PURPOSE:InPACT addresses the optimal management of locally advanced penile cancer, aiming to prospectively evaluate the relative benefits and sequencing of surgery, chemotherapy, and chemoradiotherapy. At trial inception, radiation therapy protocols for this rare cancer lacked consistency and standardization, necessitating multicenter, international collaboration to develop comprehensive radiation therapy planning, delivery, and quality assurance guidelines. METHODS AND MATERIALS:InPACT has 2 main aims; to establish the efficacy of neoadjuvant chemotherapy or chemoradiotherapy in patients with macroscopically-involved inguinal nodes. Second, to compare prophylactic pelvic lymph node dissection plus chemoradiation to the inguinal and pelvic fields versus chemoradiation alone in patients whose inguinal node histology predicts a high risk of occult pelvic node involvement. The primary outcome measure for the trial is survival time. An international group was convened to achieve consensus on radiation therapy contouring, planning, dose, fractionation, and delivery for this rare cancer. These guidelines have been used throughout the conduct of the trial to date and form part of the radiation therapy quality assurance for each participating center. RESULTS:International consensus radiation therapy guidelines were established, encompassing risk status assessment and indications for each treatment region based on radiological and pathologic risk status of nodal basins. Guidance provides a nodal contouring atlas, addresses prepubic fat coverage, and specifies dose fractionation for both neoadjuvant and adjuvant settings, including recommendations for macroscopic disease. Trial recruitment is ongoing. Oncological and toxicity outcomes will be reported in due course. CONCLUSIONS:The InPACT radiation therapy guidelines offer a step toward international consensus on contouring for inguino-pelvic radiation therapy in penile cancer.

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).

Penile cancer with bulky inguinal metastasis has a high probability of harboring pathologically involved lymph nodes best managed in a multidisciplinary care setting. Appropriate staging with cross-sectional imaging and fine-needle aspirate cytology of suspicious nodes guide decision-making for the use of platinum-based neoadjuvant chemotherapy followed by inguinal lymph node dissection. Surgical resection plays an important diagnostic, therapeutic, and guiding role in disease management. Patients with adverse pathologic features, especially those with extranodal disease extension, may derive additional benefit from adjuvant radiotherapy.

TPS7 Background: Penis cancer is a rare but potentially fatal disease. A limited body of evidence exists on which to base the majority of management decisions for patients with regional nodal metastases. Five-year survival for patients with a single involved inguinal lymph node treated with surgery alone is approximately 80%, whilst it ranges from 0 to 12% for patients with pelvic node involvement (N3). Additional strategies are required for the management regionally-advanced disease. InPACT (NCT02305654) aims to determine prospectively the relative benefits and sequencing of surgery, chemotherapy, and chemoradiotherapy in the management of patients with penis cancer who present with palpable or radiologically evident inguinal lymph node metastases. InPACT addresses the following questions: Is there a role for neoadjuvant therapy and, if so, which of the two options (chemotherapy or chemoradiotherapy) before surgery gives superior outcomes? Among patients whose inguinal node histology predicts a high risk of recurrence, does prophylactic pelvic lymph node dissection (PLND) plus chemoradiation to the inguinal and pelvic fields improve survival compared to chemoradiation alone? Methods: A Bayesian trial design aims to include a wide population of patients and incorporates two randomisations: InPACT-neoadjuvant and InPACT-pelvis. Participants are stratified by disease burden (extent of nodal involvement), by the presence or absence of high-risk radiological features, and by GFR. Participants with high disease burden where neoadjuvant treatment is thought to be indicated are randomised to neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy. Participants with intermediate disease burden are randomised to one of 3 arms: Surgery alone or neoadjuvant chemoradiotherapy followed by surgery, or neoadjuvant chemotherapy prior to surgery. Participants in the low-burden group proceed directly to surgery. Participants with postoperative inguinal node pathology that shows high-risk features may then proceed to InPACT-pelvis where randomisation is between adjuvant chemoradiotherapy ± PLND for those not previously treated with chemoradiotherapy & between PLND & observation for those previously treated with neoadjuvant chemoradiotherapy. The study aims to recruit 200 participants. The primary outcome measure is overall survival, with secondary outcome measures of disease-specific survival, disease-free survival, and freedom from locoregional recurrence and distant metastasis. Feasibility, toxicity, the type/extent of surgical complications, and quality of life will be assessed as secondary endpoints for all the InPACT treatment arms. To October 2021, 65 participants have been recruited with centres open in the UK, US and Canada. Clinical trial information: NCT02305654.

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/m 2 , 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 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.

547 Background: Platinum-based combination chemotherapy regimens are used in the treatment of carcinoma of the penis, but toxicity limits their value for patients with metastatic disease. This trial aims to define both the toxicity and the rate of disease control for the non-platinum cytotoxic agent Vinflunine. Methods: A phase II single-arm trial was designed to demonstrate a clinical benefit rate of at least 40% and to exclude a rate of less than 15% (p0 = 0.15, p1 = 0.40, α = 0.05, β = 0.80, Fleming-A’hern exact design). 22 evaluable patients were required. Key eligibility criteria included measurable, histologically-proven squamous cell carcinoma of the penis staged as M1; or M0, Tx, N3; or M0, Tx, N2 and deemed inoperable by multidisciplinary team; or M0, T4 any N. Patients were required to have ECOG performance status of 0, 1 or 2 and adequate hepatic and renal function. Treatment comprised four 21-day cycles of vinflunine (320mg/m 2 ) with RECIST v1.1 restaging following cycle 4 (response primary endpoint). Patients deemed to be benefitting from treatment were permitted to continue vinflunine at the discretion of the treating clinician until progression or unacceptable toxicity. Results: 25 patients were recruited from 8 UK centres between June 2014 and May 2017. Median age was 68 years; 19 patients had metastatic (M1) disease. All patients have completed trial treatment and primary endpoint assessment. Data cleaning for the primary analysis is currently in progress, with the snapshot for the primary analysis due in October 2017 and primary analysis to be presented to the trial oversight committees in November 2017. Conclusions: It is hoped that single-agent vinflunine will be associated with a favourable toxicity profile combined with meaningful clinical responses. The results will be available for presentation at the meeting. Clinical trial information: NCT02057913.

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 randomised 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. (C) 2014 The Authors. Published by Elsevier Ltd.

BJU InternationalVolume 113, Issue 6 p. 852-853 Comment Clinical trial strategy for penis cancer Steve Nicholson, Corresponding Author Steve Nicholson Imperial College Healthcare NHS Trust, Imperial College, London, UK International Rare Cancer Initiative in Penis Cancer, UK Correspondence: Steve Nicholson, Department of Medical Oncology, Charing Cross Hospital, London W6 8RF, UK. e-mail: wondersn@doctors.org.ukSearch for more papers by this authorOliver Kayes, Oliver Kayes Leeds Teaching Hospitals, Leeds, UKSearch for more papers by this authorSuks Minhas, Suks Minhas University College Hospital, London, UKSearch for more papers by this author Steve Nicholson, Corresponding Author Steve Nicholson Imperial College Healthcare NHS Trust, Imperial College, London, UK International Rare Cancer Initiative in Penis Cancer, UK Correspondence: Steve Nicholson, Department of Medical Oncology, Charing Cross Hospital, London W6 8RF, UK. e-mail: wondersn@doctors.org.ukSearch for more papers by this authorOliver Kayes, Oliver Kayes Leeds Teaching Hospitals, Leeds, UKSearch for more papers by this authorSuks Minhas, Suks Minhas University College Hospital, London, UKSearch for more papers by this author First published: 13 November 2013 https://doi.org/10.1111/bju.12563Citations: 12Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume113, Issue6June 2014Pages 852-853 RelatedInformation

BACKGROUND:Advanced melanoma is an aggressive disease with a poor prognosis. Approved therapy is limited in the U.K. and, until recently, no treatment had improved survival over best supportive care. A deeper understanding of current clinical practice will help new agents find a place in future treatment pathways. OBJECTIVES:To document U.K. clinical practice for the treatment of patients with unresectable stage III/IV (advanced) melanoma. METHODS:MELODY (melanoma treatment patterns and outcomes among patients with unresectable stage III/IV disease: a retrospective longitudinal survey) compiled registries of consecutive patients with malignant melanoma (any stage) between 1 July 2005 and 30 June 2006 from France, Italy and the U.K. Patients with advanced melanoma and ≥ 2 months of follow-up were eligible for analysis. RESULTS:There were 220 eligible patients identified in the U.K., of whom 117 (53.2%) received systemic therapy outside of clinical trials. Over half of these patients received dacarbazine as first- or second-line therapy. Healthcare-resource utilization was extensive and patients had short survival times: 1- and 2-year survival rates after first-line systemic treatment were 45.5% [95% confidence interval (CI) 37.1-53.6] and 24.7% (95% CI 17.7-32.3), respectively. CONCLUSIONS:Systemic and palliative treatments used to manage advanced melanoma in the U.K. are associated with considerable healthcare resource utilization and poor short-term survival.

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.

LBA9000 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. Methods: AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality of life (QoL). An associated translational study is ongoing. Results of the first pre-planned interim analysis (agreed by the IDSMC) are reported here. Results: Between July 2007 and March 2012, 1,343 pts were recruited. 56% were male; median age 56 years (range 18-88 years), 16% were stage IIB, 11% IIC, 15% IIIA, 36% IIIB, 20% IIIC, and 2% unknown stage. Ulceration status of the primary melanoma was: 38% present, 45% absent, 17% unknown. At the time of the interim analysis, 286 (21%) patients had died. Median follow-up for survival was 25 months. Median duration of Bev treatment in 671 treated pts was 51 weeks (dose intensity 86%). Main outcomes are shown in the table. Grade 3/4 adverse events were experienced in 101 (15%) Bev pts and 36 (5%) Obs pts. Conclusions: Interim analysis of this large, multicenter trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev monotherapy is well tolerated and improved DFI. Longer follow-up is required to determine an impact on the primary endpoint of 5-year OS. Clinical trial information: 81261306. [Table: see text]

BACKGROUND:Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease. METHODS:Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m(-2) day 1, cisplatin 60 mg m(-2) day 1, 5-flurouracil 750 mg m(-2) per day days 1-5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival. RESULTS:10/26 evaluable patients (38.5%, 95% CI: 20.2-59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event. CONCLUSION:Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.

A standard approach to trial design is to test a null hypothesis of no treatment effect in terms of a primary outcome measure against an alternative hypothesis of a minimal clinically relevant treatment effect as chosen by the investigators. Sample size is determined to maximise the chance that the trial detects this effect if it exists whilst minimising the chance of a false positive conclusion. We propose a reverse philosophy is used in rare diseases where the design starts with the number of patients that is feasible to collect within a sensible time frame and then, based on a Bayesian analysis, show that this amount of data could provide useful information on which to make clinical decisions in the future. This paper illustrates application of this approach to design the first ever potentially practice-changing trial in penile cancer, as part of the International Rare Cancers Initiative. The primary outcome measure is survival time with treatment effect measured as a hazard ratio. Given a predicted number of events, the design is evaluated by (i) demonstrating the information that the trial could provide for a range of possible observed results and prior distributions; and (ii) given a pre-specified decision criteria, using simulation to determine the probability that the trial will make the correct decision under different underlying true scenarios. Treatment decisions in rare diseases should be based on trial evidence but the traditional approach to design is problematic and using a Bayesian approach with reverse philosophy may provide a practical alternative.