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Clinical trial metastatic melanoma

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https://www.readbyqxmd.com/read/28104840/tumor-aneuploidy-correlates-with-markers-of-immune-evasion-and-with-reduced-response-to-immunotherapy
#1
Teresa Davoli, Hajime Uno, Eric C Wooten, Stephen J Elledge
Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8(+) T cells, and increased expression of cell proliferation markers...
January 20, 2017: Science
https://www.readbyqxmd.com/read/28103611/phase-ii-randomised-discontinuation-trial-of-the-met-vegf-receptor-inhibitor-cabozantinib-in-metastatic-melanoma
#2
Adil Daud, Harriet M Kluger, Razelle Kurzrock, Frauke Schimmoller, Aaron L Weitzman, Thomas A Samuel, Ali H Moussa, Michael S Gordon, Geoffrey I Shapiro
BACKGROUND: A phase II randomised discontinuation trial assessed cabozantinib (XL184), an orally bioavailable inhibitor of tyrosine kinases including VEGF receptors, MET, and AXL, in a cohort of patients with metastatic melanoma. METHODS: Patients received cabozantinib 100 mg daily during a 12-week lead-in. Patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumours (RECIST) at week 12 were randomised to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and postrandomisation progression-free survival (PFS)...
January 19, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28099369/the-cessation-of-anti-pd-1-antibodies-of-complete-responders-in-metastatic-melanoma
#3
Rahul Ladwa, Victoria Atkinson
The optimal duration of PD-1 antibodies for metastatic melanoma is unknown. In previous trials, there has been the potential to cease therapy if the patient achieves a complete response (CR). We aimed to assess the outcomes of patients who had ceased anti-PD-1 antibodies in this setting. A retrospective review was carried out of CR to PD-1-based therapy across two institutions. Patients were from the Pembrolizumab Named Patient Program (PEM NPP), Nivolumab monotherapy (NIVO), and reimbursed Pembrolizumab (r PEM)...
January 17, 2017: Melanoma Research
https://www.readbyqxmd.com/read/28093487/a-pilot-trial-of-the-combination-of-vemurafenib-with-adoptive-cell-therapy-in-patients-with-metastatic-melanoma
#4
Drew C Deniger, Mei Li M Kwong, Anna Pasetto, Mark E Dudley, John R Wunderlich, Michelle M Langhan, Chyi-Chia Richard Lee, Steven A Rosenberg
PURPOSE: This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist of BRAF(V600) mutations, and tumor-infiltrating lymphocytes (TIL) for the treatment of metastatic melanoma. EXPERIMENTAL DESIGN: A metastatic tumor was resected for growth of TILs, and patients were treated with vemurafenib for 2 weeks, followed by resection of a second lesion. Patients then received a nonmyeloablative preconditioning regimen, infusion of autologous TILs, and high-dose interleukin-2 administration...
January 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28087644/u-s-fda-approval-summary-nivolumab-for-treatment-of-unresectable-or-metastatic-melanoma-following-progression-on-ipilimumab
#5
Maitreyee Hazarika, Meredith K Chuk, Marc R Theoret, Sirisha Mushti, Kun He, Shawna L Weis, Alexander H Putman, Whitney S Helms, Xianhua Cao, Hongshan Li, Hong Zhao, Liang Zhao, Joel Welch, Laurie Graham, Meredith Libeg, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
On December 22, 2014, the U. S. Food and Drug Administration (FDA) granted accelerated approval to nivolumab (OPDIVO®, Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation-positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received nivolumab 3 mg/kg intravenously every 2 weeks with at least 6 months follow-up in an ongoing, randomized, open-label, active-controlled clinical trial...
January 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28073844/fda-approval-of-nivolumab-for-the-first-line-treatment-of-patients-with-brafv600-wild-type-unresectable-or-metastatic-melanoma
#6
Julia A Beaver, Marc R Theoret, Sirisha Mushti, Kun He, Meredith Libeg, Kirsten Goldberg, Rajeshwari Sridhara, Amy E McKee, Patricia Keegan, Richard Pazdur
On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO®, Bristol Myers Squibb, Co.) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the U.S. allocated 418 patients to receive nivolumab 3mg/kg intravenously every 2 weeks (n=210) or dacarbazine 1000mg/m2 intravenously every 3 weeks (n=208). Patients with disease progression who met protocol-specified criteria (~25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28064546/targeting-protein-kinase-b3-akt3-signaling-in-melanoma
#7
SubbaRao V Madhunapantula, Gavin P Robertson
Deregulated Akt activity leading to apoptosis inhibition, enhanced proliferation and drug resistance has been shown to be responsible for 35-70% of advanced metastatic melanomas. Of the three isoforms, the majority of melanomas have elevated Akt3 expression and activity. Hence, potent inhibitors targeting Akt are urgently required, which is possible only if (a) the factors responsible for the failure of Akt inhibitors in clinical trials is known; and (b) the information pertaining to synergistically acting targeted therapeutics is available...
January 9, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28064454/hgf-met-in-cancer-progression-and-biomarker-discovery
#8
REVIEW
Kunio Matsumoto, Masataka Umitsu, Dinuka M De Silva, Arpita Roy, Donald P Bottaro
Signaling driven by hepatocyte growth factor (HGF) and MET receptor facilitates conspicuous biological responses such as epithelial cell migration, 3-D morphogenesis, and survival. The dynamic migration and promotion of cell survival induced by MET activation are bases respectively for invasion-metastasis and resistance against targeted drugs in cancers. Recent studies indicated that MET in tumor-derived exosomes facilitates metastatic niche formation and metastasis in malignant melanoma. In lung cancer, gene amplification-induced MET activation and ligand-dependent MET activation in autocrine/paracrine manner are causes for resistance to EGF receptor tyrosine kinase inhibitors and ALK inhibitors...
January 8, 2017: Cancer Science
https://www.readbyqxmd.com/read/28058658/combination-treatment-of-patients-with-braf-mutant-melanoma-a-new-standard-of-care
#9
REVIEW
Ester Simeone, Antonio M Grimaldi, Lucia Festino, Vito Vanella, Marco Palla, Paolo A Ascierto
Raf-mitogen-activated protein kinase (Raf-MAPK) pathway inhibition with the BRAF inhibitors vemurafenib and dabrafenib, alone or in combination with a MEK inhibitor, has become a standard therapeutic approach in patients with BRAF-mutated metastatic melanoma. Both vemurafenib and dabrafenib have shown good safety and efficacy as monotherapy compared with chemotherapy. However, the duration of response is limited in the majority of patients treated with BRAF inhibitor monotherapy because of the development of acquired resistance...
January 6, 2017: BioDrugs: Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
https://www.readbyqxmd.com/read/28055269/targeting-pd-1-pathway-a-new-hope-for-gastrointestinal-cancers
#10
Burak Bilgin, Mehmet An Sendur, Muhammed Bülent Akıncı, Didem Şener Dede, Bülent Yalçın
BACKGROUND: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most of the Gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aimed to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in the era of published or reported recent studies...
January 5, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28045747/next-generation-sequencing-reveals-pathway-activations-and-new-routes-to-targeted-therapies-in-cutaneous-metastatic-melanoma
#11
J Andrew Carlson, Jose Candido Caldeira Xavier, Ashley Tarasen, Christine E Sheehan, Geoff Otto, Vincent A Miller, Philip J Stephens, Julia A Elvin, Jo-Anne Vergilio, James Suh, Laurie M Gay, Jeffrey S Ross
BACKGROUND: Comprehensive genomic profiling of clinical samples by next-generation sequencing (NGS) can identify one or more therapy targets for the treatment of metastatic melanoma (MM) with a single diagnostic test. METHODS: NGS was performed on hybridization-captured, adaptor ligation-based libraries using DNA extracted from 4 formalin-fixed paraffin-embedded sections cut at 10 microns from 30 MM cases. The exons of 182 cancer-related genes were fully sequenced using the Illumina HiSeq 2000 at an average sequencing depth of 1098X and evaluated for genomic alterations (GAs) including point mutations, insertions, deletions, copy number alterations, and select gene fusions/rearrangements...
January 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28039178/the-natural-history-and-patterns-of-metastases-from-mucosal-melanoma-an-analysis-of-706-prospectively-followed-patients
#12
B Lian, C L Cui, L Zhou, X Song, X S Zhang, D Wu, L Si, Z H Chi, X N Sheng, L L Mao, X Wang, B X Tang, X Q Yan, Y Kong, J Dai, S M Li, X Bai, N Zheng, Charles M Balch, J Guo
BACKGROUND: We examined whether mucosal melanomas are different in their clinical course and patterns of metastases when arising from different anatomic sites. Our hypothesis was that metastatic behavior would differ from primary mucosal melanomas at different anatomical sites. PATIENTS AND METHODS: Clinical and pathological data from 706 patients were compared for their stage distribution, patterns of metastases, CKIT/BRAF mutation status, and overall survival for different anatomical sites...
December 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28030784/dutch-melanoma-treatment-registry-quality-assurance-in-the-care-of-patients-with-metastatic-melanoma-in-the-netherlands
#13
Anouk Jochems, Maartje G Schouwenburg, Brenda Leeneman, Margreet G Franken, Alfons J M van den Eertwegh, John B A G Haanen, Hans Gelderblom, Carin A Uyl-de Groot, Maureen J B Aarts, Franchette W P J van den Berkmortel, Willeke A M Blokx, Mathilde C Cardous-Ubbink, Gerard Groenewegen, Jan Willem B de Groot, Geke A P Hospers, Ellen Kapiteijn, Rutger H Koornstra, Wim H Kruit, Marieke W Louwman, Djura Piersma, Rozemarijn S van Rijn, Albert J Ten Tije, Gerard Vreugdenhil, Michel W J M Wouters, Jacobus J M van der Hoeven
BACKGROUND: In recent years, the treatment of metastatic melanoma has changed dramatically due to the development of immune checkpoint and mitogen-activated protein (MAP) kinase inhibitors. A population-based registry, the Dutch Melanoma Treatment Registry (DMTR), was set up in July 2013 to assure the safety and quality of melanoma care in the Netherlands. This article describes the design and objectives of the DMTR and presents some results of the first 2 years of registration. METHODS: The DMTR documents detailed information on all Dutch patients with unresectable stage IIIc or IV melanoma...
December 25, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/28013301/synthesis-of-a-sulfonimidamide-based-analog-of-tasisulam-and-its-biological-evaluation-in-the-melanoma-cell-lines-skmel23-and-a375
#14
Anne-Dorothee Steinkamp, Laurenz Schmitt, Xiaoyun Chen, Katharina Fietkau, Ruth Heise, Jens M Baron, Carsten Bolm
Tasisulam is a promising antitumor agent with complex pharmacology, which is used as an antiproliferative agent in patients with metastatic melanoma and other solid tumors. Phase 2 melanoma studies showed promising results but had to be stopped because of insufficient tasisulam clearance leading to toxic side effects. To reduce the negative effects of tasisulam, we synthesized a novel sulfonimidamide-based analog to evaluate its antiproliferative effects in comparison to the original compound by performing a cell proliferation assay in melanoma cell lines SKMel23 and A375...
December 24, 2016: Skin Pharmacology and Physiology
https://www.readbyqxmd.com/read/28009966/novel-approaches-in-genetic-characterization-and-targeted-therapy-for-brain-metastases
#15
Brandyn A Castro, Ruby Kuang, Priscilla K Brastianos
Metastases to the brain are a common complication of various cancers and are associated with poor prognosis. Management of these patients requires a multidisciplinary approach including whole-brain radiation therapy, stereotactic radiosurgery, surgical resection, chemotherapy, and supportive treatment. Because of recent technological advancements in genomics, our understanding of the genetics of brain metastases is rapidly advancing. This has led to the discovery of many potential genetic therapeutic targets in metastatic brain lesions...
November 2016: Discovery Medicine
https://www.readbyqxmd.com/read/28003758/braf-inhibitors-and-radiotherapy-for-melanoma-brain-metastases-potential-advantages-and-disadvantages-of-combination-therapy
#16
REVIEW
Mudit Chowdhary, Kirtesh R Patel, Hasan H Danish, David H Lawson, Mohammad K Khan
Melanoma is an aggressive malignancy that frequently spreads to the brain, resulting in rapid deterioration in both quality and quantity of life. Historically, treatment options for melanoma brain metastases (MBM) have predominantly consisted of surgery and radiotherapy. While these options can help provide local control, the majority of patients still develop intracranial progression. Indeed, novel therapeutic options, including molecularly targeted agents and immunotherapy, have improved outcomes and are now changing the role of radiotherapy...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28003234/fingolimod-gilenya-and-melanoma
#17
Christopher Lee Robinson, Mary Guo
The Food and Drug Administration (FDA) had approved fingolimod usage for multiple sclerosis in 2010. Melanoma after the usage of fingolimod immunomodulation was reported rarely in clinical trials, and only two case reports exist in the published literature, both occurring in Europe. Most of the incidences reported in clinical trials were in-situ, whereas both case reports were of malignant melanoma. Fingolimod has been found to inhibit metastatic melanoma growth in a mouse model that depends on vascular endothelial growth factor (VEGF)-induced angiogenesis for metastasis...
December 21, 2016: BMJ Case Reports
https://www.readbyqxmd.com/read/27999751/responses-to-immune-checkpoint-inhibitors-in-nonagenarians
#18
Romany A N Johnpulle, Robert M Conry, Jeffrey A Sosman, Igor Puzanov, Douglas B Johnson
The incidence of melanoma continues to rise with the most rapid increase seen in the elderly population. Historically, elderly patients with advanced melanoma have had dismal clinical outcomes, in part, due to distinct tumor biology, and often ineligibility for effective therapies during their development. In addition, due to relatively few geriatric patients being accrued to clinical trials of novel immunotherapeutics, there is a paucity of data regarding their safety and efficacy. Herein, we present the clinical course of three consecutive nonagenarians (≥90 y old) with metastatic melanoma, who were treated with single-agent or combination immune checkpoint inhibitors...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27999747/immune-response-and-long-term-clinical-outcome-in-advanced-melanoma-patients-vaccinated-with-tumor-mrna-transfected-dendritic-cells
#19
Jon Amund Kyte, Steinar Aamdal, Svein Dueland, Stein Sæbøe-Larsen, Else Marit Inderberg, Ulf Erik Madsbu, Eva Skovlund, Gustav Gaudernack, Gunnar Kvalheim
The most effective anticancer immune responses are probably directed against patient-specific neoantigens. We have developed a melanoma vaccine targeting this individual mutanome based on dendritic cells (DCs) loaded with autologous tumor-mRNA. Here, we report a phase I/II trial evaluating toxicity, immune response and clinical outcome in 31 metastatic melanoma patients. The first cohort (n = 22) received the vaccine without any adjuvant; the next cohort (n = 9) received adjuvant IL2. Each subject received four weekly intranodal or intradermal injections, followed by optional monthly vaccines...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27991907/immunomodulating-property-of-mapk-inhibitors-from-translational-knowledge-to-clinical-implementation
#20
Mario Mandalà, Francesco De Logu, Barbara Merelli, Romina Nassini, Daniela Massi
Treatment of metastatic melanoma was radically changed by the introduction of inhibitors of BRAF, an oncogene mutated in 40-50% of patients. Another area of advancement was the use of immunotherapy, and specifically, immune checkpoint inhibitors. There is compelling evidence that oncogenic BRAF, in addition to driving melanoma proliferation, differentiation and survival, induces T-cell suppression directly through the secretion of inhibitory cytokines or through membrane expression of co-inhibitory molecules such as the PD-1 ligands PD-L1 or PD-L2...
December 19, 2016: Laboratory Investigation; a Journal of Technical Methods and Pathology
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