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455 Background: The POUT trial (CRUK/11/027; NCT01993979) previously reported (with median follow-up 30.3 months) that adjuvant chemotherapy improves disease free survival (DFS) for patients (pts) with histologically confirmed pT2-T4 N0-3 M0 UTUC. Here we present results of a pre-planned analysis updating the primary endpoint and reporting key secondary endpoints including overall survival. Methods: 261 pts with UTUC were enrolled following nephro-ureterectomy and randomised (1:1) to 4 cycles of gemcitabine-cisplatin (gemcitabine-carboplatin if GFR 30-49ml/min) or surveillance with subsequent chemotherapy if required. Pts had 6 monthly imaging and cystoscopy for 2 years, then annually to 5 years. Toxicity was assessed by CTCAE v4. Primary endpoint was DFS. Secondary endpoints included metastasis free survival (MFS), overall survival (OS), toxicity and patient reported quality of life (QoL). The trial closed to recruitment early on advice of the independent data monitoring committee due to evidence of efficacy. Time-to-event endpoints are analysed (intention-to-treat) by Cox proportional hazard models. Unadjusted and adjusted (by nodal status, planned chemotherapy type, microscopic margin status, pathological stage) hazard ratios (HR, < 1 favouring chemotherapy) are reported. Results: From May 2012 to Nov 2017, 261 pts were recruited (129 surveillance; 132 chemotherapy) at 56 UK centres. One participant withdrew consent for data usage and was excluded from analyses. Pts had median age 69 years (range 37-88), 28% pT2, 66% pT3; 91% pN0. To 09/09/2020, median follow up was 48.1 months (IQR: 36.0-60.1). The unadjusted/adjusted HR for DFS was 0.48 (95% CI: 0.33-0.71; p = 0.0003) / 0.50 (95%CI: 0.34-0.75; p = 0.001), and for MFS was 0.52 (95% CI: 0.35-0.77; p = 0.001) / 0.54 (95% CI: 0.36-0.81; p = 0.002). 93/260 (35.8%) pts have died (52/129 [40.3%] surveillance and 41/131 [31.3%] chemotherapy). Chemotherapy conferred a non-statistically significant 28% reduction in relative risk of death (HR = 0.72, 95% CI: 0.47-1.08; p = 0.11; adjusted HR = 0.79, 95% CI: 0.52-1.19; p = 0.26). 3 year OS was surveillance: 67% (95% CI: 58-74%; chemotherapy: 79% (71%-85%). There was no evidence of long-term toxicity associated with chemotherapy (Wilcoxon rank-sum test p-value for worst grade post-6 months = 0.32). Most common grade 2+ adverse events were hypertension (25/240 [10.4%]), lethargy (25/240 [10.4%]) and hearing loss (13/240 [5.4%]). There was no evidence of statistically or clinically relevant differences in QoL. 12 months after treatment (EORTC Q30 global health status mean difference 4.1 and 4.8 at 12 and 24 months respectively in favour of chemotherapy). Conclusions: With additional follow-up, the previously reported DFS benefit for chemotherapy was maintained with no detrimental long-term toxicity. No statistically significant improvement in OS was observed. Clinical trial information: NCT01993979.

Purpose: To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites. Patients and Methods: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m2 every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs. Results: Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m2. There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m2 and area under the curve (AUC)0-tn was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC0-24h were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level. Conclusion: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m2 every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.

TPS6091 Background: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. The CompARE trial is designed to test alternative approaches to intensification of treatment for these patients to improve survival. Methods: CompARE is a pragmatic phase III open-label multicenter RCT with an adaptive multi-arm multi-stage design. Eligible OPC patients include those with; HPV negative, T1-T4, N1-N3 or T3-4, N0 or HPV positive current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. The primary outcome measure is overall survival. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complications and cost-effectiveness. The trial is powered to detect a hazard ratio of 0.69 (an improvement of 10% in OS at 3-years) requiring 128 control events. It is estimated that the study will take 6.5 years to recruit sufficient patients to experience the number of events needed. Planned interim futility analyses using event-free survival (EFS) will be performed when 70 and 114 control EFS events have occurred. Current treatment arms are; (1) control: standard treatment of 3-weekly cisplatin 100mg/m2 or weekly 40mg/m2 with Intensity Modulated Radiotherapy (IMRT) using 70Gy in 35F +/- neck dissection determined by clinical and radiological assessment 3-months post treatment. (3) IMRT 64Gy in 25F + cisplatin 100mg/m2 day 1 of week 1 and week 5 or weekly 40mg/m2+/- neck dissection as per standard treatment. (4) Resection of primary + selective neck dissection followed by standard treatment. (5) One cycle of induction durvalumab 1500mg followed by standard treatment then durvalumab 1500mg every four weeks for a total of 6 months. Recruitment to arm (2) involving induction chemotherapy from the original protocol is suspended. Since July 2015, 42 patients have been randomised with 16 sites open to recruitment. The Data Monitoring Committee last reviewed progress and conduct of the trial in September 2016 and recommended continuation. ISRCTN Number: 41478539, CRUK CRUK/13/026 Clinical trial information: 41478539.

4521Background: gemcitabine (G) plus cisplatin (C) is a standard-of-care, combination chemotherapy regimen for patients (pts) with bladder cancer (BC), in both neoadjuvant and palliative settings. ...

e16138Background: The POUT trial compares surveillance (surv) with immediate chemotherapy (CT), following nephroureterectomy (NU) (CRUK/11/027). The primary endpoint is disease free survival. Secon...

448 Background: Whilst cisplatin combination therapy remains the standard of care for patients with advanced urothelial cancers, many patients are unsuitable for cisplatin and go on to receive carboplatin combination therapy. Although responses are frequent, overall outcomes remain poor, and there is a high unmet need for more effective first line treatment. Vandetanib is a well-tolerated, oral inhibitor of vascular and epidermal growth factor receptor tyrosine kinases, both of which are implicated in the pathogenesis of urothelial cancers. Methods: Patients with metastatic or inoperable urothelial cancer who had no prior chemotherapy and were unsuitable for cisplatin were randomly allocated to receive carboplatin (AUC 4.5, day 1) plus gemcitabine (1000mg/m2, days 1 and 8) plus either vandetanib (100mg od, days 1-21) (GCV) or matching placebo (GCP) in 21-day cycles up to a total of 6 cycles. Treatment allocation was double-blind. There was a planned safety review after the first 40 patients had received at least one cycle. The primary endpoint was progression free survival (PFS). Sample size (n=82) was calculated using a one-sided alpha of 0.2 and power 80% to detect a HR of 0.65 for PFS. We present the final efficacy results. The trial was coordinated by the Wales Cancer Trials Unit at Cardiff University and funded by Cancer Research UK (CRUK/09/024) and AstraZeneca. Results: Of 82 patients, 40 received GCV. 62 (76%) had a bladder primary, and 56 (68%) had poor renal function. The arms were well balanced except for age > 75 (13 (16%) GCV, 23 (28%) GCP). Median PFS was 8.5 months (m) (95% CI 6.0, 9.7) and 8.8 m (5.8, 9.0) for GCV and GCP respectively (adjusted hazard ratio (HR) 0.93 (0.50, 1.71), P=0.89). Overall survival was 10.8 m (8.0, 13.0) and 13.8 m (11.1, 16.6) for GCV and GCP respectively (adjusted HR 1.38 (0.77, 2.46), P=0.24). Response rates were 50% (n=20) and 55% (n=23) for GCV and GCP. All-grade adverse events were similar but there were significantly more grade 3+ events in the GCV arm. Conclusion: Vandetanib did not improve efficacy of chemotherapy but increased toxicity in advanced urothelial cancer not suitable for cisplatin. Clinical trial information: 68146831.

Purpose: The purpose of this trial was to establish if maintenance lapatinib after first-line chemotherapy is beneficial in HER1/HER2 positive metastatic urothelial bladder cancer (UBC) patients. Method: Patients with metastatic UBC were screened centrally for HER1/HER2 over expression. HER1/2 positive screened patients, who did not have progressive disease during chemotherapy (4-8 cycles) were randomised (1:1) to lapatinib (L) or placebo (P) after completion of first line/initial chemotherapy for metastatic disease. The primary endpoint was progression free survival (PFS). Results: Between 2007-2013, 446 UBC patients were screened and 232 HER 1 or 2 positive patients were randomised. The median PFS for L and P were 4.5 months (95% CI: 2.8 – 5.4) and 5.1 months (95% CI: 3.0 – 5.8) respectively [HR: 1.07 (95% CI: 0.81 - 1.43) p = 0.63]. The overall survival for L and P were 12.6 months (95% CI: 9.0 – 16.2) and 12.0 months (95% CI: 10.5 – 14.9) respectively [HR = 0.96 (95% CI: 0.7 - 1.31) p = 0.80]. Discontinuation due to AEs were similar in both arms (6% lapatinib and 5% placebo). The rate of grade 3-4 AEs for L and P was 8.6% vs. 8.1% (p = 0.82). Pre-planned subset analysis of i) HER1/HER2 strongly positive patients (3+ on immunohistochemistry: n= 111) ii) HER1 only positive patients (n= 102) iii) HER2 only positive patients (n= 42) showed no significant benefit with lapatinib in terms of PFS and OS (p>0.05 for each). Conclusion: This trial failed to find significant improvements in outcome by the addition of maintenance lapatinib to standard of care.

TPS4574 Background: The triple angiokinase inhibitor nintedanib (nin) has shown reduced proliferation and elevated apoptosis to a greater extent than chemotherapy alone in animal models. We aim to ...

TPS4589 Background: Urothelial cancer (UC) is a chemosensitive disease. There is a clear role for first line, platinum-based chemotherapy in advanced disease, response rates being around 40-50%. Ho...

11079 Background: Increasing demand for testing multiple markers for targeted therapies requires a platform to incorporate molecular diagnostics in the normal pathway of care. This programme was pl...

4531 Background: Standard chemotherapy for advanced germ cell tumors is 3-weekly BEP (bleomycin, etoposide, cisplatin). 5-year overall survival is > 90% in good risk disease, but only ~80% in intermediate and ~ 60% in poor risk disease. Accelerated versions of standard regimens have proven more effective in other malignancies. We aimed to determine tolerability and activity of accelerated (2-weekly) BEP by combining data from two single arm, multi-center, phase I/II trials. Methods: The UK trial (n=16) included patients with intermediate and poor risk metastatic germ cell tumours. The Australian trial (n=45) also included patients with radiologically measurable good risk disease. BEP chemotherapy was repeated every 2 weeks for 4 cycles (3 cycles for good risk). The Australian and UK regimens differed for cisplatin (20mg/m2 D1-5; 50mg/m2 D1-2), etoposide (100mg/m2 D1-5; 165mg/m2 D1-3), bleomycin (30kIU weekly x 12 or 9; 30kIU at 4-6 day intervals x 12), and pegylated G-CSF (6mg D6; 6mg D4) respectively. Primary endpoint for combined analysis was 2-year progression-free survival. Results: 61 patients were enrolled from 2004-09 (UK) and 2008-10 (Australia). 17 had poor risk, 28 intermediate risk, 16 good risk disease. Median follow-up is 27 months (range 6 to 81). Adverse events are presented in the table. 45 of 61 patients (74%) achieved a complete response to chemotherapy +/- surgery (9 of 17 poor risk (53%), 20 of 28 intermediate risk (71%), 16 of 16 good risk disease (100%)). 11 of 61 patients have relapsed. 2 patients have died of disease (both intermediate risk). 2 year overall survival is 98%. 2 year progression-free survival is 65% for poor risk, 86% for intermediate risk, and 92% for good risk disease. Conclusions: Efficacy data are promising, particularly for intermediate and poor risk disease. Adverse events appear comparable to standard BEP. These results provide the rationale for an international trial randomised trial comparing accelerated and standard versions of BEP. [Table: see text]

326 Background: Chemotherapy for penis cancer is used to palliate metastatic disease and treat locally-advanced disease. Pathologic similarities to head and neck SCC suggest that adding docetaxel (T) to platinum-based regimens may enhance efficacy. Methods: A single-stage single-arm phase II trial was conducted. Eligible patients had measurable, histologically proven penile SCC staged M1; or T4, any N, M0; or any T, N3/inoperable N2, M0; or any T, N1, M0 with Multi-Disciplinary Team agreement for chemotherapy as first-line therapy. Treatment was three 21-day cycles of TPF (day 1: T 75mg/m2, P 60mg/m2; days 1-5: F 750mg/m2/day). In 26 evaluable patients ≥14 responses were required to conclude a response rate of ≥60% (p0=0.35, p1=0.60, α=0.1, β=0.2; Fleming-A’Hern design). Primary endpoint was overall response rate at completion/discontinuation of trial treatment. Secondary endpoints included safety, tolerability, progression-free survival (PFS) and overall survival (OS). Results: 29 patients (median age 61 years) were recruited from 9 UK centres between Sept 2009 and Dec 2010. 8 patients were M1. 17 patients had performance status (PS) 0, 11 PS1, 1 PS2. 3 patients discontinued treatment early for reasons other than progression. Dose reductions/delays were reported for 13 patients. 28 patients have on-treatment toxicity data: 19 (68%) experienced grade 3/4 toxicity, with neutropenia most common (n=13, 46%). 7 patients (25%) experienced febrile neutropenia and/or neutropenic sepsis. 10/26 patients (38.5%, 95% CI: 20.2% - 59.4%) in the evaluable population responded. Twelve month PFS was 39.1% (95% CI: 20.9% - 56.8%; median PFS (all 29 patients/M1/M0): 7.1/ 3.1/ 9.6- months). Twelve month OS was 54.6% (34.9% - 70.6%; median OS (all patients/M1/M0): 13.7/ 6.9/ not reached yet-months). Conclusions: UK clinicians successfully recruited to a multi-centre trial in penis cancer, establishing a network of centres for future studies. Toxic effects of TPF were common but not unexpected. The trial did not reach its target response rate of ≥60% to justify further investigation although PFS and OS in this cohort compares favourably to reported data in literature.

235 Background: Meta-analysis data demonstrate a 5% absolute survival benefit for the use of neoadjuvant chemotherapy (NAC) using cisplatin-based combination regimens in the radical treatment of muscle-invasive bladder cancer (MIBC). However, there is currently no randomized controlled trial data on the optimum regimen for this setting. Accelerated MVAC (AMVAC) is effective in advanced disease, and has the potential advantage over other NAC regimens of minimising delays to definitive, potentially curative therapy. We present data regarding its use as NAC in MIBC patients. Methods: Retrospective analysis was performed on all 80 consecutive patients with muscle-invasive transitional cell carcinoma of the bladder, treated during a 50-month period at 2 U.K. centers. Patients received either 3 or 4 cycles of methotrexate 30mg/m2, vinblastine 3mg/m2, doxorubicin 30mg/m2 and 4-hour infusion of cisplatin 70mg/m2 at 2-week intervals, with G-CSF support, prior to definitive therapy with either radical surgery (RS) or radical radiotherapy (RT). Results: All planned cycles of chemotherapy were completed in 84% of patients. All 80 patients received their planned definitive therapy. Pathological complete response (pCR) was seen in 43% of 60 patients treated with surgery following chemotherapy. There were no chemotherapy-related deaths and grade 3 or 4 toxicities were seen in 11% of patients. Median duration of chemotherapy was 34 days. Dose reduction or delay was required in 7% and 9% of patients, respectively. Objective radiological local response was seen in 75% of patients. At a median follow-up of 27.5 months, 25 (32%) patients have relapsed and 11 (14%) died. Two-year disease-free survival was 65% overall, and was statistically significantly superior in patients who were radiologically node-negative prior to chemotherapy. Conclusions: AMVAC is a safe, well-tolerated, and easily deliverable regimen with excellent treatment outcomes and minimizes delays to definitive treatment. It is an appropriate comparator for future randomized trials. No significant financial relationships to disclose.

3080 Background: Reolysin is an isolate of reovirus, a RNA virus which replicates in cells with activated Ras signaling pathway while sparing normal cells. We conducted a phase I/II dose escalation...

e15011 Background: Granulocyte colony-stimulating factor (G-CSF) permits shorter cycle intervals and increased dose density with potential for improved therapeutic ratio. We report a phase II study...

16077 Background: Granulocyte colony-stimulating factor (G-CSF) permits shorter cycle intervals and increased dose density in breast cancer, small cell lung cancer and lymphoma. We report the first phase II study to assess the tolerability and toxicity of a dose dense accelerated BEP regimen in patients with germ cell tumours. Methods: Patients (pts) from 4 UK centres with intermediate and high risk metastatic germ cell tumour according to the IGCCG criteria entered this study. Pts were treated with 4 cycles every 14 days (d) of Cisplatin (50 mg/m2) d1–2, Etoposide (165 mg/m2) d1–3, Bleomycin (30,000 IU, 3 doses/cycle) at 4–6 d intervals and Pegfilgrastin (Neulasta, Amgen 6 mg sc) d4. The planned dose-intensity for each drug was 1.5 compared to standard BEP. Results: 12 of 20 planned pts were recruited 2004–2007. 9 pts had intermediate risk disease and 3 had high risk disease. Ten of 12 pts completed 4 cycles of treatment as planned. Complete response after chemotherapy was achieved in 1 pt (10%) and afte...