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Melanoma: HELP
Articles by Christian H. Ottensmeier
Based on 19 articles published since 2010
(Why 19 articles?)
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Between 2010 and 2020, C. Ottensmeier wrote the following 19 articles about Melanoma.
 
+ Citations + Abstracts
1 Guideline Uveal Melanoma UK National Guidelines. 2015

Nathan, P / Cohen, V / Coupland, S / Curtis, K / Damato, B / Evans, J / Fenwick, S / Kirkpatrick, L / Li, O / Marshall, E / McGuirk, K / Ottensmeier, C / Pearce, N / Salvi, S / Stedman, B / Szlosarek, P / Turnbull, N / Anonymous4080839. ·Mount Vernon Cancer Centre, Northwood, Middlesex, UK. Electronic address: nathan.pd@gmail.com. · Ocular Oncology Service, St Bartholomew's and Moorfields Eye Hospital, London, UK. · Department Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · OcuMel UK, UK. · Royal Liverpool University Hospital, Liverpool, UK. · University Hospital Aintree, Liverpool, UK. · Patient Representative, UK. · Moorfields Eye Hospital, London, UK. · The Clatterbridge Cancer Centre, NHS Foundation Trust, Liverpool, UK. · Southampton University Hospitals and University of Southampton, UK. · University Hospital Southampton, Southampton, UK. · Royal Hallamshire Hospital, Sheffield, UK. · Southampton University Hospitals, NHS Trust, Southampton, UK. · St Bartholomew's Hospital, UK; Barts Cancer Institute, Queen Mary University of London, London, UK. · Project Manager, London, UK. ·Eur J Cancer · Pubmed #26278648.

ABSTRACT: The United Kingdom (UK) uveal melanoma guideline development group used an evidence based systematic approach (Scottish Intercollegiate Guidelines Network (SIGN)) to make recommendations in key areas of uncertainty in the field including: the use and effectiveness of new technologies for prognostication, the appropriate pathway for the surveillance of patients following treatment for primary uveal melanoma, the use and effectiveness of new technologies in the treatment of hepatic recurrence and the use of systemic treatments. The guidelines were sent for international peer review and have been accredited by NICE. A summary of key recommendations is presented. The full documents are available on the Melanoma Focus website.

2 Clinical Trial DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. 2014

Gupta, A / Love, S / Schuh, A / Shanyinde, M / Larkin, J M / Plummer, R / Nathan, P D / Danson, S / Ottensmeier, C H / Lorigan, P / Collins, L / Wise, A / Asher, R / Lisle, R / Middleton, M R. ·Department of Oncology, Oxford University Hospitals NHS Trust, Oxford. ·Ann Oncol · Pubmed #24567366.

ABSTRACT: BACKGROUND: Treatment options for wild-type BRAF melanoma patients remain limited. Selumetinib, a MEK 1/2 inhibitor, suppresses pERK levels independent of BRAF and NRAS mutation status, and combination with docetaxel has demonstrated synergy in xenograft models. The aim of this study was to assess the efficacy and safety of selumetinib plus docetaxel as first-line treatment in patients with wild-type BRAF advanced melanoma. PATIENTS AND METHODS: In this double-blind multicentre phase II trial patients with wild-type BRAF melanoma were randomized (1:1) to docetaxel with selumetinib or placebo. Docetaxel 75 mg/m(2) was administered intravenously every 3 weeks up to six cycles. Selumetinib 75 mg or placebo was given orally twice daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Tumour NRAS mutation status was analysed retrospectively and correlated with treatment outcomes. RESULTS: Eighty-three patients were randomized to docetaxel plus selumetinib (n = 41) or docetaxel plus placebo (n = 42). The PFS hazard ratio (HR) (selumetinib:placebo) was 0.75 [90% confidence interval (CI) 0.50-1.14; P = 0.130], with a median PFS of 4.23 months (90% CI 3.63-6.90) for docetaxel plus selumetinib and 3.93 months (90% CI 2.07-4.16) for docetaxel alone. There was no significant difference in overall survival. The objective response rate was 32% with selumetinib versus 14% with placebo (P = 0.059). In a retrospective subset analysis, NRAS mutation status did not affect significantly upon clinical outcomes in either arm. The combination of docetaxel and selumetinib could be administered effectively to patients with metastatic melanoma, although the combination was less well tolerated than docetaxel alone. CONCLUSIONS: The combination of docetaxel with selumetinib showed no significant improvement in PFS compared with docetaxel alone, although more patients showed a response to combination therapy. We found no evidence to support using tumour NRAS mutation as a basis for selecting patients for combined MEK inhibitor and chemotherapy. CLINICAL TRIAL: DOC-MEK (EudraCT no: 2009-018153-23).

3 Clinical Trial Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. 2012

Revicki, Dennis A / van den Eertwegh, Alfons J M / Lorigan, Paul / Lebbe, Celeste / Linette, Gerald / Ottensmeier, Christian H / Safikhani, Shima / Messina, Marianne / Hoos, Axel / Wagner, Samuel / Kotapati, Srividya. ·United BioSource Corporation, Bethesda, MD 20814, USA. dennis.revicki@unitedbiosource.com ·Health Qual Life Outcomes · Pubmed #22694829.

ABSTRACT: BACKGROUND: In an international, randomized Phase III trial ipilimumab demonstrated a significant overall survival benefit in previously treated advanced melanoma patients. This report summarizes health-related quality of life (HRQL) outcomes for ipilimumab with/without gp100 vaccine compared to gp100 alone during the clinical trial's 12 week treatment induction period. METHODS: The Phase III clinical trial (MDX010-20) was a double-blind, fixed dose study in 676 previously treated advanced unresectable stage III or IV melanoma patients. Patients were randomized 3:1:1 to receive either ipilimumab (3 mg/kg q3w x 4 doses) + gp100 (peptide vaccine; 1 mg q3w x 4 doses; ipilimumab plus gp100, n = 403); gp100 vaccine + placebo (gp100 alone, n = 136); or ipilimumab + placebo (ipilimumab alone, n = 137). The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) assessed HRQL. Baseline to Week 12 changes in EORTC QLQ-C30 function, global health status, and symptom scores were analyzed for ipilimumab with/without gp100 vaccine compared to gp100 alone. Mean change in scores were categorized "no change" (0-5), "a little" (5-10 points), "moderate" (10-20 points), and "very much" (>20). RESULTS: In the ipilimumab plus gp100 and ipilimumab alone groups, mean changes from baseline to Week 12 generally indicated "no change" or "a little" impairment across EORTC QLQ-C30 global health status, function, and symptom subscales. Significant differences in constipation, favoring ipilimumab, were observed (p < 0.05). For ipilimumab alone arm, subscales with no or a little impairment were physical, emotional, cognitive, social function, global health, nausea, pain, dyspnea, constipation, and diarrhea subscales. For the gp100 alone group, the observed changes were moderate to large for global health, role function, fatigue, and for pain. CONCLUSIONS: Ipilimumab with/without gp100 vaccine does not have a significant negative HRQL impact during the treatment induction phase relative to gp100 alone in stage III or IV melanoma patients. TRIAL REGISTRATION: Clinicaltrials.gov identification number NCT00094653.

4 Clinical Trial A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma. 2011

O'Day, S / Pavlick, A / Loquai, C / Lawson, D / Gutzmer, R / Richards, J / Schadendorf, D / Thompson, J A / Gonzalez, R / Trefzer, U / Mohr, P / Ottensmeier, C / Chao, D / Zhong, B / de Boer, C J / Uhlar, C / Marshall, D / Gore, M E / Lang, Z / Hait, W / Ho, P / Anonymous1080700. ·The Angeles Clinic and Research Institute, 2001 Santa Monica Boulevard, Suite 560W, Santa Monica, CA, USA. soday@theangelesclinic.org ·Br J Cancer · Pubmed #21750555.

ABSTRACT: BACKGROUND: α(v) integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-α(v)-integrin monoclonal antibody. METHODS: In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1:1:1:1 to 1000 mg m(-2) dacarbazine+placebo (n=32), 1000 mg m(-2) dacarbazine+10 mg kg(-1) intetumumab (n=32), 10 mg kg(-1) intetumumab (n=33), or 5 mg kg(-1) intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics. RESULTS: No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg(-1) intetumumab, and 5 mg kg(-1) intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab-dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1-2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22-30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16-73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred. CONCLUSION: With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.

5 Clinical Trial Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies. 2011

Eisen, T / Marais, R / Affolter, A / Lorigan, P / Robert, C / Corrie, P / Ottensmeier, C / Chevreau, C / Chao, D / Nathan, P D / Jouary, T / Harries, M / Negrier, S / Montegriffo, E / Ahmad, T / Gibbens, I / James, M G / Strauss, U P / Prendergast, S / Gore, M E. ·Department of Oncology (R4), Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. tgqe2@cam.ac.uk ·Br J Cancer · Pubmed #21750549.

ABSTRACT: METHOD: The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study. RESULTS: In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m(-2) dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0). CONCLUSION: Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

6 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.)

7 Clinical Trial Clinical and immunological responses in metastatic melanoma patients vaccinated with a high-dose poly-epitope vaccine. 2010

Dangoor, Adam / Lorigan, Paul / Keilholz, Ulrich / Schadendorf, Dirk / Harris, Adrian / Ottensmeier, Christian / Smyth, John / Hoffmann, Klaus / Anderson, Richard / Cripps, Martin / Schneider, Joerg / Hawkins, Robert. ·Bristol Haematology and Oncology Centre, Horfield Rd, Bristol, BS2 8ED, UK. adamd@doctors.org.uk ·Cancer Immunol Immunother · Pubmed #20043222.

ABSTRACT: BACKGROUND: Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. METHODS: Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-gamma ELISPOT assays. Safety and clinical responses were monitored. RESULTS: Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit-one PR (24 months+), five SD (5 months+) and two mixed responses-seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression (P = 0.037) and 71 week increase in survival (P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. CONCLUSIONS: DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation.

8 Article Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial. 2018

Corrie, P G / Marshall, A / Nathan, P D / Lorigan, P / Gore, M / Tahir, S / Faust, G / Kelly, C G / Marples, M / Danson, S J / Marshall, E / Houston, S J / Board, R E / Waterston, A M / Nobes, J P / Harries, M / Kumar, S / Goodman, A / Dalgleish, A / Martin-Clavijo, A / Westwell, S / Casasola, R / Chao, D / Maraveyas, A / Patel, P M / Ottensmeier, C H / Farrugia, D / Humphreys, A / Eccles, B / Young, G / Barker, E O / Harman, C / Weiss, M / Myers, K A / Chhabra, A / Rodwell, S H / Dunn, J A / Middleton, M R / Anonymous781066. ·Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Warwick Clinical Trials Unit, University of Warwick, Coventry, UK. · Medical Oncology, Mount Vernon Hospital, Northwood, UK. · Department of Medical Oncology, Christie Hospital, Manchester, UK. · Royal Marsden Hospital NHS Trust, London, UK. · Oncology Research, Broomfield Hospital, Chelmsford, UK. · Oncology Department, Leicester Royal Infirmary, Leicester, UK. · Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle upon Tyne, UK. · Leeds Cancer Centre, St James's University Hospital, Leeds, UK. · Weston Park Hospital, Academic Unit of Clinical Oncology, Sheffield, UK. · Cancer & Palliative Care, St. Helen's Hospital, St. Helens, UK. · Oncology Department, Royal Surrey County Hospital, Guildford, UK. · Rosemere Cancer Centre, Royal Preston Hospital, Preston, UK. · Clinical Trials Unit, Beatson WOS Cancer Centre, Glasgow, UK. · Department of Clinical Oncology, Norfolk & Norwich University Hospital, Norwich, UK. · Guy's & St. Thomas' Hospital, Guy's Cancer Centre, London, UK. · Velindre Cancer Centre, Cardiff, UK. · Exeter Oncology Centre, Royal Devon and Exeter Hospital, Exeter, UK. · St George's Hospital, Cancer Centre, London, UK. · Cancer Centre, Queen Elizabeth Hospital, Birmingham, UK. · Sussex Cancer Centre, Royal Sussex County Hospital, Brighton, UK. · Cancer Centre, Ninewells Hospital, Dundee, UK. · Royal Free Hospital, London, UK. · Castle Hill Hospital, Cottingham, UK. · Academic Unit of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK. · CRUK and NIHR Southampton Experimental Cancer Medicine Centre, Southampton University Hospitals NHS Foundation Trust, Southampton, UK. · Oncology Centre, Cheltenham General Hospital, Cheltenham, UK. · Oncology Department, James Cook University Hospital, Middlesbrough, UK. · Oncology Department, Poole Hospital, Dorset, UK. · Department of Oncology, University of Oxford, Oxford, UK. · Experimental Cancer Medicine Centre, Oxford, UK. · Melanoma Focus, Cambridge, UK. · Oxford NIHR Biomedical Research Centre, Oxford, UK. ·Ann Oncol · Pubmed #30010756.

ABSTRACT: Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

9 Article Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial. 2018

Patel, Poulam M / Ottensmeier, Christian H / Mulatero, Clive / Lorigan, Paul / Plummer, Ruth / Pandha, Hardev / Elsheikh, Somaia / Hadjimichael, Efthymios / Villasanti, Naty / Adams, Sally E / Cunnell, Michelle / Metheringham, Rachael L / Brentville, Victoria A / Machado, Lee / Daniels, Ian / Gijon, Mohamed / Hannaman, Drew / Durrant, Lindy G. ·Academic Department of Clinical Oncology, Division of Cancer & Stem Cells, University of Nottingham, Nottingham, UK. · Southampton Experimental Cancer Medicine Centre and Southampton University Hospitals, Faculty of Medicine, Southampton, UK. · St James's University Hospital, Leeds, UK. · Institute of Cancer Sciences, University of Manchester, The Christie NHS Foundation Trust, Manchester, UK. · Northern Institute for Cancer Research, Medical School, University of Newcastle-upon-Tyne and Wear, UK. · Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK. · University of Nottingham, School of Medicine Queen's Medical Centre, Nottingham, UK. · Scancell Limited, Academic Department of Clinical Oncology, University of Nottingham, Nottingham, UK. · Ichor Medical Systems, Inc., San Diego, CA, USA. ·Oncoimmunology · Pubmed #29872563.

ABSTRACT: A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2-8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (

10 Article Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease. 2018

Karydis, Ioannis / Gangi, Alexandra / Wheater, Matthew J / Choi, Junsung / Wilson, Iain / Thomas, Kerry / Pearce, Neil / Takhar, Arjun / Gupta, Sanjay / Hardman, Danielle / Sileno, Sean / Stedman, Brian / Zager, Jonathan S / Ottensmeier, Christian. ·Cancer Sciences Academic Unit, University of Southampton, Southampton, United Kingdom. · University Hospital Southampton, Southampton, United Kingdom. · Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. · Department of Radiology, Moffitt Cancer Center, Tampa, Florida. · Morsani School of Medicine, University of South Florida, Tampa, Florida. ·J Surg Oncol · Pubmed #29284076.

ABSTRACT: BACKGROUND: Metastatic uveal melanoma (UM) carries a poor prognosis; liver is the most frequent and often solitary site of recurrence. Available systemic treatments have not improved outcomes. Melphalan percutaneous hepatic perfusion (M-PHP) allows selective intrahepatic delivery of high dose cytotoxic chemotherapy. METHODS: Retrospective analysis of outcomes data of UM patients receiving M-PHP at two institutions was performed. Tumor response and toxicity were evaluated using RECIST 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) v4.03, respectively. RESULTS: A total of 51 patients received 134 M-PHP procedures (median of 2 M-PHPs). 25 (49%) achieved a partial (N = 22, 43.1%) or complete hepatic response (N = 3, 5.9%). In 17 (33.3%) additional patients, the disease stabilized for at least 3 months, for a hepatic disease control rate of 82.4%. After median follow-up of 367 days, median overall progression free (PFS) and hepatic progression free survival (hPFS) was 8.1 and 9.1 months, respectively and median overall survival was 15.3 months. There were no treatment related fatalities. Non-hematologic grade 3-4 events were seen in 19 (37.5%) patients and were mainly coagulopathic (N = 8) and cardiovascular (N = 9). CONCLUSIONS: M-PHP results in durable intrahepatic disease control and can form the basis for an integrated multimodality treatment approach in appropriately selected UM patients.

11 Article BILATERAL METASTATIC CUTANEOUS MELANOMA TO RETINA AND VITREOUS AFTER IPILIMUMAB TREATED WITH PARS PLANA VITRECTOMY AND RADIOTHERAPY. 2018

Kanavati, Sam / Ottensmeier, Christian / Foria, Vipul / Krishnan, Radhika. ·Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. · Cancer Sciences Unit and Southampton Experimental Cancer Medicine Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. · Department of Histopathology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom. ·Retin Cases Brief Rep · Pubmed #27828902.

ABSTRACT: PURPOSE: To report a patient with bilateral metastatic cutaneous melanoma to the retina and vitreous presenting as a right panuveitis. METHODS: A 63-year-old woman with metastatic malignant cutaneous melanoma treated with ipilimumab and prolonged high-dose steroids presented with a right panuveitis and right blurred vision. Dilated fundus examination revealed bilateral, off-white, large, globular vitreous opacities and bilateral retinal lesions. These retinal lesions had a pale yellow appearance with a cuff of haemorrhage. The unpigmented appearance of the vitreous opacities raised the suspicion of candida endophthalmitis. RESULTS: Bilateral, sequential pars plana vitrectomy with pathomorphologic examination of the vitreous specimen demonstrated metastatic melanoma. Ocular radiotherapy followed by cataract surgery resulted in the regression of retinal lesions in both eyes and no recurrence of the vitreous metastases. CONCLUSION: The development of vitreous and retinal metastases despite a systemic response to ipilimumab identifies the challenge of immunotherapy in an immune privileged site. Treatment is challenging, and outcomes are variable. A local approach of bilateral pars plana vitrectomy, external beam radiotherapy, and subsequent bilateral cataract surgery provided an excellent visual result with no recurrence at 12 months.

12 Article Evaluation of immune infiltration in the colonic mucosa of patients with ipilimumab-related colitis. 2016

Arriola, Edurne / Wheater, Matthew / Lopez, Maria Antonette / Thomas, Gareth / Ottensmeier, Christian. ·Southampton NIHR Experimental Cancer Medicine Center, Faculty of Medicine, University of Southampton, Southampton, UK; University Hospital Southampton NHS Foundation Trust, Southampton, UK. · University Hospital Southampton NHS Foundation Trust , Southampton, UK. ·Oncoimmunology · Pubmed #27757302.

ABSTRACT: Approximately 30% of patients treated with ipilimumab will develop gastrointestinal toxicity. The immunological drivers that underpin the clinical observations in human tissues are poorly understood. We report here on the immune consequences of ipilimumab treatment in the colorectal mucosa of patients with treatment-related colitis. Using immunohistochemistry, we evaluated the immune infiltrate by CD8

13 Article Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma. 2016

Karydis, Ioannis / Chan, Pui Ying / Wheater, Matthew / Arriola, Edurne / Szlosarek, Peter W / Ottensmeier, Christian H. ·Cancer Sciences Academic Unit, University of Southampton , Southampton, United Kingdom. · Department of Medical Oncology, St Bartholomew's Hospital , London. · Medical Oncology, University Hospital Southampton , Southampton, United Kingdom. · Department of Medical Oncology, St Bartholomew's Hospital, London; Barts Cancer Institute, Queen Mary University of London, London. ·Oncoimmunology · Pubmed #27467964.

ABSTRACT: BACKGROUND: Untreated metastatic uveal melanoma (UM) carries a grave prognosis. Unlike cutaneous melanoma (CM), there are no established treatments known to significantly improve outcomes for a meaningful proportion of patients. Inhibition of the PD1-PDL1 axis has shown promise in the management of CM and we here report a two center experience of UM patients receiving pembrolizumab. METHODS: To assess the efficacy and safety of pembrolizumab, we retrospectively analyzed outcome data of 25 consecutive UM patients participating in the MK3475 expanded access program (EAP) who received pembrolizumab at 2 mg/kg 3 weekly. Tumor assessment was evaluated using RECIST 1.1 and immune-related Response Criteria (irRC) by CT scanning. Toxicity was recorded utilizing Common Terminology Criteria for Adverse Events ("CTCAE") v4.03. RESULTS: Twenty-five patients were identified receiving a median of six cycles of treatment. Two patients achieved a partial response and six patients stable disease. After a median follow-up of 225 d median progression free survival (PFS) was 91 d and overall survival (OS) was not reached. There was a significant trend for improved outcomes in patients with extrahepatic disease progression as opposed to liver only progression at the outset. Five patients experienced grade 3 or 4 adverse events (AEs); there were no treatment related deaths. CONCLUSIONS: Pembrolizumab 2mg/kg q3w is a safe option in UM patients. Disease control rates, particularly in the subgroup of patients without progressive liver disease at the outset are promising; these results merit further investigation in clinical trials possibly incorporating liver targeted treatment modalities.

14 Article Immunosuppression for ipilimumab-related toxicity can cause 2015

Arriola, Edurne / Wheater, Matthew / Krishnan, Radhika / Smart, James / Foria, Vipul / Ottensmeier, Christian. ·Cancer Sciences Unit; University of Southampton and University Hospital Southampton NHS Foundation Trust ; Southampton, UK ; University Hospital Southampton NHS Foundation Trust ; Southampton, UK ; Southampton Experimental Cancer Medicine Center; University of Southampton and University Hospital Southampton NHS Foundation Trust ; Southampton, UK. · University Hospital Southampton NHS Foundation Trust ; Southampton, UK ; Southampton Experimental Cancer Medicine Center; University of Southampton and University Hospital Southampton NHS Foundation Trust ; Southampton, UK. · University Hospital Southampton NHS Foundation Trust ; Southampton, UK. ·Oncoimmunology · Pubmed #26451305.

ABSTRACT: Ipilimumab is a standard therapy for advanced melanoma. Severe immune related adverse events occur in up to 30% of patients and require treatment with immunosuppressants such as steroids or the anti-TNFα antibody, infliximab. We describe two patients with advanced melanoma treated with ipilimumab. Both suffered from severe immune related side effects and required prolonged immunosuppression with steroids and/or infliximab. Both patients recovered and in spite of the immune suppression, demonstrate clinical evidence of tumor control. This argues that distinct immunological effector functions control nosocomial infection and tumor, respectively. To our knowledge, these are also the first two case reports of pneumocystis pneumonia in this setting.

15 Article Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients. 2015

Ahmad, Saif S / Qian, Wendi / Ellis, Sarah / Mason, Elaine / Khattak, Muhammad A / Gupta, Avinash / Shaw, Heather / Quinton, Amy / Kovarikova, Jarmila / Thillai, Kiruthikah / Rao, Ankit / Board, Ruth / Nobes, Jenny / Dalgleish, Angus / Grumett, Simon / Maraveyas, Anthony / Danson, Sarah / Talbot, Toby / Harries, Mark / Marples, Maria / Plummer, Ruth / Kumar, Satish / Nathan, Paul / Middleton, Mark R / Larkin, James / Lorigan, Paul / Wheater, Matthew / Ottensmeier, Christian H / Corrie, Pippa G. ·aDepartment of Oncology bCambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, Cambridge cSouthampton Experimental Cancer Medicine Center, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton dDepartment of Medical Oncology, The Christie, Manchester eDepartment of Medicine, Royal Marsden NHS Foundation Trust, London fOxford NIHR Biomedical Research Centre, Oxford gDepartment of Medical Oncology, Mount Vernon Hospital, Northwood hDepartment of Medical Oncology, Velindre Cancer Centre, Cardiff iNorthern Centre for Cancer Care, Newcastle upon Tyne jDirectorate of Haematology and Oncology, Guy's and St. Thomas' NHS Foundation Trust, London kDepartment of Medical Oncology, Royal Wolverhampton Hospitals lDepartment of Medical Oncology, Royal Preston Hospital mClinical Oncology, Norfolk and Norwich University Hospital nDivision of Clinical Sciences, St George's Hospital Medical School, London oDepartment of Oncology, Castle Hill Hospital, Hull pSheffield Experimental Cancer Medicine Centre, University of Sheffield, Weston Park Hospital, Sheffield qClinical Oncology Department, Royal Cornwall Hospitals rSt. James's Institute of Oncology, St. James's University Hospital, Leeds, UK. ·Melanoma Res · Pubmed #26225580.

ABSTRACT: Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.

16 Article NY-ESO-1 specific antibody and cellular responses in melanoma patients primed with NY-ESO-1 protein in ISCOMATRIX and boosted with recombinant NY-ESO-1 fowlpox virus. 2015

Chen, Ji-Li / Dawoodji, Amina / Tarlton, Andrea / Gnjatic, Sacha / Tajar, Abdelouahid / Karydis, Ioannis / Browning, Judy / Pratap, Sarah / Verfaille, Christian / Venhaus, Ralph R / Pan, Linda / Altman, Douglas G / Cebon, Jonathan S / Old, Lloyd L / Nathan, Paul / Ottensmeier, Christian / Middleton, Mark / Cerundolo, Vincenzo. ·Radcliffe Department of Medicine, MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DU, United Kingdom. ·Int J Cancer · Pubmed #25081390.

ABSTRACT: Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8(+) or CD4(+) T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4(+) T cell and antibody response, which was maintained by both regiments at similar levels. However, CD8(+) T cell responses were significantly boosted in 3 out of 18 patients in Arm A after the first rF-NY-ESO-1 injection and such responses were maintained until the end of the trial, while no patients in Arm B showed similar CD8(+) T cell responses. In addition, our results clearly identified immunodominant regions in the NY-ESO-1 protein: NY-ESO-179-102 and NY-ESO-1115-138 for CD4+ T cells and NY-ESO-185-108 for CD8+ T cells in a large proportion of vaccinated patients. These regions of NY-ESO-1 protein should be considered in future clinical trials as immunodominant epitopes.

17 Article Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. 2014

Kvistborg, Pia / Philips, Daisy / Kelderman, Sander / Hageman, Lois / Ottensmeier, Christian / Joseph-Pietras, Deborah / Welters, Marij J P / van der Burg, Sjoerd / Kapiteijn, Ellen / Michielin, Olivier / Romano, Emanuela / Linnemann, Carsten / Speiser, Daniel / Blank, Christian / Haanen, John B / Schumacher, Ton N. ·The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. p.kvistborg@nki.nl t.schumacher@nki.nl. · The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands. · National Institute for Health Research Southampton Experimental Cancer Medicine Centre and Southampton University Hospitals, Tremona Road, Southampton, Hampshire SO16 6YD, UK. · Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, Netherlands. · Ludwig Center for Cancer Research, Department of Oncology, University of Lausanne, Rue Pierre-Decker 4, 1011 Lausanne, Switzerland. ·Sci Transl Med · Pubmed #25232180.

ABSTRACT: Anti-CTLA-4 treatment improves the survival of patients with advanced-stage melanoma. However, although the anti-CTLA-4 antibody ipilimumab is now an approved treatment for patients with metastatic disease, it remains unknown by which mechanism it boosts tumor-specific T cell activity. In particular, it is unclear whether treatment amplifies previously induced T cell responses or whether it induces new tumor-specific T cell reactivities. Using a combination ultraviolet (UV)-induced peptide exchange and peptide-major histocompatibility complex (pMHC) combinatorial coding, we monitored immune reactivity against a panel of 145 melanoma-associated epitopes in a cohort of patients receiving anti-CTLA-4 treatment. Comparison of pre- and posttreatment T cell reactivities in peripheral blood mononuclear cell samples of 40 melanoma patients demonstrated that anti-CTLA-4 treatment induces a significant increase in the number of detectable melanoma-specific CD8 T cell responses (P = 0.0009). In striking contrast, the magnitude of both virus-specific and melanoma-specific T cell responses that were already detected before start of therapy remained unaltered by treatment (P = 0.74). The observation that anti-CTLA-4 treatment induces a significant number of newly detected T cell responses-but only infrequently boosts preexisting immune responses-provides strong evidence for anti-CTLA-4 therapy-enhanced T cell priming as a component of the clinical mode of action.

18 Article Melanoma sentinel node biopsy and prediction models for relapse and overall survival. 2010

Mitra, A / Conway, C / Walker, C / Cook, M / Powell, B / Lobo, S / Chan, M / Kissin, M / Layer, G / Smallwood, J / Ottensmeier, C / Stanley, P / Peach, H / Chong, H / Elliott, F / Iles, M M / Nsengimana, J / Barrett, J H / Bishop, D T / Newton-Bishop, J A. ·Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS97TF, UK. a.mitra@leeds.ac.uk ·Br J Cancer · Pubmed #20859289.

ABSTRACT: BACKGROUND: To optimise predictive models for sentinal node biopsy (SNB) positivity, relapse and survival, using clinico-pathological characteristics and osteopontin gene expression in primary melanomas. METHODS: A comparison of the clinico-pathological characteristics of SNB positive and negative cases was carried out in 561 melanoma patients. In 199 patients, gene expression in formalin-fixed primary tumours was studied using Illumina's DASL assay. A cross validation approach was used to test prognostic predictive models and receiver operating characteristic curves were produced. RESULTS: Independent predictors of SNB positivity were Breslow thickness, mitotic count and tumour site. Osteopontin expression best predicted SNB positivity (P=2.4 × 10⁻⁷), remaining significant in multivariable analysis. Osteopontin expression, combined with thickness, mitotic count and site, gave the best area under the curve (AUC) to predict SNB positivity (72.6%). Independent predictors of relapse-free survival were SNB status, thickness, site, ulceration and vessel invasion, whereas only SNB status and thickness predicted overall survival. Using clinico-pathological features (thickness, mitotic count, ulceration, vessel invasion, site, age and sex) gave a better AUC to predict relapse (71.0%) and survival (70.0%) than SNB status alone (57.0, 55.0%). In patients with gene expression data, the SNB status combined with the clinico-pathological features produced the best prediction of relapse (72.7%) and survival (69.0%), which was not increased further with osteopontin expression (72.7, 68.0%). CONCLUSION: Use of these models should be tested in other data sets in order to improve predictive and prognostic data for patients.

19 Minor Infliximab for IPILIMUMAB-Related Colitis-Letter. 2015

Arriola, Edurne / Wheater, Matthew / Karydis, Ioannis / Thomas, Gareth / Ottensmeier, Christian. ·Southampton NIHR Experimental Cancer Medicine Centre, Faculty of Medicine, University of Southampton Tremona Road, Southampton, United Kingdom. University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, United Kingdom. e.arriola-aperribay@soton.ac.uk. · University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, United Kingdom. · Southampton NIHR Experimental Cancer Medicine Centre, Faculty of Medicine, University of Southampton Tremona Road, Southampton, United Kingdom. University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, United Kingdom. ·Clin Cancer Res · Pubmed #26672088.

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