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Clinical trials for metastatic melanoma

Marta Polkowska, Edyta Czepielewska, Małgorzata Kozłowska-Wojciechowska
Advanced melanoma is related to a very grim prognosis and fast progression. Until recently, there has been no indicated treatment that would affect the disease's outcome. However, the progress in immunotherapy and molecular therapy has significantly changed the unfavourable prognosis of melanoma progression and its short survival rate. Both approaches have improved patients' outcomes and provided renewed hope for successful treatment. Moreover, in order to further enhance patients' outcomes and to avoid mechanisms of tumour resistance, investigators attempted a combined approach...
December 2016: Current Treatment Options in Oncology
Troels Holz Borch, Lotte Engell-Noerregaard, Trine Zeeberg Iversen, Eva Ellebaek, Özcan Met, Morten Hansen, Mads Hald Andersen, Per Thor Straten, Inge Marie Svane
INTRODUCTION: Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant melanoma (MM)...
2016: Oncoimmunology
M Arenbergerova, I Mrazova, J Horazdovsky, E Sticova, A Fialova, P Arenberger
Vemurafenib is a selective inhibitor of the BRAF-kinase approved for the treatment of metastatic melanoma harboring BRAF mutation. Skin toxicity, including maculopapular exanthema, photosensitivity and keratoacanthoma, are the most common treatment-related adverse events of vemurafenib, affecting more than 90% of patients (1,2). It rarely presents with intense severity, with less than 1% of grade-4 toxicities reported in clinical trials (3,4). This article is protected by copyright. All rights reserved.
October 14, 2016: Journal of the European Academy of Dermatology and Venereology: JEADV
Jessie Signorelli, Arpita Shah Gandhi
OBJECTIVE: To review and summarize data on cobimetinib, which was approved by the US Food and Drug Administration (FDA) in November 2015 for use in combination with vemurafenib for unresectable or metastatic melanoma with a BRAFV600E or V600K mutation. DATA SOURCES: A literature search using PubMed was conducted using the terms cobimetinib, MEK inhibitor, and melanoma from January 2000 to June 2016. STUDY SELECTION AND DATA EXTRACTION: The literature search was confined to human studies published in English...
October 3, 2016: Annals of Pharmacotherapy
Ana Cebollero, Teresa Puértolas, Isabel Pajares, Lourdes Calera, Antonio Antón
A retrospective observational study was conducted on patients diagnosed with serine/threonine-protein kinase B-Raf (BRAF)-mutated metastatic melanoma, who underwent first-line therapy with BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors (vemurafenib, dabrafenib or a combination of dabrafenib and trametinib) at the Miguel Servet University Hospital (Zaragoza, Spain) between November, 2011 and August, 2015. The aim of this study was to analyse the toxicity produced by BRAF and MEK inhibitors...
October 2016: Molecular and Clinical Oncology
Jin Hai Zheng, Jung-Joon Min
Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside tumor tissues and inhibit tumor growth. Among them, attenuated Salmonella typhimurium (S. typhimurium) has been widely studied in animal cancer models and Phase I clinical trials in human patients. S. typhimurium genes are easily manipulated; thus diverse attenuated strains of S. typhimurium have been designed and engineered as tumor-targeting therapeutics or drug delivery vehicles that show both an excellent safety profile and therapeutic efficacy in mouse models...
September 2016: Chonnam Medical Journal
Susan M Hiniker, Sunil A Reddy, Holden T Maecker, Priyanka B Subrahmanyam, Yael Rosenberg-Hasson, Susan M Swetter, Saurabh Saha, Lei Shura, Susan J Knox
PURPOSE: Local radiation therapy (RT) combined with systemic anti-cytotoxic T-lymphocyte-associated protein-4 immunotherapy may enhance induction of systemic antimelanoma immune responses. The primary objective of the present trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. The secondary objectives included laboratory assessment of induction of antimelanoma immune responses. METHODS AND MATERIALS: In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles...
November 1, 2016: International Journal of Radiation Oncology, Biology, Physics
U Leiter, R Gutzmer, M Alter, C Ulrich, A S Lonsdorf, M M Sachse, U Hillen
Squamous cell carcinoma (SCC) of the skin accounts for 20 % of non-melanoma skin cancer and is one of the most frequent types of cancer in Caucasian populations. Diagnosis is based on the clinical features and should be histopathologically confirmed to adequately address the prognosis and treatment. Complete surgical excision with histopathological control of excision margins is the gold standard in the treatment of primary SCC. Sentinel lymph node biopsies (SLNB) can be considered in SCC with a tumor thickness of >6 mm but there is currently no evidence concerning prognostic and therapeutic effects...
September 28, 2016: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
Gregory S Alexander, Joshua D Palmer, Madalina Tuluc, Jianqing Lin, Adam P Dicker, Voichita Bar-Ad, Larry A Harshyne, Jennifer Louie, Colette M Shaw, D Craig Hooper, Bo Lu
BACKGROUND: Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient's own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20-40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment...
2016: Journal of Hematology & Oncology
Kevin Wood, Jason J Luke
PURPOSE OF REVIEW: The therapeutic landscape for metastatic melanoma has been revolutionized in recent years. This review will discuss existing evidence for therapeutic approaches for BRAF-mutated metastatic melanoma. RECENT FINDINGS: Clinical trials involving combined BRAF/MEK inhibition with either vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown improved overall survival compared to monotherapy with BRAF inhibitors alone. In a subset of patients with good prognostic factors, long-term clinical benefit has been noted...
November 2016: Current Oncology Reports
Lindsay A Edmondson, Leticia V Smith, Alka Mallik
The programmed-death-1 inhibitors selectively block programmed-death-1 interaction with its receptor, which restores active T-cell response directed at tumor cells, inducing an anti-tumor effect. This nonspecific activation of the immune system can also lead to a wide spectrum of side effects. Nivolumab has been used effectively to prolong survival in patients with metastatic melanoma and is recommended as a category 1 agent for systemic therapy in metastatic or unresectable melanoma per the National Comprehensive Cancer Network guidelines...
September 8, 2016: Journal of Oncology Pharmacy Practice
Paolo A Ascierto, Vito Vanella, Antonio Maria Grimaldi, Festino Lucia, Marco Palla, Ester Simeone, Nicola Mozzillo
The anti-PD-1 agent, nivolumab, has been approved both as monotherapy and in combination with ipilimumab for the treatment of unresectable or metastatic melanoma in the USA and European Union. Here we present the case of a patient with treatment-naive, metastatic mucosal melanoma and baseline LDH approximately seven times the upper limit of normal. The patient was enrolled in a clinical trial (CheckMate 066) and achieved a partial response, followed by a durable complete response with nivolumab treatment. The patient's LDH levels were documented in each cycle and dropped markedly within 2 months, when partial response to treatment was already evident...
September 7, 2016: Cancer Immunology, Immunotherapy: CII
Elizabeth Marie Krcik
PURPOSE: To analyze current preclinical trials and early clinical trials on the effects of concomitant anti-programmed death ligand 1 (anti-PD-L1) immunotherapy and radiation therapy on progression-free survival (PFS) and overall survival (OS) for advanced melanoma and metastatic non-small cell lung cancer (NSCLC) patients. METHODS: A literature review was conducted to find current articles about radiation and anti-PD-L1 combinatorial therapy to gain knowledge about T-lymphocyte (T-cell) mediated immune responses, preclinical mouse tumor trials, and early clinical trials...
September 2016: Radiologic Technology
Yasuto Akiyama, Chizu Nonomura, Ryota Kondou, Haruo Miyata, Tadashi Ashizawa, Chie Maeda, Koichi Mitsuya, Nakamasa Hayashi, Yoko Nakasu, Ken Yamaguchi
Immune checkpoint antibody-mediated blockade has gained attention as a new cancer immunotherapy strategy. Accumulating evidence suggests that this therapy imparts a survival benefit to metastatic melanoma and non-small cell lung cancer patients. A substantial amount of data on immune checkpoint antibodies has been collected from clinical trials; however, the direct effect of the antibodies on human peripheral blood mononuclear cells (PBMCs) has not been exclusively investigated. In this study, we developed an anti-programmed death-1 (PD-1) antibody (with biosimilarity to nivolumab) and examined the effects of the antibody on PBMCs derived from cancer patients...
September 2016: International Journal of Oncology
Helena Linardou, Helen Gogas
Checkpoint inhibitors have revolutionized the treatment of patients with metastatic melanoma offering improved responses and significant survival benefit. These agents are now approved for the treatment of metastatic melanoma, squamous and non-squamous non-small cell lung cancer (NSCLC) and kidney cancer, while they are now being investigated in a range of other malignancies. In addition, another anti-PD-L1 monoclonal antibody (atezolizumab) was recently approved for urothelial cancer. Ipilimumab, an anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody and the anti-PD-1 agents nivolumab and pembrolizumab have followed large clinical development programs, therefore, information regarding their safety and toxicity profile is readily available...
July 2016: Annals of Translational Medicine
Xinqi Wu, Anita Giobbie-Hurder, Xiaoyun Liao, Donald Lawrence, David McDermott, Jun Zhou, Scott Rodig, F Stephen Hodi
Immune recognition of tumor targets by specific cytotoxic lymphocytes is essential for the effective rejection of tumors. A phase I clinical trial of ipilimumab (an antibody that blocks CTLA-4 function) in combination with bevacizumab (an antibody that inhibits angiogenesis) in patients with metastatic melanoma found favorable clinical outcomes were associated with increased tumor endothelial activation and lymphocyte infiltration. To better understand the underlying mechanisms, we sought features and factors that changed as a function of treatment in patients...
October 2016: Cancer Immunology Research
Ivar S Jensen, Emily Zacherle, Christopher M Blanchette, Jie Zhang, Wes Yin
BACKGROUND: Although a number of monoimmunotherapies and targeted therapies are available to treat BRAF+ advanced melanoma, response rates remain relatively low in the range of 22-53% with progression-free survival (PFS) in the range of 4.8-8.8 months. Recently, combination targeted therapies have improved response rates to about 66-69%, PFS to 11.0-12.6 months and overall survival (OS) to 25.1-25.6 months. While combination immunotherapies have improved response rates of 67 compared with 19-29% with monotherapies and improved PFS of 11...
2016: Drugs in Context
Alexander N Shoushtari, Rodrigo R Munhoz, Deborah Kuk, Patrick A Ott, Douglas B Johnson, Katy K Tsai, Suthee Rapisuwon, Zeynep Eroglu, Ryan J Sullivan, Jason J Luke, Tara C Gangadhar, April K S Salama, Varina Clark, Clare Burias, Igor Puzanov, Michael B Atkins, Alain P Algazi, Antoni Ribas, Jedd D Wolchok, Michael A Postow
BACKGROUND: Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS: A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials...
August 17, 2016: Cancer
Alain P Algazi, Katy K Tsai, Alexander N Shoushtari, Rodrigo R Munhoz, Zeynep Eroglu, Josep M Piulats, Patrick A Ott, Douglas B Johnson, Jimmy Hwang, Adil I Daud, Jeffrey A Sosman, Richard D Carvajal, Bartosz Chmielowski, Michael A Postow, Jeffrey S Weber, Ryan J Sullivan
BACKGROUND: Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized. METHODS: Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis...
August 17, 2016: Cancer
Karly P Garnock-Jones
Talimogene laherparepvec (Imlygic™) is a first-in-class oncolytic viral immunotherapy derived from herpes simplex virus type 1, which has been genetically modified to increase tumour selectivity and stimulate antitumour immune response. This article reviews the pharmacological properties of intralesional talimogene laherparepvec and its clinical efficacy and tolerability in patients with unresectable metastatic melanoma. In the phase III OPTiM trial, talimogene laherparepvec was more effective than subcutaneous human granulocyte-macrophage colony-stimulating factor (GM-CSF), both in patients with stage IIIB-IV melanoma [intention-to-treat (ITT) population] and in those with stage IIIB-IVM1a disease (in an exploratory subgroup analysis)...
October 2016: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
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