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Melanoma: HELP
Articles by Jose Lutzky
Based on 19 articles published since 2008

Between 2008 and 2019, J. Lutzky wrote the following 19 articles about Melanoma.
+ Citations + Abstracts
1 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.

2 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.

3 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.

4 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.

5 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.

6 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.

7 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.

8 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.

9 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.

10 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.)

11 Clinical Trial Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. 2010

Wolchok, Jedd D / Neyns, Bart / Linette, Gerald / Negrier, Sylvie / Lutzky, Jose / Thomas, Luc / Waterfield, William / Schadendorf, Dirk / Smylie, Michael / Guthrie, Troy / Grob, Jean-Jacques / Chesney, Jason / Chin, Kevin / Chen, Kun / Hoos, Axel / O'Day, Steven J / Lebbé, Celeste. ·Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. wolchokj@mskcc.org ·Lancet Oncol · Pubmed #20004617.

ABSTRACT: BACKGROUND: Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. METHODS: We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. FINDINGS: The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group). INTERPRETATION: Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. FUNDING: Bristol-Myers Squibb.

12 Clinical Trial Phase II multicenter trial of maintenance biotherapy after induction concurrent Biochemotherapy for patients with metastatic melanoma. 2009

O'Day, Steven J / Atkins, Michael B / Boasberg, Peter / Wang, He-Jing / Thompson, John A / Anderson, Clay M / Gonzalez, Rene / Lutzky, Jose / Amatruda, Thomas / Hersh, Evan M / Weber, Jeffrey S. ·Melanoma Program, The Angeles Clinic and Research Institute, 2001 Santa Monica Blvd, Suite 560 W, Santa Monica, CA 90404, USA. soday@theangelesclinic.org ·J Clin Oncol · Pubmed #19917850.

ABSTRACT: PURPOSE: Biochemotherapy improves responses in metastatic melanoma, but not overall survival, in randomized trials. We developed a maintenance biotherapy regimen after induction biochemotherapy in an attempt to improve durability of responses and overall survival. PATIENTS AND METHODS: One hundred thirty-three chemotherapy-naïve patients with metastatic melanoma without CNS metastases were treated at 10 melanoma centers. The biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo interleukin-2 (IL-2), and interferon alfa-2b with granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine support. Patients not experiencing disease progression were eligible for maintenance biotherapy with low-dose IL-2 and GM-CSF followed by intermittent pulses of decrescendo IL-2 over 12 months. Patients were observed for response, progression-free survival, toxicity, and overall survival. RESULTS: The response rate to induction biochemotherapy was 44% (95% CI, 35% to 52%; complete response, 8%; partial response, 36%; stable disease, 29%). The median number of biochemotherapy cycles was four, and the median number of maintenance biotherapy cycles was five. The median progression-free survival was 9 months, and the median survival was 13.5 months. The 12-month and 24-month survival rates were 57% and 23%, respectively. Twenty percent of patients remain alive (12 without disease), with median follow-up of 30 months (95% CI, 25+ to 45+ months). Thirty-nine percent of patients developed CNS metastases. The median times to CNS progression and death were 8 months and 5 months, respectively. CONCLUSION: Maintenance biotherapy after induction biochemotherapy seems to prolong progression-free survival and improve overall survival compared with recent multicenter trials of biochemotherapy or chemotherapy. The regimen should be studied in a randomized clinical trial in patients with advanced metastatic melanoma. CNS progression remains a formidable challenge.

13 Clinical Trial A phase 1 study of granulocyte macrophage colony-stimulating factor (sargramostim) and escalating doses of thalidomide in patients with high-risk malignant melanoma. 2009

Lutzky, Jose / Weber, Robert / Nunez, Yvonne / Gillett, Matt / Spitler, Lynn. ·Mount Sinai Comprehensive Cancer Center Melanoma Program, Miami Beach, FL 33140, USA. JLutzky@aptiumoncology.com ·J Immunother · Pubmed #19307996.

ABSTRACT: This phase 1 study evaluated the safety and tolerability of adjuvant treatment with subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF) administered in combination with escalating doses of thalidomide in patients with surgically resected stage II (T4), III, or IV melanoma at high risk for recurrence. Adjuvant treatment included GM-CSF 125 microg/m2 subcutaneously for 14 days and thalidomide at an initial dose of 50 mg/d, escalated in cohorts of 3 to 6 patients each to a maximum of 400 mg/d followed by 14 days of rest. Treatment was continued for up to 1 year in the absence of disease progression. Of 19 patients treated, the most common toxicities were grade 1/2 constipation (68%), fatigue (58%), neuropathy (42%), bone and joint pain (37%), and dyspnea, dizziness, injection site skin reaction, and somnolence (32% each). Thrombotic events in 3 of 19 patients (16%), including 1 treatment-related death, were the most serious adverse events and were thought to be due to thalidomide. With a median follow-up of 945 days (2.6 y), 8 (42%) patients were alive, including 1 with disease and 7 without evidence of disease. GM-CSF plus thalidomide as adjuvant therapy for patients with resected high-risk melanoma was associated with a high incidence of thrombotic events. Because life-threatening events are unacceptable in the adjuvant setting, up-front antithrombotic prophylaxis will be necessary for further evaluation of GM-CSF plus thalidomide as a viable regimen in this patient group.

14 Clinical Trial Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. 2009

Johnston, R L / Lutzky, J / Chodhry, A / Barkin, J S. ·Division of Gastroenterology, University of Miami Miller School of Medicine, Miami, FL, USA. ·Dig Dis Sci · Pubmed #19104936.

ABSTRACT: Anti-CTLA-4 antibodies are human monoclonal antibodies previously studied in the treatment of metastatic melanoma (MM). CTLA-4 is an inhibitory receptor on cytotoxic T cells, blockade of which will activate T cells allowing them to attack malignant cells. Normal host cells may also be affected, and immune-mediated enterocolitis can occur. This is a prospective observational study on the use of corticosteroids and infliximab in the treatment of patients with immune-mediated colitis secondary to anti-CTLA-4 antibody treatment of MM. Five patients presented with colitis after medication administration. Patients were treated with high-dose corticosteroids for 1 week, but diarrhea did not completely abate in any of them. They were then treated successfully with infliximab. One patient had recurrence of symptoms and responded to repeat treatment with infliximab. Patients who develop immune-mediated colitis after administration of anti-CTLA-4 antibodies have previously been reported to respond to corticosteroids, but in our study, all required treatment with infliximab.

15 Clinical Trial Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. 2008

Testori, Alessandro / Richards, Jon / Whitman, Eric / Mann, G Bruce / Lutzky, Jose / Camacho, Luis / Parmiani, Giorgio / Tosti, Giulio / Kirkwood, John M / Hoos, Axel / Yuh, Lianng / Gupta, Renu / Srivastava, Pramod K / Anonymous5270592. ·Istituto Europeo di Oncologia, Milan, Italy. ·J Clin Oncol · Pubmed #18281670.

ABSTRACT: PURPOSE: To assess the antitumor activity of vitespen (autologous, tumor- derived heat shock protein gp96 peptide complexes) by determining whether patients with stage IV melanoma treated with vitespen experienced longer overall survival than patients treated with physician's choice. PATIENTS AND METHODS: Patients (N = 322) were randomly assigned 2:1 to receive vitespen or physician's choice (PC) of a treatment containing one or more of the following: dacarbazine, temozolomide, interleukin-2, or complete tumor resection. This open-label trial was conducted at 71 centers worldwide. Patients were monitored for safety and overall survival. RESULTS: Therapy with vitespen is devoid of significant toxicity. Patients randomly assigned to the vitespen arm received variable number of injections (range, 0 to 87; median, 6) in part because of the autologous nature of vitespen therapy. Intention-to-treat analysis showed that overall survival in the vitespen arm is statistically indistinguishable from that in the PC arm. Exploratory landmark analyses show that patients in the M1a and M1b substages receiving a larger number of vitespen immunizations survived longer than those receiving fewer such treatments. Such difference was not detected for substage M1c patients. CONCLUSION: These results are consistent with the immunologic mechanism of action of vitespen, indicating delayed onset of clinical activity after exposure to the vaccine. The results suggest patients with M1a and M1b disease who are able to receive 10 or more doses of vitespen as the candidate population for a confirmatory study.

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 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.

19 Minor Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. 2008

Lutzky, Jose / Bauer, Juergen / Bastian, Boris C. · ·Pigment Cell Melanoma Res · Pubmed #18510589.

ABSTRACT: -- No abstract --