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Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7·5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16–37) in the bevacizumab group and 25 months (17–37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0·97, 95% CI 0·78–1·22; p=0·76); this finding persisted after adjustment for stratification variables (HR 1·03; 95% CI 0·81–1·29; p=0·83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21–52) and dose intensity was 86% (41–96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0·83, 95% CI 0·70–0·98, p=0·03), but no significant difference between groups for distant-metastasis-free interval (HR 0·88, 95% CI 0·73–1·06, p=0·18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years. Cancer Research UK.

For many years, first-line treatment for locally advanced or metastatic soft-tissue sarcoma has been doxorubicin. This study compared gemcitabine and docetaxel versus doxorubicin as first-line treatment for advanced or metastatic soft-tissue sarcoma. The GeDDiS trial was a randomised controlled phase 3 trial done in 24 UK hospitals and one Swiss Group for Clinical Cancer Research (SAKK) hospital. Eligible patients had histologically confirmed locally advanced or metastatic soft-tissue sarcoma of Trojani grade 2 or 3, disease progression before enrolment, and no previous chemotherapy for sarcoma or previous doxorubicin for any cancer. Patients were randomly assigned 1:1 to receive six cycles of intravenous doxorubicin 75 mg/m2 on day 1 every 3 weeks, or intravenous gemcitabine 675 mg/m2 on days 1 and 8 and intravenous docetaxel 75 mg/m2 on day 8 every 3 weeks. Treatment was assigned using a minimisation algorithm incorporating a random element. Randomisation was stratified by age (≤18 years vs >18 years) and histological subtype. The primary endpoint was the proportion of patients alive and progression free at 24 weeks in the intention-to-treat population. Adherence to treatment and toxicity were analysed in the safety population, consisting of all patients who received at least one dose of their randomised treatment. The trial was registered with the European Clinical Trials (EudraCT) database (no 2009–014907–29) and with the International Standard Randomised Controlled Trial registry (ISRCTN07742377), and is now closed to patient entry. Between Dec 3, 2010, and Jan 20, 2014, 257 patients were enrolled and randomly assigned to the two treatment groups (129 to doxorubicin and 128 to gemcitabine and docetaxel). Median follow-up was 22 months (IQR 15·7–29·3). The proportion of patients alive and progression free at 24 weeks did not differ between those who received doxorubicin versus those who received gemcitabine and docetaxel (46·3% [95% CI 37·5–54·6] vs 46·4% [37·5–54·8]); median progression-free survival (23·3 weeks [95% CI 19·6–30·4] vs 23·7 weeks [18·1–20·0]; hazard ratio [HR] for progression-free survival 1·28, 95% CI 0·99–1·65, p=0·06). The most common grade 3 and 4 adverse events were neutropenia (32 [25%] of 128 patients who received doxorubicin and 25 [20%] of 126 patients who received gemcitabine and docetaxel), febrile neutropenia (26 [20%] and 15 [12%]), fatigue (eight [6%] and 17 [14%]), oral mucositis (18 [14%] and two [2%]), and pain (ten [8%] and 13 [10%]). The three most common serious adverse events, representing 111 (39%) of all 285 serious adverse events recorded, were febrile neutropenia (27 [17%] of 155 serious adverse events in patients who received doxorubicin and 15 [12%] of 130 serious adverse events in patients who received gemcitabine and docetaxel, fever (18 [12%] and 19 [15%]), and neutropenia (22 [14%] and ten [8%]). 154 (60%) of 257 patients died in the intention-to-treat population: 74 (57%) of 129 patients in the doxorubicin group and 80 (63%) of 128 in the gemcitabine and docetaxel group. No deaths were related to the treatment, but two deaths were due to a combination of disease progression and treatment. Doxorubicin should remain the standard first-line treatment for most patients with advanced soft-tissue sarcoma. These results provide evidence for clinicians to consider with their patients when selecting first-line treatment for locally advanced or metastatic soft-tissue sarcoma. Cancer Research UK, Sarcoma UK, and Clinical Trial Unit Kantonsspital St Gallen.

BackgroundAxitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer.MethodsAxi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon’s two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata.ResultsBetween 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events.ConclusionsAxitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials.Clinical Trial RegistrationISRCTN 60791336

BackgroundIn the peripheral blood, the neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) change in response to malignancy. These biomarkers are associated with adverse outcomes in numerous cancers, but the evidence is limited in relation to melanoma. This study sought to investigate the association between these biomarkers and survival in Stages I–III cutaneous melanoma.MethodsThis multicenter cohort study investigated a consecutive series of patients who underwent wide excision of biopsy-proven cutaneous melanoma and sentinel lymph node biopsy during a 10-year period. The baseline NLR and PLR were calculated immediately before sentinel lymph node biopsy. Adjusted hazard ratios (HRs) for overall and melanoma-specific survival were generated.ResultsOverall, 1351 patients were included in the study. During surveillance, 184 of these patients died (14%), with 141 of the deaths (77%) attributable to melanoma. Worse overall survival was associated with a baseline NLR lower than 2.5 [HR 2.2; 95% confidence interval (CI) 2.0 to 2.3; p < 0.001] and a baseline PLR lower than 100 (HR 1.8; 95% CI 1.7 to 1.8; p < 0.001). Melanoma-specific survival also was worse, with a baseline NLR lower than 2.5 (HR 1.9; 95% CI 1.6 to 2.2; p < 0.001) and a baseline PLR lower than 100 (HR 1.9; 95% CI 1.7 to 2.2; p < 0.001). The 5-year survival for patients with sentinel lymph node metastases and a low NLR and PLR was approximately 50%.ConclusionThis study provides important new data on biomarkers in early-stage melanoma, which contrast with biomarker profiles in advanced disease. These biomarkers may represent the host inflammatory response to melanoma and therefore could help select patients for adjuvant therapy and enhanced surveillance.

BackgroundSCIB1 and iSCIB1+, are novel DNA cancer vaccines incorporating CD8 and CD4 epitopes from TRP-2/gp100 into an antibody framework to allow direct and Fc targeting of activated dendritic cells. iSCIB1+ has additional epitopes applicable to more HLA haplotypes, A2, A3, A31, Bw4, B35 & B44 that represent 80% of the population (figure 1).MethodsThis phase 2 open label single arm parallel multi-cohort clinical program evaluates the immune response, safety and efficacy of SCIB1/iSCIB1+ in 140 advanced first line melanoma patients at 16 clinical sites in the United Kingdom.Cohort 1 has 43 patients all with HLA A2 receiving ipilimumab and nivolumab with 10 doses of intra-muscular SCIB1 over 24-months. Cohort 3 evaluates iSCIB1+ in 50 patients, 39 with the matched HLA haplotypes. Ongoing Cohort 4 has 31 patients with intra-dermal accelerated dosing. Cohort 2 has 10 HLA A2 patients who received SCIB 1 with pembrolizumab and was stopped due to slow enrolment.ResultsELISpot assays demonstrated that 19/31 (61.2%) patients made a T-cell response to iSCIB1+ which increased to 79% (15/19) amongst clinical responders. All six iSCIB1+ epitopes generated T cell responses. SCIB1 reactive T cells expressed IFNg, GZMB and PRF1.The ORR (Objective Response Rate) and DCR (Disease Control Rate) determined by RECIST 1.1 scans were:Cohort 1: 63.4% (26/41) and 83% (34/41), respectively with a Progression Free Survival (PFS) of 55.6% at 23 months, following exclusion of two non-protocol patients, with acral melanoma and active brain metastases.Cohort 3: 64.5% (20/31) and 80.6% (25/31), respectively with a PFS of 77.8% at 11 months. 1 patient with active brain metastases excluded. 7 yet to reach their first 13 week imaging timepoint (figure 2).Cohort 3 with non-matched HLA haplotypes: 27.3% (3/11) and 54.5% (6/11), respectively with a PFS of 45.5% at 12 months. Statistically significant difference in ORR (p value < 0.043) when compared to HLA matched patients.Cohort 2: 70% (7/10) for both outcomes with a PFS of 80% at 6 months.Vaccines were well tolerated with no increase in clinically meaningful adverse events. Of the 163 treatment emergent adverse events of Grades 3 or more, 30 were related to the vaccine whilst 113 to checkpoint inhibitors.ConclusionsFollowing on from this compelling interim readout we progress to registrational trials evaluating iSCIB1+ in stage III and IV melanoma in the advanced and neoadjuvant settings.Trial RegistrationRegistry Name - Clinicaltrials.gov Registration Number:NCT04079166Ethics ApprovalThis phase 2 study was conducted in keeping with ICH GCP guidelines with all participants giving their informed consent before taking part. The protocol, patient information sheet and informed consent form were reviewed and approved by the institutional ethics committees of each of the recruiting clinical trial sites located in the United Kingdom as listed below, prior to site initiation and patient enrolment: (1)Mount Vernon Cancer Centre, Northwood (2)University College London Hospital (3)Nottingham Hospitals University Trust (4)Churchill Hospital, Oxford University Hospitals (5) Velindre University NHS Trust, Cardiff (6) Sheffield Teaching Hospital NHS Trust, (7) University Hospitals NHS Trust, Plymouth (8)Somerset NHS Foundation Trust, Taunton (9) Royal Preston Hospital (10) Southampton General Hospital (11) St James’s University Hospital, Leeds (12) The Royal Marsden Hospital, Surrey (13) The Royal Marsden Hospital, London (14) Addenbrooke’s Hospital, Cambridge, (15) Royal Free Hospitals, London (16) Guys Hospital London.Abstract 1325 Figure 1Vaccine design with T cell response to all six epitopes. SCIB1 & iSCIB1+ encoding two clusters of CD8 epitopes, TRP-2 and gp100, with ELISpot T cell responses to all epitopes in HLA matched patients[Image Omitted. See PDF.]Abstract 1325 Figure 2RECIST 1.1 best overall response and progression free survival. Waterfall plot and progression free survival curves for HLA matched patients in Cohorts 1 & 3 showing an ORR of 46/72 (63.8%)[Image Omitted. See PDF.]

BackgroundTo compare the clinical efficacy of New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) vaccine with ISCOMATRIX adjuvant versus ISCOMATRIX alone in a randomized, double-blind phase II study in participants with fully resected melanoma at high risk of recurrence.MethodsParticipants with resected stage IIc, IIIb, IIIc and IV melanoma expressing NY-ESO-1 were randomized to treatment with three doses of NY-ESO-1/ISCOMATRIX or ISCOMATRIX adjuvant administered intramuscularly at 4-week intervals, followed by a further dose at 6 months. Primary endpoint was the proportion free of relapse at 18 months in the intention-to-treat (ITT) population and two per-protocol populations. Secondary endpoints included relapse-free survival (RFS) and overall survival (OS), safety and NY-ESO-1 immunity.ResultsThe ITT population comprised 110 participants, with 56 randomized to NY-ESO-1/ISCOMATRIX and 54 to ISCOMATRIX alone. No significant toxicities were observed. There were no differences between the study arms in relapses at 18 months or for median time to relapse; 139 vs 176 days (p=0.296), or relapse rate, 27 (48.2%) vs 26 (48.1%) (HR 0.913; 95% CI 0.402 to 2.231), respectively. RFS and OS were similar between the study arms. Vaccine recipients developed strong positive antibody responses to NY-ESO-1 (p≤0.0001) and NY-ESO-1-specific CD4+ and CD8+ responses. Biopsies following relapse did not demonstrate differences in NY-ESO-1 expression between the study populations although an exploratory study demonstrated reduced (NY-ESO-1)+/Human Leukocyte Antigen (HLA) class I+ double-positive cells in biopsies from vaccine recipients performed on relapse in 19 participants.ConclusionsThe vaccine was well tolerated, however, despite inducing antigen-specific immunity, it did not affect survival endpoints. Immune escape through the downregulation of NY-ESO-1 and/or HLA class I molecules on tumor may have contributed to relapse.

Introduction Immune checkpoint inhibitors (ICIs) are immunomodulatory molecules that downregulate T-cell inhibiting-receptors or ligands to promote an enhanced anti-tumour response. Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4) that has been shown to significantly improve survival in patients with metastatic melanoma. Immune-related adverse events (irAEs) occur in some patients with increased T-cell activation, of which ipilimumab-related hypophysitis (IH) is an important endocrine complication. The aim of this study is to determine the incidence of IH and characterise clinical presentation and outcomes in these patients. Patients and Methods We retrospectively evaluated consecutive adult patients with melanoma treated between December 2010 and August 2019 at a tertiary cancer centre. All patients received ipilimumab (3mg/kg) monotherapy or in combination with PD-1 (programmed cell death protein 1) inhibitors (nivolumab or pembrolizumab). Symptoms, pituitary hormone assessment, pituitary imaging and patient survival were assessed. Results Of 189 patients, 23 patients (12.2%, 13 male; age 59.2±11.8 years) presented with hypophysitis, two having received ipilimumab monotherapy. The median onset was at 17.3 weeks (range: 6.7-160 weeks) after treatment start, occurring in 57% after the fourth infusion (n=13). Five patients developed late-onset IH (range: 30.1-160 weeks) whilst on treatment with PD-1 inhibitors. Three of the patients developing hypophysitis (13%) received only a single ipilimumab infusion. Additional irAEs were diagnosed in 16 patients (70%) with IH, including six cases of destructive thyroiditis and one of autoimmune diabetes. The main presenting symptom of IH was lethargy (n=18, 78%) followed by headache (n=8, 35%). Corticotroph deficiency with cortisol levels <83 nmol/l (<3μg/dL) at presentation were observed in all patients. At diagnosis, a drop in cortisol level of >70% over a median time of 22 days (range: 3-39 days) was evident in 87% patients. A fall in fT4 level of at least 20% from baseline was observed in ten patients (59%, 10/17 – after excluding patients with thyroiditis) at a median of 4 weeks (range: 0-8 weeks) prior to the diagnosis of IH. Gonadotroph deficiency was detected in three male patients. At the end of follow-up (median 14.3 months, range: 1-61.5 months after IH diagnosis), corticotroph deficiency was persistent in all patients; seven of ten patients recovered thyrotroph function and gonadotroph deficit resolved in one patient. Three patients with hypophysitis died within the first year of immunotherapy. Conclusion The incidence of IH was 12.2%, predominantly occurring after the fourth infusion. IH is characterised by acute severe drop in cortisol levels to less than 3μg/dL. A falling fT4 may herald development of ACTH deficiency.

Dacarbazine chemotherapy has been the mainstay of melanoma treatment for >30 years. In the early 2000s, carboplatin (with or without other agents, such as paclitaxel) was the most commonly used second-line therapy in the UK. The aim of the present study was to report a significant response rate to second-line carboplatin in patients from three UK institutions who had been previously treated and failed to respond to dacarbazine, and investigate whether sequential therapy may be more effective compared with combination therapy. A total of 104 patients were identified, the majority of whom were treated with carboplatin (area under the curve 5-6) every 3 weeks for a maximum of 6 cycles. A total of 102 patients were evaluable for response, among whom 11 patients had an objective response (1 complete response and 10 partial responses) and 15 had stable disease, giving an overall response rate of 11% and disease control rate of 26%. The median progression-free survival was 1.8 months (range, 0.2-36+ months) and the median overall survival was 4.6 months (range, 0.2-36+ months). Surprisingly, the majority of the patients who benefited from second-line carboplatin therapy were those with visceral metastases, the survival of whom would not be expected to exceed 6 months after first-line treatment.

Objectives To assess the clinical impact of 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) compared with contrast-enhanced computed tomography (CECT) in patients referred via the Specialist Skin Cancer Multidisciplinary Team (SSMDT) with recurrent stage III/IV malignant melanoma (MM). Methods Forty-five patients were referred for further evaluation with FDG PET-CT. Findings on FDG PET-CT were compared with prior CECT and the clinical impact on subsequent management decisions was determined retrospectively. A major clinical impact was defined as a change in treatment plan resulting from identification of additional sites of disease or by characterisation of indeterminate findings on prior imaging. A minor impact was defined as confirmation of known sites of disease as identified on prior CECT. Results Fifty-one PET-CT examinations were performed. FDG PET-CT had a major clinical impact in 21 cases (41.2 %), of which 18 examinations were performed in patients with proven or suspected stage IV MM. FDG PET-CT had a minor impact in 23 cases (45.1 %), and there were five false-positive cases (9.8 %) and two false-negative cases (3.9 %). Conclusion FDG PET-CT is an effective tool in recurrent stage III/IV MM with a significant clinical impact on management decisions in patients who are appropriately referred via the highly specialised forum of the SSMDT. Key Points • FDG PET-CT is an effective tool in recurrent stage III/IV malignant melanoma. • FDG PET-CT has a significant clinical impact on management decisions. • Effective use of FDG PET-CT is via referral from the Specialist Skin Cancer Multidisciplinary Team.

To assess the clinical impact of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) compared with contrast-enhanced computed tomography (CECT) in patients referred via the Specialist Skin Cancer Multidisciplinary Team (SSMDT) with recurrent stage III/IV malignant melanoma (MM). Forty-five patients were referred for further evaluation with FDG PET-CT. Findings on FDG PET-CT were compared with prior CECT and the clinical impact on subsequent management decisions was determined retrospectively. A major clinical impact was defined as a change in treatment plan resulting from identification of additional sites of disease or by characterisation of indeterminate findings on prior imaging. A minor impact was defined as confirmation of known sites of disease as identified on prior CECT. Fifty-one PET-CT examinations were performed. FDG PET-CT had a major clinical impact in 21 cases (41.2 %), of which 18 examinations were performed in patients with proven or suspected stage IV MM. FDG PET-CT had a minor impact in 23 cases (45.1 %), and there were five false-positive cases (9.8 %) and two false-negative cases (3.9 %). FDG PET-CT is an effective tool in recurrent stage III/IV MM with a significant clinical impact on management decisions in patients who are appropriately referred via the highly specialised forum of the SSMDT. • FDG PET-CT is an effective tool in recurrent stage III/IV malignant melanoma. • FDG PET-CT has a significant clinical impact on management decisions. • Effective use of FDG PET-CT is via referral from the Specialist Skin Cancer Multidisciplinary Team.