Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial.

Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49).

VinCaP: a phase II trial of vinflunine in locally advanced and metastatic squamous carcinoma of the penis.

BACKGROUND: We investigated the first-line activity of vinflunine in patients with penis cancer. Cisplatin-based combinations are commonly used, but survival is not prolonged; many patients are unfit for such treatment or experience toxicity that outweighs clinical benefit. METHODS: Twenty-five patients with inoperable squamous carcinoma of the penis were recruited to a single-arm, Fleming-A'Hern exact phase II trial. Treatment comprised 4 cycles of vinflunine 320 mg/m2, given every 21 days. Primary endpoint was clinical benefit rate (CBR: objective responses plus stable disease) assessed after 4 cycles. Seven or more objective responses or disease stabilisations observed in 22 evaluable participants would exclude a CBR of <15%, with a true CBR of >40% being probable. RESULTS: Twenty-two participants were evaluable. Ten objective responses or disease stabilisations were confirmed. CBR was 45.5%, meeting the primary endpoint; partial response rate was 27.3%. Seven patients received >4 cycles of vinflunine. Dose reduction or treatment delay was required for 20% of cycles. In all, 68% of patients experienced at least one grade 3 adverse event. Two deaths on treatment were not caused by disease progression. CONCLUSIONS: Pre-specified clinical activity threshold was exceeded. Toxicity was in keeping with experience in other tumours. Vinflunine merits further study in this disease. TRIAL REGISTRATION: NCT02057913.

The International Penile Advanced Cancer Trial (InPACT): Rationale and Current Status.

The historic international penile cancer trial InPACT is now open and accruing patients in the UK and USA. The trial is geared to answer important questions for patients with evidence of inguinal lymph node disease at presentation. This clinical trial update provides an overview of the study and progress to date.

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial.

BACKGROUND: Regorafenib inhibits VEGF receptors 1, 2, and 3 and PDGF receptors like other anti-angiogenic tyrosine-kinase inhibitors approved for treatment of advanced renal-cell cancer. Regorafenib also inhibits other potentially important angiogenic kinases like TIE2, activation of which is thought to be important in tumour escape mechanisms. This phase 2, open-label, non-randomised study assessed the safety and efficacy of the multikinase inhibitor regorafenib for treatment of renal-cell carcinoma. METHODS: Patients were recruited from 18 academic oncology centres across Europe and USA. Patients with previously untreated metastatic or unresectable clear-cell renal-cell carcinoma received oral regorafenib (160 mg per day) in repeating cycles of 3 weeks on, 1 week off until disease progression or until patients met the criteria for removal from study. The primary efficacy endpoint was the proportion of patients who achieved an objective overall response, assessed in all patients who were evaluable for response. The trial has finished. This trial is registered with ClinicalTrials.gov, number NCT00664326. FINDINGS: The study was done between April 30, 2008, and June 1, 2011. We screened 64 patients, of whom 49 received regorafenib. Median duration of treatment was 7·1 months (range 0·7-34·4, IQR 2·5-18·0) and at the time of data cutoff, six patients (12%) were still receiving treatment. 48 patients were assessable for tumour response. 19 patients (39·6%, 90% CI 27·7-52·5) had an objective response, all of which were partial responses. Drug-related adverse events occurred in 48 patients (98%) and drug-related serious adverse events in 17 (35%). Grade 3 drug-related adverse events were common, most frequently hand and foot skin reaction (16 patients, 33%), diarrhoea (five patients, 10%), renal failure (five patients, 10%), fatigue (four patients, 8%), and hypertension (three patients, 6%). Two patients had grade 4 treatment-related adverse events: two cardiac ischaemia or infarction, one hypomagnesaemia, and one pain in the chest or thorax. Four patients died during study treatment or within 30 days of last dose, of which two were deemed likely to be related to the study drug. INTERPRETATION: Regorafenib has antitumour activity as first-line treatment for metastatic or unresectable renal-cell carcinoma. The drug's safety profile requires close monitoring.

Chemotherapy for bladder cancer in patients with impaired renal function.

Carcinoma of the bladder is a common, chemosensitive malignancy. The value of chemotherapy for transitional cell carcinoma (the commonest malignant bladder histology in the developed world) has been demonstrated in both the palliative and the neoadjuvant settings, with survival benefits in both scenarios being achieved with cisplatin-based regimens. Conventional drug treatment is, therefore, dependent on adequate renal function, but renal impairment is a common confounding factor in patients with bladder cancer, due in part to obstruction of the urinary tract and in part to comorbidity in an elderly population. A recent consensus statement deems patients with impaired renal function unsuitable for cisplatin treatment, but the limited available evidence does not support the exclusion of cisplatin in patients with moderate renal impairment. The literature on which to base alternative, non-cisplatin-based chemotherapy is inadequate, but the perception that carboplatin-based combinations are inferior to cisplatin-based combinations is probably incorrect. Trials are needed to specifically examine chemotherapy in patients with bladder cancer and renal impairment.

A phase 2 study of vatalanib in metastatic melanoma patients.

BACKGROUND: A phase 2 study of vatalanib (PTK787/ZK222584) an oral tyrosine kinase inhibitor of VEGFR 1, 2 and 3 was undertaken in patients with metastatic melanoma. METHODS: Adults with pathologically confirmed metastatic melanoma, WHO Performance status 0-2, and adequate haematological, hepatic and renal function, were treated with vatalanib until disease progression. The trial used Fleming's single stage design. RESULTS: Tumour control rate (CR+PR+SD) was 35% at 16 weeks, with objective response seen in only 1 patient. Median progression-free survival was 1.8 months (95% CI 1.8-3.7 months) and median overall survival was 6.5 months (95% CI 3.9-10.2 months). CONCLUSION: Vatalanib stabilised disease in a proportion of patients, although overall survival was disappointing.

Recent advances in bacillus Calmette-Guerin immunotherapy in bladder cancer.

The concept of using Mycobacterium for cancer treatment goes back to the 19th Century. Today, bacillus Calmette-Guerin (BCG) vaccine is a well-established treatment for human bladder cancer that is arguably superior to intravesical chemotherapy for superficial disease and is commonly used as the first-line adjuvant treatment. Much has been learnt about the effects of BCG on bladder cancer and the immune system, but deeper understanding is required in order to improve its efficacy further, to be able to reliably predict responders and ultimately to adapt this most successful form of cancer immunotherapy for the treatment of other malignancies. This article summarizes the current understanding of BCG cancer immunotherapy mechanisms and discusses possible future developments.

Aggressive combined-modality therapy for squamous cell carcinoma of the female urethra.

BACKGROUND: A 48-year old woman presented to an emergency department with acute urinary retention necessitating suprapubic catheterization. INVESTIGATIONS: Pelvic examination under anesthetic by both a urologist and gynecologist, biopsy of the urethral tumor and of the cervix, pathological analysis, MRI of the pelvis, CT of the chest, abdomen and pelvis. DIAGNOSIS: Poorly differentiated squamous cell carcinoma of the urethra, T4N0M0. MANAGEMENT: The patient received two cycles of neoadjuvant TIP (paclitaxel, ifosfamide, cisplatin) chemotherapy, resulting in complete remission, followed by consolidative chemoradiation therapy (radiation therapy given with synchronous weekly cisplatin). She remained relapse-free 48 months after diagnosis, with normal voiding and sexual function.

A phase I trial of idiotypic vaccination with HMFG1 in ovarian cancer.

INTRODUCTION: An extended phase I trial was conducted in a total of 26 patients with ovarian cancer. The objectives were to assess the safety and tolerability of idiotypic vaccination using the murine monoclonal antibody HMFG1 (anti-MUC1), and to develop robust assays to monitor humoral immune responses generated against either the antibody or MUC1. MATERIAL AND METHODS: All patients had undergone standard debulking surgery (where appropriate) and at least one regimen of platinum-based chemotherapy. Eligibility criteria included: (a) residual disease at the end of chemotherapy, (b) relapsed disease, and (c) pathologically confirmed second complete remission following salvage chemotherapy. Patients received a priming dose of 25 mg of HMFG1 either intravenously or intraperitoneally, followed by up to six intradermal doses of HMFG1 in 10% Alhydrogel at intervals of 1 month. The three dose levels were 0.5 mg, 1 mg and 5 mg. We devised modifications of published protocols for the measurement of anti-idiotypic and anti-MUC1 antibody responses and also extended the use of the IAsys resonant mirror biosensor to measure the kinetics of the idiotypic network response in these patients. RESULTS: There were no serious adverse events at any dose level. The trial confirmed that all doses could be administered safely with minimal toxicity. No clinical responses were seen in patients with evaluable disease. ELISA for anti-idiotypic antibodies (Ab2) showed significant levels in patients who completed the protocol. There were no significant differences in the levels of Ab2 generated by the different doses of antibody. These results were confirmed by biosensor assays for Ab2, which also showed affinity maturation of the Ab2 response as patients progressed through the vaccination protocol. Biosensor assays also demonstrated no difference in the affinity of Ab2 generated by different booster doses of HMFG1. ELISA for anti-MUC1 antibodies showed less consistent results, with very small but statistically significant rises in anti-MUC1 signals seen in 38% of patients who completed the vaccination regimen. DISCUSSION: The clinical endpoints of safety and tolerability were met. The assays developed for this project have shown reproducibility and may provide surrogate endpoints to assess vaccination for future trials. The use of similar biosensors may be of particular relevance for monitoring of humoral immune responses in other vaccine trials. The low levels of anti-MUC1 antibodies generated may correspond with the lack of clinical efficacy in the few patients with evaluable disease.

Does knowledge influence melanoma-prone behavior? Awareness, exposure, and sun protection among five social groups.

PURPOSE/OBJECTIVES: To examine melanoma-related knowledge, sun exposure, and sun protection to determine whether increased awareness is associated with a reduction in risk. DESIGN: Quantitative/empiricist study conducted by purpose- designed mailed questionnaire. PARTICIPANTS: Consultant oncologists at one teaching hospital in London, England; specialist registrars (oncologists in training) contacted through a London-based educational group; oncology-trained nursing staff from oncology departments at two London teaching hospitals; medical students; general (nononcology) nurses; and members of the lay public from one London teaching hospital. SETTING: Two teaching hospitals in London, both registered cancer centers that possess specialist departments of oncology and are staffed by clinical and medical oncologists. METHODS: Anonymous, self-completion, mailed questionnaire. RESEARCH VARIABLES: Sun exposure; use of sun protection and avoidance; knowledge of the biologic effects of sun exposure, moles, and malignant melanoma; melanoma-prone behavior. FINDINGS: No significant differences were found in sun exposure or melanoma-prone behavior across the five groups studied. No correlation existed between knowledge and melanoma-prone behavior. Differences in knowledge and protection scores were demonstrated across all groups and were statistically significant, but they did not translate into changes in exposure or behavior scores. CONCLUSIONS: Public health policy that seeks to reduce the incidence of melanoma is based on the false premise that increasing awareness of melanoma risk will reduce melanoma-prone behavior. Increasing awareness of the risks of sun exposure may improve the use of sun protection, but it does not reduce melanoma-prone behavior, even among specialist healthcare professionals. IMPLICATIONS FOR NURSING: This study provides a new epidemiologic tool for nurses working in the specialty.