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Melanoma: HELP
Articles by Patrick Alexander Ott
Based on 48 articles published since 2008
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Between 2008 and 2019, Patrick Ott wrote the following 48 articles about Melanoma.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline NCCN Guidelines Insights: Melanoma, Version 3.2016. 2016

Coit, Daniel G / Thompson, John A / Algazi, Alain / Andtbacka, Robert / Bichakjian, Christopher K / Carson, William E / Daniels, Gregory A / DiMaio, Dominick / Fields, Ryan C / Fleming, Martin D / Gastman, Brian / Gonzalez, Rene / Guild, Valerie / Johnson, Douglas / Joseph, Richard W / Lange, Julie R / Martini, Mary C / Materin, Miguel A / Olszanski, Anthony J / Ott, Patrick / Gupta, Aparna Priyanath / Ross, Merrick I / Salama, April K / Skitzki, Joseph / Swetter, Susan M / Tanabe, Kenneth K / Torres-Roca, Javier F / Trisal, Vijay / Urist, Marshall M / McMillian, Nicole / Engh, Anita. ·From Memorial Sloan Kettering Cancer Center; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance; UCSF Helen Diller Family Comprehensive Cancer Center; Huntsman Cancer Institute at the University of Utah; University of Michigan Comprehensive Cancer Center; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute; UC San Diego Moores Cancer Center; Fred & Pamela Buffett Cancer Center; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine; The University of Tennessee Health Science Center; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute; University of Colorado Cancer Center; Aim at Melanoma; Vanderbilt-Ingram Cancer Center; Mayo Clinic Cancer Center; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Robert H. Lurie Comprehensive Cancer Center of Northwestern University; Yale Cancer Center/Smilow Cancer Hospital; Fox Chase Cancer Center; Dana-Farber/Brigham and Women's Cancer Center; The University of Texas MD Anderson Cancer Center; Duke Cancer Institute; Roswell Park Cancer Institute; Stanford Cancer Institute; Massachusetts General Hospital Cancer Center; Moffitt Cancer Center; City of Hope Comprehensive Cancer Center; University of Alabama at Birmingham Comprehensive Cancer Center; and National Comprehensive Cancer Network. ·J Natl Compr Canc Netw · Pubmed #27496110.

ABSTRACT: The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

2 Editorial Kinase inhibitors and immune check-point blockade for the treatment of metastatic melanoma and advanced cancer: synergistic or antagonistic? 2013

Luke, Jason John / Ott, Patrick Alexander. ·Dana-Farber Cancer Institute, Harvard Medical School, Melanoma Disease Center, Early Drug Development Center, Center for Immuno Oncology , 450 Brookline Ave, Boston, MA 02215 , USA +1 6176324715 ; +1 6176326727 ; Jason_luke@dfci.harvard.edu. ·Expert Opin Pharmacother · Pubmed #24138302.

ABSTRACT: In recent years, therapeutic approaches for many tumors have broadened or even shifted entirely from cytotoxic chemotherapy to specific targeting of dysregulated proteins (predominately kinases), and more recently, harnessing of the anti-tumor immune response. The most prominent example of this shift is the management of metastatic melanoma, where BRAF and MEK inhibition and CLTA-4 blockade have established an entirely new standard of care in the last 3 years. Targeted kinase inhibition and immune checkpoint blockade have different strengths and weaknesses. Kinase inhibitors generally have rapid and impressive response rates but modest progression-free survival while immunotherapy can achieve durable tumor control, but is often associated with lower response rates and slower time to clinical benefit. These approaches would seem to be complementary however the results of early combination studies suggest that caution is advised when combining targeted kinase inhibition with immunotherapy. In this context, rigorous biomarker driven clinical trials are needed to further elucidate mechanisms of both benefit and toxicity. Depending on disease specific biology, it seems likely that both combination and sequential approaches of kinase inhibitors with immunotherapy will be required in order to harness the full potential of these approaches.

3 Review Combining forces: the promise and peril of synergistic immune checkpoint blockade and targeted therapy in metastatic melanoma. 2017

Hermel, David J / Ott, Patrick A. ·Resident Physician, University of Southern California, Los Angeles, CA, USA. · Melanoma Disease Center and Center for Immuno-Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, 02215-5450, USA. Patrick_Ott@DFCI.harvard.edu. ·Cancer Metastasis Rev · Pubmed #28181070.

ABSTRACT: Both immune checkpoint inhibitors and molecularly targeted agents have dramatically improved clinical outcomes for patients with metastatic melanoma. These two therapeutic approaches harness distinct mechanistic pathways-on the one hand, monoclonal antibodies against the immune checkpoints CTLA-4 and PD-1/PD-L1 stimulate the T cell mediated host immune response, while targeted inhibitors of the proto-oncogenes BRAF and MEK disrupt constitutive kinase activity responsible for tumor growth. The prospect of combining these two treatment modalities has been proposed as a potential way to increase overall response rate, extend durability of the anti-tumor response, and circumvent the immune-mediated resistance to targeted therapy. This review explores the preclinical rationale-building upon a wealth of in vitro and in vivo studies-for improved anti-tumor efficacy from combined immune checkpoint inhibition and targeted therapy. In the process, we detail the early clinical trials that have assessed the compatibility of combining these two therapies and the unexpected challenges faced from studies showing increased toxicity from these regimens. Ultimately, with more clinical data expected to mature and accrue in the near future, we elucidate a potentially novel and promising strategy for patients with advanced melanoma.

4 Review PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. 2015

Luke, Jason J / Ott, Patrick A. ·Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA. · Melanoma Disease Center, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. ·Oncotarget · Pubmed #25682878.

ABSTRACT: Checkpoint inhibitors are revolutionizing treatment options and expectations for patients with melanoma. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), was the first approved checkpoint inhibitor. Emerging long-term data indicate that approximately 20% of ipilimumab-treated patients achieve long-term survival. The first programmed death 1 (PD-1) inhibitor, pembrolizumab, was recently approved by the United States Food and Drug Administration for the treatment of melanoma; nivolumab was previously approved in Japan. PD-1 inhibitors are also poised to become standard of care treatment for other cancers, including non-small cell lung cancer, renal cell carcinoma and Hodgkin's lymphoma. Immunotherapy using checkpoint inhibition is a different treatment approach to chemotherapy and targeted agents: instead of directly acting on the tumor to induce tumor cell death, checkpoint inhibitors enhance or de novo stimulate antitumor immune responses to eliminate cancer cells. Initial data suggest that objective anti-tumor response rates may be higher with anti-PD-1 agents compared with ipilimumab and the safety profile may be more tolerable. This review explores the development and next steps for PD-1 pathway inhibitors, including discussion of their novel mechanism of action and clinical data to-date, with a focus on melanoma.

5 Review Vaccines and melanoma. 2014

Ott, Patrick A / Fritsch, Edward F / Wu, Catherine J / Dranoff, Glenn. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Melanoma Disease Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Center for Immuno-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02215, USA. Electronic address: Patrick_Ott@DFCI.harvard.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02215, USA; Cancer Vaccine Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. ·Hematol Oncol Clin North Am · Pubmed #24880947.

ABSTRACT: The potential for therapeutic efficacy of a melanoma vaccine has been evident preclinically for many years. In melanoma patients, vaccines have resulted in the induction of immune responses, although clinical benefit has not been clearly documented. The recent achievements with immune-checkpoint blockade have shown that immunotherapy can be a powerful tool in cancer therapy. With increased understanding of tumor immunity, the limitations of previous cancer vaccination approaches have become evident. Rapid progress in technologies that enable better vaccine design raise the expectation that these limitations can be overcome, thus leading to a clinically effective melanoma vaccine in the near future.

6 Review CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. 2013

Ott, Patrick A / Hodi, F Stephen / Robert, Caroline. ·Authors' Affiliations: Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; and Institut Gustave Roussy, Villejuif-Paris Sud, Paris, France. ·Clin Cancer Res · Pubmed #24089443.

ABSTRACT: Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 has emerged as a successful treatment approach for patients with advanced melanoma. Ipilimumab is the first agent associated with a documented improved overall survival benefit in this patient population. A striking attribute of CTLA-4 blockade is the durability of objective responses, leading to speculation of a possible cure for some patients. Many tumor responses achieved with PD-1 and PD-L1 inhibition were durable in the phase I trials and were seen in a higher proportion of patients with melanoma than typically observed with ipilimumab. Biomarker development to identify the subset of patients with melanoma who will achieve durable clinical benefit with checkpoint blockade is critical; tumor PD-L1 expression has been promising in early studies. The contrast between unprecedented response rates but limited durability of responses achieved with BRAF and MEK inhibition in BRAF(V600)-mutated melanoma and the impressive durability but relatively low rate of response achieved with immune checkpoint blockade is striking. Preclinical data on potential synergies between CTLA-4/PD-1/PD-L1 inhibition and MAPK-targeted therapy is emerging, and combined immune checkpoint blockade and MAPK inhibition are being explored in clinical trials. Other promising approaches to increase the number of patients with melanoma who benefit from durable responses with immune checkpoint blockade include concurrent or sequenced CTLA-4 and PD-1/PD-L1 inhibition and combination with other immunotherapeutic strategies. Clin Cancer Res; 19(19); 5300-9. ©2013 AACR.

7 Review Surgical approach to primary cutaneous melanoma. 2011

Ott, Patrick A / Berman, Russell S. ·Division of Medical Oncology, Department of Medicine, New York University School of Medicine, New York University Cancer Institute, 160 East 34th Street, 9th Floor, New York, NY 10016, USA. ·Surg Oncol Clin N Am · Pubmed #21111958.

ABSTRACT: The surgical management of primary cutaneous melanoma, from the diagnostic biopsy through the wide local excision and nodal staging, must be carefully planned, and the biology of the melanoma, microstaging and primary tumor pathologic features of the melanoma, location on the body, patient preferences, and comorbidities must be considered. The treating surgeon must balance preservation of oncologic principles, with optimization of functional and aesthetic outcome. This article reviews the rationale behind the surgical approach in the patient with a primary melanoma.

8 Review Mucosal melanomas: a case-based review of the literature. 2010

Seetharamu, Nagashree / Ott, Patrick A / Pavlick, Anna C. ·NYU Cancer Institute, 160E 34th Street, New York, New York 10016, USA. anna.pavlick@nyumc.org ·Oncologist · Pubmed #20571149.

ABSTRACT: Mucosal melanoma is a rare cancer that is clearly distinct from its cutaneous counterpart in biology, clinical course, and prognosis. Recent studies have shown important differences in the frequencies of various genetic alterations in different subtypes of melanoma. Activating mutations in the c-KIT gene are detected in a significant number of patients with mucosal melanoma. This observation has resulted in the initiation of several clinical trials aimed at exploring the role of receptor tyrosine kinases that inhibit c-KIT in this patient population. We herein present a comprehensive literature review of mucosal melanoma along with case vignettes of a number of pertinent cases. We further discuss melanomas of the head and neck, the female genital tract, and the anorectum, which are the three most common sites of mucosal melanoma, with a particular focus on the diagnostic, prognostic, and therapeutic data available in the literature.

9 Review Novel therapeutics for melanoma. 2009

Seetharamu, Nagashree / Ott, Patrick A / Pavlick, Anna C. ·NYU Cancer Institute, New York University Medical Center, New York, NY 10016, USA. ·Expert Rev Anticancer Ther · Pubmed #19496721.

ABSTRACT: Advanced melanoma has the highest per-death loss of years of potential life expectancy except for adult leukemia. Standard therapy with agents such as dacarbazine, temozolomide and IL-2 is associated with notoriously low response rates. The identification of new active agents is, therefore, critical in this disease. In recent years, better understanding of melanoma biology, as well as cancer and immune biology in general has led to the development of a number of new potential therapeutic agents for advanced melanoma. While many of these compounds are being tested in clinical trials, there are more agents in various stages of preclinical development. These novel therapeutics offer hope for this aggressive and so far largely treatment-resistant disease. In this review we will discuss some of the most promising novel therapeutic agents for advanced melanoma.

10 Clinical Trial Results from phase II trial of HSP90 inhibitor, STA-9090 (ganetespib), in metastatic uveal melanoma. 2018

Shah, Shalin / Luke, Jason J / Jacene, Heather A / Chen, Tianqi / Giobbie-Hurder, Anita / Ibrahim, Nageatte / Buchbinder, Elizabeth L / McDermott, David F / Flaherty, Keith T / Sullivan, Ryan J / Lawrence, Donald P / Ott, Patrick A / Hodi, F Stephen. ·Department of Medicine, Medical University of South Carolina, Charleston, South Carolina. · Department of Medicine, University of Chicago, Chicago, Illinois. · Department of Radiology, Brigham and Women's Hospital. · Department of Biostatics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Department of Medicine, Dana-Farber Cancer Institute. · Department of Medicine, Beth Israel Deaconess Medical Center. · Department of Medicine, Massachusetts General Hospital Cancer Center. ·Melanoma Res · Pubmed #30211813.

ABSTRACT: Uveal melanoma (UM) is a rare form of melanoma without effective therapy. The biology of UM relies on several heat-shock protein 90 (Hsp90)-dependent molecules such as MET, MEK and AKT, making Hsp90 inhibition a rational approach. Patients with stage IV UM, measurable disease, and no previous chemotherapy were eligible. Patients received either ganetespib 200 mg weekly (cohort A) or 150 mg twice a week (cohort B). Primary endpoint response rate (RR) was assessed by RECIST. A total of 17 patients were accrued for this study, with seven in cohort A and 10 in cohort B. Liver metastases were present in 59%. Response outcomes included one partial response, four stable disease, 11 progressive disease, and one withdrawal for ORR: 5.9% and disease control rate of 29.4%. Progression-free survival was 1.6 months (cohort A) and 1.8 months (cohort B). Overall survival was 8.5 months (cohort A) and 4.9 months (cohort B). An overall 31% of adverse events were grade 3-4 and were mostly related to gastrointestinal toxicities. Early on-treatment (1 months) positron emission tomography showed reduction in metabolic activity in 24% of patients, suggesting a pharmacodynamic effect of Hsp90 inhibition. These early metabolic changes did not seem to be durable and/or clinically significant in relation to the 2-month response assessment. Hsp90 inhibition with ganetespib resulted in modest clinical benefit on two dosing schedules and was associated with significant, although manageable, gastrointestinal toxicity. Evidence of pharmacodynamic activity for Hsp90 inhibition was observed via positron emission tomography, which did not translate into clinical benefit, suggesting rapid development of resistance.

11 Clinical Trial An immunogenic personal neoantigen vaccine for patients with melanoma. 2017

Ott, Patrick A / Hu, Zhuting / Keskin, Derin B / Shukla, Sachet A / Sun, Jing / Bozym, David J / Zhang, Wandi / Luoma, Adrienne / Giobbie-Hurder, Anita / Peter, Lauren / Chen, Christina / Olive, Oriol / Carter, Todd A / Li, Shuqiang / Lieb, David J / Eisenhaure, Thomas / Gjini, Evisa / Stevens, Jonathan / Lane, William J / Javeri, Indu / Nellaiappan, Kaliappanadar / Salazar, Andres M / Daley, Heather / Seaman, Michael / Buchbinder, Elizabeth I / Yoon, Charles H / Harden, Maegan / Lennon, Niall / Gabriel, Stacey / Rodig, Scott J / Barouch, Dan H / Aster, Jon C / Getz, Gad / Wucherpfennig, Kai / Neuberg, Donna / Ritz, Jerome / Lander, Eric S / Fritsch, Edward F / Hacohen, Nir / Wu, Catherine J. ·Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. · Harvard Medical School, Boston, Massachusetts 02215, USA. · Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. · Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. · Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, USA. · Center for Immuno-Oncology (CIO), Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. · CuriRx, Inc., Wilmington, Massachusetts 01887, USA. · Oncovir, Inc., 3203 Cleveland Avenue, NW, Washington DC 20008, USA. · Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ·Nature · Pubmed #28678778.

ABSTRACT: Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4

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

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

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

13 Clinical Trial PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course. 2016

Nishino, Mizuki / Ramaiya, Nikhil H / Awad, Mark M / Sholl, Lynette M / Maattala, Jennifer A / Taibi, Myriam / Hatabu, Hiroto / Ott, Patrick A / Armand, Philippe F / Hodi, F Stephen. ·Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. Mizuki_Nishino@dfci.harvard.edu. · Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. ·Clin Cancer Res · Pubmed #27535979.

ABSTRACT: PURPOSE: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor-related pneumonitis in advanced cancer patients. EXPERIMENTAL DESIGN: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. Chest CT scans were reviewed to assess extent, distribution, and radiographic patterns of pneumonitis. RESULTS: Among 170 patients treated in 10 different trials of nivolumab, 20 patients (10 melanoma, 6 lymphoma, and 4 lung cancer) developed pneumonitis. Five patients received nivolumab monotherapy, and 15 received combination therapy. The median time from therapy initiation to pneumonitis was 2.6 months. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 13, nonspecific interstitial pneumonia (NSIP) in 3, hypersensitivity pneumonitis (HP) in 2, and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The AIP/ARDS pattern had the highest grade, followed by COP, whereas NSIP and HP had lower grade (median grade: 3, 2, 1, 1, respectively; P = 0.006). The COP pattern was most common in all tumors and treatment regimens. Most patients (17/20; 85%) received corticosteroids, and 3 (15%) also required infliximab. Seven patients restarted nivolumab therapy; 2 of them developed recurrent pneumonitis and were successfully retreated with corticosteroids. One of the patients experienced a pneumonitis flare after completion of corticosteroid taper without nivolumab retreatment. CONCLUSIONS: PD-1 inhibitor-related pneumonitis showed a spectrum of radiographic patterns, reflecting pneumonitis grades. COP was the most common pattern across tumor types and therapeutic regimens. Most patients were successfully treated with corticosteroids. Recurrent pneumonitis and pneumonitis flare were noted in a few patients. Clin Cancer Res; 22(24); 6051-60. ©2016 AACRSee related commentary by Castanon, p. 5956.

14 Clinical Trial Safety, Antitumor Activity, and Immune Activation of Pegylated Recombinant Human Interleukin-10 (AM0010) in Patients With Advanced Solid Tumors. 2016

Naing, Aung / Papadopoulos, Kyriakos P / Autio, Karen A / Ott, Patrick A / Patel, Manish R / Wong, Deborah J / Falchook, Gerald S / Pant, Shubham / Whiteside, Melinda / Rasco, Drew R / Mumm, John B / Chan, Ivan H / Bendell, Johanna C / Bauer, Todd M / Colen, Rivka R / Hong, David S / Van Vlasselaer, Peter / Tannir, Nizar M / Oft, Martin / Infante, Jeffrey R. ·Aung Naing, Rivka R. Colen, David S. Hong, and Nizar M. Tannir, MD Anderson Cancer Center, Houston · Kyriakos P. Papadopoulos and Drew R. Rasco, START Center for Cancer Care, San Antonio, TX · Karen A. Autio, Memorial Sloan Kettering Cancer Center, New York, NY · Patrick A. Ott, Dana-Farber Cancer Institute, Boston, MA · Manish R. Patel, Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL · Deborah J. Wong, University of California Los Angeles, Los Angeles · Melinda Whiteside, John B. Mumm, Ivan H. Chan, Peter Van Vlasselaer, and Martin Oft, ARMO BioSciences, Redwood City, CA · Gerald S. Falchook, Sarah Cannon Research Institute at HealthONE, Denver, CO · Shubham Pant, Oklahoma University, Oklahoma City, OK · and Johanna C. Bendell, Todd M. Bauer, and Jeffrey R. Infante, Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN. ·J Clin Oncol · Pubmed #27528724.

ABSTRACT: Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

15 Clinical Trial Phase I/II study of the antibody-drug conjugate glembatumumab vedotin in patients with advanced melanoma. 2014

Ott, Patrick A / Hamid, Omid / Pavlick, Anna C / Kluger, Harriet / Kim, Kevin B / Boasberg, Peter D / Simantov, Ronit / Crowley, Elizabeth / Green, Jennifer A / Hawthorne, Thomas / Davis, Thomas A / Sznol, Mario / Hwu, Patrick. ·Patrick A. Ott and Anna C. Pavlick, New York University Cancer Institute, New York, NY · Omid Hamid and Peter D. Boasberg, The Angeles Clinic and Research Institute, Los Angeles, CA · Harriet Kluger and Mario Sznol, Yale Cancer Center, New Haven, CT · Kevin B. Kim and Patrick Hwu, University of Texas MD Anderson Cancer Center, Houston, TX · Ronit Simantov, Elizabeth Crowley, Jennifer A. Green, Thomas Hawthorne, and Thomas A. Davis, Celldex Therapeutics, Hampton, NJ. ·J Clin Oncol · Pubmed #25267741.

ABSTRACT: PURPOSE: The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB (gpNMB) to the potent cytotoxin monomethyl auristatin E. This study evaluated the safety and activity of glembatumumab vedotin in patients with advanced melanoma. PATIENTS AND METHODS: Patients received glembatumumab vedotin every 3 weeks (schedule 1) in a dose escalation and phase II expansion at the maximum-tolerated dose (MTD). Dosing during 2 of 3 weeks (schedule 2) and weekly (schedule 3) was also assessed. The primary end points were safety and pharmacokinetics. The secondary end points included antitumor activity, gpNMB expression, and immunogenicity. RESULTS: One hundred seventeen patients were treated using schedule 1 (n = 79), schedule 2 (n = 15), or schedule 3 (n = 23). The MTDs were 1.88, 1.5, and 1.0 mg/kg for schedules 1, 2, and 3, respectively. Grade 3/4 treatment-related toxicities that occurred in two or more patients included rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea. Three treatment-related deaths (resulting from pneumococcal sepsis, toxic epidermal necrolysis, and renal failure) occurred at doses exceeding the MTDs. In the schedule 1 phase II expansion cohort (n = 34), five patients (15%) had a partial response and eight patients (24%) had stable disease for ≥ 6 months. The objective response rate (ORR) was 2 of 6 (33%) for the schedule 2 MTD and 3 of 12 (25%) for the schedule 3 MTD. Rash was correlated with a greater ORR and improved progression-free survival. CONCLUSION: Glembatumumab vedotin is active in advanced melanoma. The schedule 1 MTD (1.88 mg/kg once every 3 weeks) was associated with a promising ORR and was generally well tolerated. More frequent dosing was potentially associated with a greater ORR but increased toxicity.

16 Clinical Trial Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. 2013

Trunzer, Kerstin / Pavlick, Anna C / Schuchter, Lynn / Gonzalez, Rene / McArthur, Grant A / Hutson, Thomas E / Moschos, Stergios J / Flaherty, Keith T / Kim, Kevin B / Weber, Jeffrey S / Hersey, Peter / Long, Georgina V / Lawrence, Donald / Ott, Patrick A / Amaravadi, Ravi K / Lewis, Karl D / Puzanov, Igor / Lo, Roger S / Koehler, Astrid / Kockx, Mark / Spleiss, Olivia / Schell-Steven, Annette / Gilbert, Houston N / Cockey, Louise / Bollag, Gideon / Lee, Richard J / Joe, Andrew K / Sosman, Jeffrey A / Ribas, Antoni. ·Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu ·J Clin Oncol · Pubmed #23569304.

ABSTRACT: PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.

17 Clinical Trial Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. 2013

Kim, Kevin B / Kefford, Richard / Pavlick, Anna C / Infante, Jeffrey R / Ribas, Antoni / Sosman, Jeffrey A / Fecher, Leslie A / Millward, Michael / McArthur, Grant A / Hwu, Patrick / Gonzalez, Rene / Ott, Patrick A / Long, Georgina V / Gardner, Olivia S / Ouellet, Daniele / Xu, Yanmei / DeMarini, Douglas J / Le, Ngocdiep T / Patel, Kiran / Lewis, Karl D. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. kkim@mdanderson.org ·J Clin Oncol · Pubmed #23248257.

ABSTRACT: PURPOSE: BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma. PATIENTS AND METHODS: This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. RESULTS: In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. CONCLUSION: Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

18 Clinical Trial Oblimersen in combination with temozolomide and albumin-bound paclitaxel in patients with advanced melanoma: a phase I trial. 2013

Ott, Patrick A / Chang, Jason / Madden, Kathleen / Kannan, Rajni / Muren, Caroline / Escano, Crystal / Cheng, Xin / Shao, Yongzhao / Mendoza, Sandra / Gandhi, Alex / Liebes, Leonard / Pavlick, Anna C. ·Division of Medical Oncology, NYU Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. Patrick_Ott@DFCI.harvard.edu ·Cancer Chemother Pharmacol · Pubmed #23064957.

ABSTRACT: PURPOSE: The combination of oblimersen, a bcl-2 antisense oligonucleotide, and dacarbazine lead to superior progression-free survival in advanced melanoma patients. Albumin-bound paclitaxel (nab-paclitaxel) has single-agent activity in melanoma. METHODS: In a phase I trial, chemotherapy-naïve patients with metastatic melanoma and normal LDH levels were enrolled on 3 cohorts. The treatment regimen consisted of 56-day cycles of oblimersen (7 mg/kg/day continuous IV infusion on day 1-7 and 22-28 in cohort 1 and 2; 900 mg fixed dose, twice weekly in weeks 1-2, 4-5 for cohort 3), temozolomide (75 mg/m(2), days 1-42), and nab-paclitaxel (175 mg/m(2) in cohort 1 and 3, 260 mg/m(2) in cohort 2 on day 7 and 28). Apoptosis markers were tested in pre- and post-treatment specimens of a subset of patients. RESULTS: Six grade 3 events (neutropenia, renal insufficiency, hyponatremia, elevated creatinine, allergic reaction, and neuropathy) and 2 grade 4 events (neutropenia and thrombocytopenia) were seen in 32 patients. The objective response rate was 40.6% (2 complete responses and 11 partial responses) and 11 patients had stable disease, for a disease control rate of 75%. CONCLUSIONS: The combination of oblimersen, temozolomide, and nab-paclitaxel was well tolerated and demonstrated encouraging activity in patients with advanced melanoma.

19 Clinical Trial Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in patients with advanced melanoma. 2013

Ott, Patrick A / Carvajal, Richard D / Pandit-Taskar, Neeta / Jungbluth, Achim A / Hoffman, Eric W / Wu, Bor-Wen / Bomalaski, John S / Venhaus, Ralph / Pan, Linda / Old, Lloyd J / Pavlick, Anna C / Wolchok, Jedd D. ·Department of Medical Oncology, New York University School of Medicine, New York, NY, USA. Patrick_Ott@dfci.harvard.edu ·Invest New Drugs · Pubmed #22864522.

ABSTRACT: Background Arginine deiminase (ADI) is an enzyme that degrades arginine, an amino acid that is important for growth and development of normal and neoplastic cells. Melanoma cells are auxotrophic for arginine, because they lack argininosuccinatesynthetase (ASS), a key enzyme required for the synthesis of arginine. Patients and methods Patients with advanced melanoma were treated with 40, 80 or 160 IU/m(2) ADI-PEG 20 i.m. weekly. Primary endpoints were toxicity and tumor response, secondary endpoints included metabolic response by (18)FDG-PET, pharmacodynamic (PD) effects upon circulating arginine levels, and argininosuccinate synthetase tumor expression by immunohistochemistry. Results 31 previously treated patients were enrolled. The main toxicities were grade 1 and 2 adverse events including injection site pain, rash, and fatigue. No objective responses were seen. Nine patients achieved stable disease (SD), with 2 of these durable for >6 months. Four of the 9 patients with SD had uveal melanoma. PD analysis showed complete plasma arginine depletion in 30/31 patients by day 8. Mean plasma levels of ADI-PEG 20 correlated inversely with ADI-PEG 20 antibody levels. Immunohistochemical ASS expression analysis in tumor tissue was negative in 24 patients, whereas 5 patients had <5 % cells positive. Conclusions ADI-PEG 20 is well tolerated in advanced melanoma patients and leads to consistent, but transient, arginine depletion. Although no RECIST responses were observed, the encouraging rate of SD in uveal melanoma patients indicates that it may be worthwhile to evaluate ADI-PEG 20 in this melanoma subgroup.

20 Clinical Trial A phase II trial of sorafenib in metastatic melanoma with tissue correlates. 2010

Ott, Patrick A / Hamilton, Anne / Min, Christina / Safarzadeh-Amiri, Sara / Goldberg, Lauren / Yoon, Joanne / Yee, Herman / Buckley, Michael / Christos, Paul J / Wright, John J / Polsky, David / Osman, Iman / Liebes, Leonard / Pavlick, Anna C. ·Department of Medical Oncology, New York University School of Medicine, New York, New York, United States of America. ·PLoS One · Pubmed #21206909.

ABSTRACT: BACKGROUND: Sorafenib monotherapy in patients with metastatic melanoma was explored in this multi-institutional phase II study. In correlative studies the impact of sorafenib on cyclin D1 and Ki67 was assessed. METHODOLOGY/PRINCIPAL FINDINGS: Thirty-six patients treatment-naïve advanced melanoma patients received sorafenib 400 mg p.o. twice daily continuously. Tumor BRAF(V600E) mutational status was determined by routine DNA sequencing and mutation-specific PCR (MSPCR). Immunohistochemistry (IHC) staining for cyclin D1 and Ki67 was performed on available pre- and post treatment tumor samples. The main toxicities included diarrhea, alopecia, rash, mucositis, nausea, hand-foot syndrome, and intestinal perforation. One patient had a RECIST partial response (PR) lasting 175 days. Three patients experienced stable disease (SD) with a mean duration of 37 weeks. Routine BRAF(V600E) sequencing yielded 27 wild-type (wt) and 6 mutant tumors, whereas MSPCR identified 12 wt and 18 mutant tumors. No correlation was seen between BRAF(V600E) mutational status and clinical activity. No significant changes in expression of cyclin D1 or Ki67 with sorafenib treatment were demonstrable in the 15 patients with pre-and post-treatment tumor samples. CONCLUSIONS/SIGNIFICANCE: Sorafenib monotherapy has limited activity in advanced melanoma patients. BRAF(V600E) mutational status of the tumor was not associated with clinical activity and no significant effect of sorafenib on cyclin D1 or Ki67 was seen, suggesting that sorafenib is not an effective BRAF inhibitor or that additional signaling pathways are equally important in the patients who benefit from sorafenib. TRIAL REGISTRATION: Clinical Trials.gov NCT00119249.

21 Clinical Trial A phase II trial of the epothilone B analog ixabepilone (BMS-247550) in patients with metastatic melanoma. 2010

Ott, Patrick A / Hamilton, Anne / Jones, Amanda / Haas, Naomi / Shore, Tsiporah / Liddell, Sandra / Christos, Paul J / Doyle, L Austin / Millward, Michael / Muggia, Franco M / Pavlick, Anna C. ·Department of Medical Oncology, New York University Cancer Institute, New York, New York, United States of America. ·PLoS One · Pubmed #20098694.

ABSTRACT: BACKGROUND: Ixabepilone (BMS-247550), an epothilone B analog, is a microtubule stabilizing agent which has shown activity in several different tumor types and preclinical models in melanoma. In an open label, one-arm, multi-center phase II trial the efficacy and toxicity of this epothilone was investigated in two different cohorts: chemotherapy-naïve (previously untreated) and previously treated patients with metastatic melanoma. METHODOLOGY/PRINCIPAL FINDINGS: Eligible patients had histologically-confirmed stage IV melanoma, with an ECOG performance status of 0 to 2. Ixabepilone was administered at a dose of 20 mg/m(2) on days 1, 8, and 15 during each 28-day cycle. The primary endpoint was response rate (RR); secondary endpoints were time to progression (TTP) and toxicity. Twenty-four patients were enrolled and 23 were evaluable for response. Initial serum lactate dehydrogenase (LDH) levels were elevated in 6/11 (55%) of the previously treated and in 5/13 (38%) of the previously untreated patients. No complete or partial responses were seen in either cohort. One patient in the previously treated group developed neutropenia and fatal septic shock. Seventeen patients (8 in the previously untreated group and 9 in the previously treated group) progressed after 2 cycles, whereas six patients (3 in each group) had stable disease after 2-6 cycles. Median TTP was 1.74 months in the previously untreated group (95% CI = 1.51 months, upper limit not estimated) and 1.54 months in the previously treated group (95% CI = 1.15 months, 2.72 months). Grade 3 and/or 4 toxicities occurred in 5/11 (45%) of previously untreated and in 5/13 (38%) of previously treated patients and included neutropenia, peripheral neuropathy, fatigue, diarrhea, and dyspnea. CONCLUSIONS/SIGNIFICANCE: Ixabepilone has no meaningful activity in either chemotherapy-naïve (previously untreated) or previously treated patients with metastatic melanoma. Further investigation with ixabepilone as single agent in the treatment of melanoma is not warranted. TRIAL REGISTRATION: Clinical Trials.gov NCT00036764.

22 Clinical Trial Phase II trial of dacarbazine and thalidomide for the treatment of metastatic melanoma. 2009

Ott, Patrick A / Chang, Jason L / Oratz, Ruth / Jones, Amanda / Farrell, Kathleen / Muggia, Franco / Pavlick, Anna C. ·Division of Medical Oncology, New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA. patrick.ott@nyumc.org ·Chemotherapy · Pubmed #19451711.

ABSTRACT: OBJECTIVE: This phase II study evaluated the efficacy and tolerability of dacarbazine in combination with thalidomide in metastatic melanoma patients. METHODS: Chemotherapy-naïve patients with histologically confirmed, measurable metastatic melanoma with no evidence of brain metastases and adequate hematologic and organ function received dacarbazine (1,000 mg/m(2) i.v. every 3 weeks) and thalidomide (starting dose of 200 mg/day orally at night, escalated every 3 weeks) as tolerated. The primary endpoint was objective tumor response, evaluated after every 3 cycles of treatment. Fifteen patients, age range 29-77 years, were accrued for this study. All had stage IV disease (1 M1a, 5 M1b, 9 M1c). Nine patients had had no prior adjuvant therapy, 6 had received prior immunotherapy. The median number of cycles was 5 (range 1-18), with 8 patients receiving >or=3 cycles. The median thalidomide dose administered was 200 mg/day with a maximum tolerated dose of 400 mg/day. RESULTS: Of the 13 patients evaluable for response, 1 patient had a partial response, 3 patients had stable disease and 9 patients had progressive disease. No complete responses were seen. Two patients were not evaluable for response: 1 withdrew due to toxicity and 1 died of unrelated causes. Grade III neutropenia, thrombocytopenia and nausea were attributed to dacarbazine. Grade III/IV constipation, peripheral neuropathy, fatigue, edema and rash were attributed to thalidomide. CONCLUSION: The addition of thalidomide to dacarbazine in metastatic melanoma yielded activity insufficient to proceed with additional trials of this combination. Thalidomide dose escalation beyond 200 mg/day was limited by unacceptable toxicity. Therefore, this combination does not warrant further investigation.

23 Article Management of metastatic melanoma: improved survival in a national cohort following the approvals of checkpoint blockade immunotherapies and targeted therapies. 2018

Dobry, Allison S / Zogg, Cheryl K / Hodi, F Stephen / Smith, Timothy R / Ott, Patrick A / Iorgulescu, J Bryan. ·Harvard Medical School, Boston, MA, USA. · Department of Dermatology, University of California Irvine, School of Medicine, Irvine, CA, USA. · Center for Surgery and Public Health, Brigham and Women's Hospital, Boston, MA, USA. · Yale School of Medicine, New Haven, CT, USA. · Melanoma Center and Center for Immuno-Oncology, Dana-Farber Cancer Center, Boston, MA, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Neurosurgery, Brigham and Women's Hospital, Computational Neuroscience Outcomes Center, Boston, MA, USA. · Harvard Medical School, Boston, MA, USA. jiorgulescu@bwh.harvard.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. jiorgulescu@bwh.harvard.edu. · Department of Neurosurgery, Brigham and Women's Hospital, Computational Neuroscience Outcomes Center, Boston, MA, USA. jiorgulescu@bwh.harvard.edu. · Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA. jiorgulescu@bwh.harvard.edu. ·Cancer Immunol Immunother · Pubmed #30191256.

ABSTRACT: BACKGROUND: Immune checkpoint blockade (ICB) and BRAF METHODS: Patients who presented with cutaneous melanoma during 2004-2015 using the National Cancer Database, which comprises > 70% of all newly diagnosed cancers in the U.S., were evaluated for predictors of presenting with stage 4 disease and receiving ICB, and for their associated unadjusted and risk-adjusted overall survival (OS). RESULTS: 17,975 patients presented with stage 4 metastatic cutaneous melanoma. Overall, patients who presented after the FDA's initial approvals (starting in 2011) for ICB and BRAF CONCLUSIONS: In a national "real-life" treatment population, we show that the wide availability of the novel treatment modalities ICB and BRAF

24 Article Response to single agent PD-1 inhibitor after progression on previous PD-1/PD-L1 inhibitors: a case series. 2017

Martini, Dylan J / Lalani, Aly-Khan A / Bossé, Dominick / Steinharter, John A / Harshman, Lauren C / Hodi, F Stephen / Ott, Patrick A / Choueiri, Toni K. ·Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave D1230, Boston, MA, 02215, USA. · Melanoma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. · Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, Boston, MA, 02215, USA. · Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave D1230, Boston, MA, 02215, USA. Toni_Choueiri@dfci.harvard.edu. ·J Immunother Cancer · Pubmed #28807048.

ABSTRACT: BACKGROUND: Monoclonal antibodies targeting the PD-1/PD-L1 axis have gained increasing attention across many solid tumors and hematologic malignancies due to their efficacy and favorable toxicity profile. With more than 1 agent now FDA-approved in a wide variety of tumor types, and with others in clinical trials, it is becoming more common that patients present to clinic for potential treatment with a second PD-1/PD-L1 inhibitor. CASE PRESENTATION: In this report, we present two patients with renal cell carcinoma and one with melanoma who received PD-1/PD-L1 inhibitors. Upon progression on their first-line PD-1/PD-L1 inhibitors, these patients received a different PD-1 inhibitor (nivolumab in all cases) and all had progressive disease as their best response to the subsequent PD-1 inhibitor. The reported clinical information focuses on the course of the disease and the responses to all treatment regimens. CONCLUSIONS: Clinicians should refrain from using multiple PD-1/PD-L1 inhibitors sequentially outside of clinical trials until there is sufficient data to support this practice routinely. Prospective studies that allow prior treatment with PD-1/PD-L1 are needed to validate the efficacy and safety of these drugs in the second line or later setting. Furthermore, ongoing efforts that aim to identify mechanisms of resistance to immunotherapy will be informative and may ultimately assist physicians in select the optimal treatment following progression on PD-1/PD-L1 inhibitor.

25 Article Regression of multifocoal in transit melanoma metastases after palliative resection of dominant masses and 2 years after treatment with ipilimumab. 2017

Moreira, Raphael B / Hamieh, Lana / Gjini, Evisa / Lako, Ana / Krajewski, Katherine M / Yoon, Charles H / Ott, Patrick A. ·Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. · Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. · Department of Imaging, Dana Farber Cancer Institute, Brigham and Women's Hospital Harvard Medical School, Boston, MA, USA. · Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA. Patrick_Ott@dfci.harvard.edu. · Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Patrick_Ott@dfci.harvard.edu. · Melanoma Disease Center & Center for Immuno-Oncology, Dana Farber Cancer Institute Harvard Medical School, Boston, MA, 02215, USA. Patrick_Ott@dfci.harvard.edu. ·J Immunother Cancer · Pubmed #28716097.

ABSTRACT: BACKGROUND: Spontaneous regression of metastatic melanoma and delayed responses more than one year after treatment with ipilimumab are rarely seen. CASE PRESENTATION: Here, we present the case of a patient with in transit metastases from cutaneous melanoma on his right lower extremity who achieved complete regression of all metastatic lesions 13 months after the first of two consecutive palliative resections of dominant masses and more than two years after treatment with ipilimumab. CONCLUSION: The exact cause of our patient's sudden onset of tumor regression remains speculative. We hypothesize that the operative trauma followed by the postoperative infections augmented an innate immune response.

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