced melanoma in a phase 1 dose-escalation trial. The objective of the current study was to investigate further the antitumor activity of glembatumumab vedotin at the recommended phase 2 dose in heavily pretreated patients with melanoma. METHODS: This single-arm, phase 2 study enrolled patients with stage IV melanoma who were refractory to checkpoint inhibition and to B-raf proto-oncogene, serine/threonine kinase (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibition (in the presence of a BRAF valine mutation at codon 600). Patients received 1.9 mg/kg glembatumumab vedotin intravenously every 3 weeks until they developed disease progression or intolerance. The primary endpoint was objective response rate (ORR), which was determined according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included progression-free survival (PFS), duration of response, overall survival (OS), safety, and clinical efficacy versus tumor glycoprotein NMB (gpNMB) expression. Tumor expression of gpNMB was assessed using immunohistochemistry. RESULTS: In total, 62 patients received treatment. The ORR was 11% and the median response duration was 6.0 months (95% confidence interval [CI], 4.1 months to not reached). The median PFS was 4.4 months (95% CI, 2.6-5.5 months), and the median OS was 9.0 months (95% CI, 6.1-11.7 months). For patients who developed rash during the first cycle versus those who did not, the ORR was 21% versus 7%, respectively, and there was an overall improvement in PFS (hazard ratio, 0.43; P = .013) and OS (hazard ratio, 0.43; P = .017). The most frequent adverse events were alopecia, neuropathy, rash, fatigue, and neutropenia. With one exception, all evaluable tumors were positive for gpNMB, and 46 of 59 tumors (76%) had 100% gpNMB-positive epithelial cells. CONCLUSIONS: Glembatumumab vedotin had modest activity and an acceptable safety profile in patients with advanced melanoma who were refractory to checkpoint inhibitors and MEK/BRAF inhibition. Treatment-related rash may be associated with response.

6 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.

7 Clinical Trial Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB-IVM1c melanoma. 2018

Chesney, Jason / Awasthi, Sanjay / Curti, Brendan / Hutchins, Laura / Linette, Gerald / Triozzi, Pierre / Tan, Marcus C B / Brown, Russell E / Nemunaitis, John / Whitman, Eric / Windham, Christopher / Lutzky, Jose / Downey, Gerald F / Batty, Nicolas / Amatruda, Thomas. ·Department of Medicine, University of Louisville, Louisville, Kentucky. · Department of Medical Oncology, City of Hope, Duarte. · Earle A Chiles Research Institute, Providence Cancer Center, Portland, Oregon. · Department of Internal Medicine, Division of Hematology Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. · Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. · Section of Hematology and Oncology, Wake Forest School of Medicine, Winston-Salem. · Division of Surgical Oncology, University of South Alabama, Mobile, Alabama. · Department of Surgery, Ochsner Medical Center, New Orleans, Louisiana. · Department of Medical Hematology and Oncology, Mary Crowley Cancer Research Center, Dallas, Texas. · Department of Endocrine and Oncologic Surgery, Atlantic Melanoma Center, Atlantic Health System Cancer Care, Morristown, New Jersey. · Department of Oncology, Cone Health, Greensboro, North Carolina. · Division of Hematology and Oncology, Mount Sinai Medical Center, Miami Beach, Florida. · Center for Design and Analysis, Amgen Limited, Cambridge, UK. · Department of Clinical Research, Amgen Inc., Thousand Oaks, California. · Department of Hematology and Oncology, Minnesota Oncology, Fridley, Minnesota. ·Melanoma Res · Pubmed #29176501.

ABSTRACT: Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

8 Clinical Trial Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. 2017

Atkinson, Thomas M / Hay, Jennifer L / Shoushtari, Alexander / Li, Yuelin / Paucar, Daniel J / Smith, Sloane C / Kudchadkar, Ragini R / Doyle, Austin / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Schwartz, Gary K / Carvajal, Richard D. ·Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. atkinsot@mskcc.org. · Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, 641 Lexington Ave., 7th Floor, New York, NY, 10022, USA. · Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY, USA. · Winship Cancer Institute of Emory University, Atlanta, GA, USA. · Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA. · Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. · Mayo Clinic, Rochester, MN, USA. · University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Princess Margaret Hospital University Health Network, Toronto, ON, Canada. · Penn Medicine, Philadelphia, PA, USA. · University of Chicago, Chicago, IL, USA. · Mount Sinai Medical Center, Miami Beach, FL, USA. · University of Michigan, Ann Arbor, MI, USA. · Minnesota Oncology, Woodbury, MN, USA. · Univeristy of Wisconsin School of Medicine and Public Health, Madison, WI, USA. · Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. · University of Colorado - Denver, Denver, CO, USA. · Columbia University Medical Center, New York, NY, USA. ·J Cancer Res Clin Oncol · Pubmed #27921276.

ABSTRACT: PURPOSE: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied. METHODS: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications. RESULTS: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores. CONCLUSIONS: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct.

9 Clinical Trial Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition. 2015

Carvajal, Richard D / Lawrence, Donald P / Weber, Jeffrey S / Gajewski, Thomas F / Gonzalez, Rene / Lutzky, Jose / O'Day, Steven J / Hamid, Omid / Wolchok, Jedd D / Chapman, Paul B / Sullivan, Ryan J / Teitcher, Jerrold B / Ramaiya, Nikhil / Giobbie-Hurder, Anita / Antonescu, Cristina R / Heinrich, Michael C / Bastian, Boris C / Corless, Christopher L / Fletcher, Jonathan A / Hodi, F Stephen. ·Memorial Sloan Kettering Cancer Center, New York, New York. Weill Medical College of Cornell University, New York, New York. · Massachusetts General Hospital, Boston, Massachusetts. · H. Lee Moffitt Cancer Center, Tampa, Florida. · The University of Chicago, Chicago, Illinois. · The University of Colorado Cancer Center, Aurora, Colorado. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Beverly Hills Cancer Center, Beverly Hills, California. · Angeles Clinic and Research Institute, Los Angeles, California. · Memorial Sloan Kettering Cancer Center, New York, New York. · Dana Farber Cancer Institute, Boston, Massachusetts. · Oregon Health and Science University, Portland, Oregon. · The University of California San Francisco, San Francisco, California. · Dana Farber Cancer Institute, Boston, Massachusetts. Stephen_hodi@dfci.harvard.edu. ·Clin Cancer Res · Pubmed #25695690.

ABSTRACT: PURPOSE: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. EXPERIMENTAL DESIGN: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon two-stage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. RESULTS: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. CONCLUSIONS: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

10 Clinical Trial Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. 2014

Carvajal, Richard D / Sosman, Jeffrey A / Quevedo, Jorge Fernando / Milhem, Mohammed M / Joshua, Anthony M / Kudchadkar, Ragini R / Linette, Gerald P / Gajewski, Thomas F / Lutzky, Jose / Lawson, David H / Lao, Christopher D / Flynn, Patrick J / Albertini, Mark R / Sato, Takami / Lewis, Karl / Doyle, Austin / Ancell, Kristin / Panageas, Katherine S / Bluth, Mark / Hedvat, Cyrus / Erinjeri, Joseph / Ambrosini, Grazia / Marr, Brian / Abramson, David H / Dickson, Mark Andrew / Wolchok, Jedd D / Chapman, Paul B / Schwartz, Gary K. ·Memorial Sloan-Kettering Cancer Center, New York, New York2Weill Medical College of Cornell University, New York, New York. · Vanderbilt University Medical Center, Department of Hematology-Oncology, Nashville, Tennessee. · Mayo Clinic, Rochester, Minnesota. · University of Iowa Hospital and Clinics, Iowa City. · Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · H. Lee Moffitt Cancer Center, Tampa, Florida. · Washington University, St Louis, Missouri. · University of Chicago, Chicago, Illinois. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Winship Cancer Institute of Emory University, Atlanta, Georgia. · University of Michigan, Ann Arbor. · Metro Minnesota Community Clinical Oncology Program, St Louis Park. · University of Wisconsin, Madison. · Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania. · University of Colorado, Aurora. · Investigational Drug Branch, National Cancer Institute, Rockville, Maryland. · Memorial Sloan-Kettering Cancer Center, New York, New York. ·JAMA · Pubmed #24938562.

ABSTRACT: IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.

11 Clinical Trial Multicenter, phase II study of axitinib, a selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, in patients with metastatic melanoma. 2011

Fruehauf, John / Lutzky, Jose / McDermott, David / Brown, Charles K / Meric, Jean-Baptiste / Rosbrook, Brad / Shalinsky, David R / Liau, Katherine F / Niethammer, Andreas G / Kim, Sinil / Rixe, Olivier. ·University of California, Irvine, Orange, 92868, USA. johnfruehauf@msn.com ·Clin Cancer Res · Pubmed #21976544.

ABSTRACT: PURPOSE: This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate. RESULTS: Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels. CONCLUSIONS: Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing.

12 Clinical Trial KIT as a therapeutic target in metastatic melanoma. 2011

Carvajal, Richard D / Antonescu, Cristina R / Wolchok, Jedd D / Chapman, Paul B / Roman, Ruth-Ann / Teitcher, Jerrold / Panageas, Katherine S / Busam, Klaus J / Chmielowski, Bartosz / Lutzky, Jose / Pavlick, Anna C / Fusco, Anne / Cane, Lauren / Takebe, Naoko / Vemula, Swapna / Bouvier, Nancy / Bastian, Boris C / Schwartz, Gary K. ·Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA. carvajar@mskcc.org ·JAMA · Pubmed #21642685.

ABSTRACT: CONTEXT: Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. OBJECTIVE: To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. DESIGN, SETTING, AND PATIENTS: A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. INTERVENTION: Imatinib mesylate, 400 mg orally twice daily. MAIN OUTCOME MEASURES: Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. RESULTS: Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%-30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6-18 weeks; 95% CI, 11-18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P = .05), indicating positive selection for the mutated allele. CONCLUSIONS: Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance. Trial Registration clinicaltrials.gov Identifier: NCT00470470.

13 Clinical Trial Improved survival with ipilimumab in patients with metastatic melanoma. 2010

Hodi, F Stephen / O'Day, Steven J / McDermott, David F / Weber, Robert W / Sosman, Jeffrey A / Haanen, John B / Gonzalez, Rene / Robert, Caroline / Schadendorf, Dirk / Hassel, Jessica C / Akerley, Wallace / van den Eertwegh, Alfons J M / Lutzky, Jose / Lorigan, Paul / Vaubel, Julia M / Linette, Gerald P / Hogg, David / Ottensmeier, Christian H / Lebbé, Celeste / Peschel, Christian / Quirt, Ian / Clark, Joseph I / Wolchok, Jedd D / Weber, Jeffrey S / Tian, Jason / Yellin, Michael J / Nichol, Geoffrey M / Hoos, Axel / Urba, Walter J. ·Dana-Farber Cancer Institute, Boston, MA 02115, USA. stephen_hodi@dfci.harvard.edu ·N Engl J Med · Pubmed #20525992.

ABSTRACT: BACKGROUND: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. METHODS: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. RESULTS: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. CONCLUSIONS: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)

14 Article Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series. 2020

Holbrook, Kourtney / Lutzky, Jose / Davies, Michael A / Davis, Jessica Michaud / Glitza, Isabella C / Amaria, Rodabe N / Diab, Adi / Patel, Sapna P / Amin, Asim / Tawbi, Hussein. ·The University of Texas MD Anderson Cancer Center, Houston, Texas. · Mount Sinai Comprehensive Cancer Center, Miami Beach, Florida. · Levine Cancer Institute, Atrium Health, Charlotte, North Carolina. ·Cancer · Pubmed #31658370.

ABSTRACT: BACKGROUND: Sixty percent of patients with stage IV melanoma may develop brain metastases, which result in significantly increased morbidity and a poor overall prognosis. Phase 3 studies of melanoma usually exclude patients with untreated brain metastases; therefore, clinical data for intracranial responses to treatments are limited. METHODS: A multicenter, retrospective case series investigation of consecutive BRAF-mutant patients with melanoma brain metastases (MBMs) treated with a combination of BRAF inhibitor encorafenib and MEK inhibitor binimetinib was conducted to evaluate the antitumor response. Assessments included the intracranial, extracranial, and global objective response rates (according to the modified Response Evaluation Criteria in Solid Tumors, version 1.1); the clinical benefit rate; the time to response; the duration of response; and safety. RESULTS: A total of 24 patients with stage IV BRAF-mutant MBMs treated with encorafenib plus binimetinib in 3 centers in the United States were included. Patients had received a median of 2.5 prior lines of treatment, and 88% had prior treatment with BRAF/MEK inhibitors. The intracranial objective response rate was 33%, and the clinical benefit rate was 63%. The median time to a response was 6 weeks, and the median duration of response was 22 weeks. Among the 21 patients with MBMs and prior BRAF/MEK inhibitor treatment, the intracranial objective response rate was 24%, and the clinical benefit rate was 57%. Similar outcomes were observed for extracranial and global responses. The safety profile for encorafenib plus binimetinib was similar to that observed in patients with melanoma without brain metastases. CONCLUSIONS: Combination therapy with encorafenib plus binimetinib elicited intracranial activity in patients with BRAF-mutant MBMs, including patients previously treated with BRAF/MEK inhibitors. Further prospective studies are warranted and ongoing.

15 Article Phase 1/2 study of epacadostat in combination with ipilimumab in patients with unresectable or metastatic melanoma. 2019

Gibney, Geoffrey T / Hamid, Omid / Lutzky, Jose / Olszanski, Anthony J / Mitchell, Tara C / Gajewski, Thomas F / Chmielowski, Bartosz / Hanks, Brent A / Zhao, Yufan / Newton, Robert C / Maleski, Janet / Leopold, Lance / Weber, Jeffrey S. ·Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA. geoffrey.t.gibney@gunet.georgetown.edu. · Present Address: Lombardi Comprehensive Cancer Center, Medstar-Georgetown University Hospital, 3800 Reservoir Road NW, Podium A, Washington, DC, 20007, USA. geoffrey.t.gibney@gunet.georgetown.edu. · Melanoma and Skin Cancers Center, The Angeles Clinic and Research Institute, 11818 Wilshire Blvd, Suite #200, Los Angeles, CA, USA. · Division of Hematology & Oncology, Mount Sinai Medical Center, 4306 Alton Rd, Miami Beach, FL, USA. · Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA, USA. · Division of Hematology Oncology, Abramson Cancer Center, Hospital of the University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA, USA. · Department of Hematology/Oncology, University of Chicago, 5841 S Maryland Ave, MC2115, Chicago, IL, USA. · Jonsson Comprehensive Medical Center, University of California, Los Angeles, 10945 Le Conte Ave #2339, Los Angeles, CA, USA. · Department of Medicine, Duke University Medical Center, 20 Duke Medicine Cir, Durham, NC, USA. · Incyte Corporation, 1801 Augustine Cutoff, Wilmington, DE, USA. · Donald A. Adam Melanoma and Skin Cancer Research Center of Excellence, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, USA. · Present Address: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA. ·J Immunother Cancer · Pubmed #30894212.

ABSTRACT: BACKGROUND: Epacadostat is a potent inhibitor of the immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) enzyme. We present phase 1 results from a phase 1/2 clinical study of epacadostat in combination with ipilimumab, an anti-cytotoxic T-lymphocyte-associated protein 4 antibody, in advanced melanoma (NCT01604889). METHODS: Only the phase 1, open-label portion of the study was conducted, per the sponsor's decision to terminate the study early based on the changing melanoma treatment landscape favoring exploration of programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor-based combination strategies. Such decision was not related to the safety of epacadostat plus ipilimumab. Patients received oral epacadostat (25, 50, 100, or 300 mg twice daily [BID]; 75 mg daily [50 mg AM, 25 mg PM]; or 50 mg BID intermittent [2 weeks on/1 week off]) plus intravenous ipilimumab 3 mg/kg every 3 weeks. RESULTS: Fifty patients received ≥1 dose of epacadostat. As of January 20, 2017, 2 patients completed treatment and 48 discontinued, primarily because of adverse events (AEs) and disease progression (n = 20 each). Dose-limiting toxicities occurred in 11 patients (n = 1 each with epacadostat 25 mg BID, 50 mg BID intermittent, 75 mg daily; n = 4 each with epacadostat 50 mg BID, 300 mg BID). The most common immune-related treatment-emergent AEs included rash (50%), alanine aminotransferase elevation (28%), pruritus (28%), aspartate aminotransferase elevation (24%), and hypothyroidism (10%). Among immunotherapy-naive patients (n = 39), the objective response rate was 26% by immune-related response criteria and 23% by Response Evaluation Criteria in Solid Tumors version 1.1. No objective response was seen in the 11 patients who received prior immunotherapy. Epacadostat exposure was dose proportional, with clinically significant IDO1 inhibition at doses ≥25 mg BID. CONCLUSIONS: When combined with ipilimumab, epacadostat ≤50 mg BID demonstrated clinical and pharmacologic activity and was generally well tolerated in patients with advanced melanoma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01604889 . Registration date, May 9, 2012, retrospectively registered.

16 Article Ipilimumab-induced thrombotic thrombocytopenic purpura (TTP). 2017

King, Jeanelle / de la Cruz, Javier / Lutzky, Jose. ·Mount Sinai Comprehensive Cancer Center, Division of Hematology/Oncology, 4306 Alton Road, Miami Beach, FL 33140 USA. · Mount Sinai Medical Center, Department of Internal Medicine, 4300 Alton Road, Miami Beach, FL 33140 USA. ·J Immunother Cancer · Pubmed #28344807.

ABSTRACT: BACKGROUND: CTLA-4 (Cytotoxic T-lymphocyte-associated protein 4) was the first immune checkpoint receptor clinically targeted for use in cancer treatment. It is expressed exclusively on T-cells where its primary role is to regulate the amplitude of the early stages of T-cell activation.1 Ipilimumab, a CTLA-4 blocking antibody, has been widely used for the treatment of patients with high risk and metastatic melanoma. Given its mechanism of action and consequent immune activation, the side effect profile of this drug greatly differs from that of standard cytotoxic chemotherapy. Adverse events are from the most part immune-mediated, ranging from the more common, such as rash and fatigue, to the less common, such as immune endocrinopathy and colitis. CASE PRESENTATION: We describe a case of immune-mediated thrombotic thrombocytopenic purpura (TTP) in a 68 year-old woman with high risk, stage III melanoma occurring after 3 cycles of adjuvant treatment with ipilimumab as part of a clinical trial. CONCLUSION: The range of immune-mediated adverse events during treatment with ipilimumab is wide and varied and clinicians should have a high degree of suspicion when managing these patients.

17 Article Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint inhibitor. 2017

Escandon, Julia / Peacock, Stephanie / Trabolsi, Asaad / Thomas, David B / Layka, Ayman / Lutzky, Jose. ·Mount Sinai Medical Center, Miami Beach, FL USA ; Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL USA. · Mount Sinai Medical Center, Miami Beach, FL USA. · Department of Pathology, University of Miami, Miami, FL USA. · Mount Sinai Medical Center, Miami Beach, FL USA ; Melanoma Program, Division of Hematology/Oncology, Mount Sinai Comprehensive Cancer Center, 4306 Alton Road, Miami Beach, FL 33140 USA. ·J Immunother Cancer · Pubmed #28105370.

ABSTRACT: BACKGROUND: Immune checkpoint inhibitors have become the first line therapy in melanoma treatment and their use is extending to other malignancies. However, we are still learning about immune side effects produced by these drugs and their severity especially in patients with history of inflammatory diseases. CASE PRESENTATION: We present two cases of metastatic melanoma treated with nivolumab and pembrolizumab (anti PD-1). Both patients developed acute interstitial nephritis during immune checkpoint therapy. We emphasize the causal association between immune checkpoint inhibitors and the nephritis. The timing of drug administration and appearance of nephritis is suggestive of a causal relation between the checkpoint inhibitor therapy and this adverse event. CONCLUSIONS: Although uncommon, some side effects from checkpoint inhibitors can be severe and may need to be addressed with immunosuppression. Given the increasing frequency of immunotherapy use, awareness should be raised in regards to immune side effects and their appropriate management.

18 Article A retrospective analysis of High-Dose Interleukin-2 (HD IL-2) following Ipilimumab in metastatic melanoma. 2016

Buchbinder, Elizabeth I / Gunturi, Anasuya / Perritt, Jessica / Dutcher, Janice / Aung, Sandra / Kaufman, Howard L / Ernstoff, Marc S / Miletello, Girald P / Curti, Brendan D / Daniels, Gregory A / Patel, Sapna P / Kirkwood, John M / Hallmeyer, Sigrun / Clark, Joseph I / Gonzalez, Rene / Richart, John M / Lutzky, Joe / Morse, Michael A / Sullivan, Ryan J / McDermott, David F. ·Dana Farber Cancer Institute, Boston, MA USA. · The Cancer Center - Lowell General Hospital, Lowell, MA 01854 USA. · Prometheus Labs, 9410 Carroll Park Drive, San Diego, CA 92121 USA. · Cancer Research Foundation of New York, Chappaqua, NY USA. · Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ USA. · Cleveland Clinic, Cleveland, OH USA. · Hematology/Oncology clinic, Baton Rouge, LA USA. · Providence Health & Services, Portland, OR USA. · Moores UCSD Cancer Center, La Jolla, CA USA. · The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA USA. · Oncology Specialists, SC, Park Ridge, IL USA. · Loyola Medicine, Maywood, IL USA. · University of Colorado, Aurora, CO USA. · Saint Louis University, Saint Louis, MO 63110 USA. · Mount Sinai Medical Center, Miami Beach, FL USA. · Duke, Durham, NC USA. · Massachusetts General Hospital, Boston, MA USA. · Beth Israel Deaconess Medical Center, Boston, MA USA. ·J Immunother Cancer · Pubmed #27660706.

ABSTRACT: BACKGROUND: High dose interleukin-2 (HD IL-2) can induce durable responses in a subset of patients leading to long-term survival. Immune checkpoint blockade (ICB) has demonstrated similarly durable responses in a larger proportion of patients. However, not all patients respond to immune checkpoint blockade and subsequent therapeutic options need to be explored. METHODS: The PROCLAIM database was queried for patients with metastatic melanoma who had received HD IL-2 after treatment with ipilimumab or without prior ICB. Patient characteristics, toxicity and efficacy were analyzed. RESULTS: A total of 52 metastatic melanoma patients were treated with high dose IL-2 after ipilimumab and 276 patients were treated with high dose IL-2 without prior ICB. The overall response rate in the prior ipilimumab group was 21 % as compared to 12 % in the group that had not received prior ipilimumab. The median overall survival, measured from the initiation of HD IL-2 therapy, was 19.3 months in the prior ipilimumab group and 19.4 months in the no prior ICB group. Toxicities observed on HD IL-2 were relatively equivalent between the groups although there were cases of CTLA4 antibody-induced colitis reported after HD IL-2 treatment and a CTLA4 antibody-induced colitis related death. CONCLUSION: In this retrospective analysis HD IL-2 therapy displayed antitumor activity in melanoma patients who progressed following treatment with ipilimumab. Most HD IL-2 toxicity was not worsened by prior ipilimumab therapy except for one treatment related death from colitis. Care should be taken to avoid reactivation of CTLA4 antibody-induced colitis.

19 Article Ipilimumab was safe and effective in two patients with metastatic melanoma and end-stage renal disease. 2015

Cavalcante, Ludimila / Amin, Asim / Lutzky, Jose. ·Department of Hematology and Oncology, Mount Sinai Medical Center, Miami Beach, FL, USA. · Levine Cancer Institute, Charlotte, NC, USA. ·Cancer Manag Res · Pubmed #25632239.

ABSTRACT: This is a unique report of two cases of patients with end-stage renal disease on hemodialysis, receiving ipilimumab for treatment of metastatic melanoma, as there is a paucity of safety and efficacy data in this patient subgroup.

20 Article Checkpoint inhibitors in the treatment of cutaneous malignant melanoma. 2014

Lutzky, Jose. ·Melanoma Program, Division of Hematology/Oncology, Mount Sinai Comprehensive Cancer Center, Miami Beach, FL 33140, USA. Jose.Lutzky@msmc.com. ·Chin Clin Oncol · Pubmed #25841456.

ABSTRACT: Advanced malignant melanoma has historically been considered a uniformly lethal disease. Recent scientific strides have led to unprecedented understanding of both the molecular alterations and the mechanisms of immune evasion in this malignancy. The realization that an intense and dynamic interplay of stimulatory and inhibitory signals occurs in the "immune synapses" among T cells, tumor cells and dendritic cells, led to the development and subsequent clinical testing of agonist and antagonist monoclonal antibodies (mAb) that can modulate these signals. The resulting positive outcomes of the clinical trials utilizing CTLA-4, PD-1 and PD-L1 modulating drugs, has catapulted the field of immunotherapy into the realm of standard treatment. In this article we review the most important agents and clinical data feeding the ongoing paradigm change in the treatment of advanced melanoma.

21 Article Serial monitoring of circulating tumor cells predicts outcome of induction biochemotherapy plus maintenance biotherapy for metastatic melanoma. 2010

Koyanagi, Kazuo / O'Day, Steven J / Boasberg, Peter / Atkins, Michael B / Wang, He-Jing / Gonzalez, Rene / Lewis, Karl / Thompson, John A / Anderson, Clay M / Lutzky, Jose / Amatruda, Thomas T / Hersh, Evan / Richards, Jon / Weber, Jeffrey S / Hoon, Dave S B. ·Department of Molecular Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA. ·Clin Cancer Res · Pubmed #20371696.

ABSTRACT: PURPOSE: Molecular biomarkers in blood are promising for assessment of tumor progression and treatment response. We hypothesized that serial monitoring of circulating tumor cells (CTC) with the use of multimarker quantitative real-time reverse transcriptase-PCR assays could be a surrogate predictor of outcome for melanoma patients enrolled in a multicenter phase II clinical trial of biochemotherapy (BCT) combined with maintenance biotherapy (mBT). EXPERIMENTAL DESIGN: Blood specimens were collected from 87 patients before and during induction BCT and mBT for stage IV melanoma. Expression of five melanoma-associated CTC biomarkers (MART-1, GalNAc-T, PAX-3, MAGE-A3, and Mitf) was assessed by quantitative real-time reverse transcriptase-PCR, and correlated with treatment response and disease outcome. RESULTS: The number of positive CTC biomarkers decreased overall during induction BCT (P < 0.0001). CTC biomarker detection after two cycles of BCT was correlated with treatment response (P = 0.005) and overall survival (P = 0.001): an increase in the number of CTC biomarkers was associated with poor response (P = 0.006) and overall survival (P < 0.0001). Multivariate analyses with the use of a Cox proportional hazards model identified the change in CTC biomarkers after two cycles of BCT as an independent prognostic factor for disease progression (risk ratio, 12.6; 95% confidence interval, 4.78-33.4; P < 0.0001) and overall survival (risk ratio, 6.11; 95% confidence interval, 2.37-15.7; P = 0.0005). CONCLUSION: Serial monitoring of CTC during induction BCT may be useful for predicting therapeutic efficacy and disease outcome in patients receiving BCT and mBT for stage IV melanoma.