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Background The open-label, phase II RECORD-2 trial compared efficacy and safety of first-line everolimus plus bevacizumab (EVE/BEV) with interferon plus bevacizumab (IFN/BEV) in patients with metastatic renal cell carcinoma. Patients and methods Previously untreated patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with either everolimus 10 mg/day (EVE/BEV) or interferon (9 MIU 3 times/week, if tolerated) (IFN/BEV). Tumor assessments occurred every 12 weeks. The primary objective was the assessment of treatment effect on progression-free survival (PFS), based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results Baseline characteristics were balanced between the EVE/BEV (n = 182) and IFN/BEV (n = 183) arms. The median PFS was 9.3 and 10.0 months in the EVE/BEV and IFN/BEV arms, respectively (P = 0.485). The predicted probability of phase III success was 5.05% (hazard ratio = 0.91; 95% confidence interval 0.69–1.19). The median duration of exposure was 8.5 and 8.3 months for EVE/BEV and IFN/BEV, respectively. The percentage of patients discontinuing because of adverse events (AEs) was 23.4% for EVE/BEV and 26.9% for IFN/BEV. Common grade 3/4 AEs included proteinuria (24.4%), stomatitis (10.6%), and anemia (10.6%) for EVE/BEV and fatigue (17.1%), asthenia (14.4%), and proteinuria (10.5%) for IFN/BEV. The median overall survival was 27.1 months in both arms. Conclusions The efficacy of EVE/BEV and IFN/BEV appears similar. No new or unexpected safety findings were identified and, with the exception of proteinuria in about one-fourth of the population, EVE/BEV was generally well tolerated. Clinical trial registry and trial registration number ClinicalTrials.gov: NCT00719264.

This study aimed to clarify epigenetic and genetic alterations that occur during renal carcinogenesis. The original method includes chromosome 3 specific NotI-microarrays containing 180 NotI-clones associated with 188 genes for hybridization with 23 paired normal/tumor DNA samples of primary clear cell renal cell carcinomas (ccRCC). Twenty-two genes showed methylation and/or deletion in 17–57% of tumors. These genes include tumor suppressors or candidates (VHL, CTDSPL, LRRC3B, ALDH1L1, andEPHB1) and genes that were not previously considered as cancer-associated (e.g.,LRRN1, GORASP1, FGD5, andPLCL2). Bisulfite sequencing analysis confirmed methylation as a frequent event in ccRCC. A set of six markers (NKIRAS1/RPL15, LRRN1, LRRC3B, CTDSPL, GORASP1/TTC21A, andVHL) was suggested for ccRCC detection in renal biopsies. The mRNA level decrease was shown for 6 NotI-associated genes in ccRCC using quantitative PCR:LRRN1, GORASP1, FOXP1, FGD5, PLCL2,andALDH1L1. The majority of examined genes showed distinct expression profiles in ccRCC and papillary RCC. The strongest extent and frequency of downregulation were shown forALDH1L1gene both in ccRCC and papillary RCC. Moreover, the extent ofALDH1L1mRNA level decrease was more pronounced in both histological types of RCC stage III compared with stages I and II (P=0.03). The same was observed forFGD5gene in ccRCC (P<0.06).

INTRODUCTION AND OBJECTIVES: In screening test for bladder cancer (BCa), conventional urine cytology (CUC) is subjective exam with low sensitivity and cystoscopy is invasive and expensive exam for patients. We developed the new fluorescent urine cytology using spectrophotometer for voided urine treated with 5-ALA. The objective of this study is to elucidate the sensitivity of CUC and 5-ALAphotodynamic diagnosis (ALA-PDD). METHODS: 143 urine samples were collected from 58 patients who were proved BCa by TURBT and 85 patients who were proved no bladder mass by cystoscopy. Half of each urine sediment was exposed to 5-ALA (1mM) for 2 hours and the rest of that was used as negative control. The fluorescent intensity of protoporphyrin IX (PPIX), which is the metabolite of 5-ALA in the heme biosynthetic pathway, was measured using the spectrophotometer (excitation filter 380-420 nm, emission filter 590 nm). The sample treated with 5-ALA, which indicated stronger intensity than untreated sample, was evaluated as positive. After histological diagnosis, the results of ALA-PDD were compared with the histological diagnosis. RESULTS: Of 58 cases with proven BCa, 48 were evaluated as positive by ALA-PDD (sensitivity: 83 %) and 28 were evaluated as positive by CUC (sensitivity: 48 %). Of 85 cases with proven no cancer with cystoscopy, 17 ALA-PDD positive cases were detected (specificity: 80 %). The positive and negative predictive value of ALA-PDD was 74 % and 87 %. The proportion of ALA-PDD positive in proven cancer was increased to 70% in pTa, 85% in pT1, 91% in pTis and 100% in T2, respectively (

Hydraulic Fracturing in Western Siberia, Russia is a common practice that the need of stimulating wells in mature oil fields cannot be limited to non-complicated reservoirs. Wells requiring hydraulic fracturing with water zones either above or below is what we mean as reservoirs that require techniques that are out of the ordinary and day to day operations. A technique using dry solid material to contain the hydraulic fracture job within the zone of interest has been used in several wells and will be presented in this paper. The oil field Nivagalskoe which is located in Nizhnevartovsk area, Western Siberia, Russia is considered a mature oil field where due to the low value of the reservoir permeability, hydraulic fracturing these reservoirs require more than a skin bypass frac. Achieving a lengthier propped frac and descent net pressure increase is always a challenge on any hydraulic fracturing job execution but is always a must for the oil fields in the Nizhnevartovsk area. The challenge becomes when there are water zones close to the zone of interest to be stimulated via hydraulic fracturing. The objective is only not to design a job that will be limited in height by optimizing parameters commonly used in limiting frac geometry but to guarantee at best that the frac will not grow into the water zone. Several cas histories will be presented where all cases the water cut was measured before and after the hydraulic fracturing job. The technique used and recommendations will be presented to optimize future jobs. All other options to limit frac geometry considered will also be presented.

4518 Background: In the pivotal RECORD-1 trial, EVE was superior to placebo in pts with mRCC previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and ...

e16003 Background: Technetium Tc99m trofolastat chloride is a novel small molecule SPECT radiotracer with high affinity binding to the external domain of prostate specific membrane antigen highly e...

94 Background: Technetium (Tc99m) trofolastat (USANC) is a novel urea-based small molecule SPECT radiotracer with utility in imaging overexpression of PSMA in prostate cancer (PCa). Unlike earlier agents targeting PSMA, this ligand is rapidly internalized and retained in tumors. We conducted an open-label, multicenter phase 2 study in the US and Europe (NCT01667536). An interim analysis was performed at approximately 50% accrual. Methods: Patients (pts) with confirmed adenocarcinoma of the prostate scheduled for RP with EPLND at high risk for disease outside of the prostate gland were eligible. High risk pts were ≥cT3 or Kattan nomogram score ≥130. Within 30 days of screening, pts required a bone scan and pelvic MRI. After enrollment, pts received trofolastat followed by whole-body planar and SPECT/CT imaging 3 to 6 hrs later. Pts then underwent RP with EPLND within 21 days. SPECT/CT images were evaluated centrally by 3 readers blinded to clinical information and compared to on-site pathology assessments using a common scoring template. The primary endpoint was the ability of trofolastat to detect PCa within the gland. Secondary endpoints included detection of extent and location within the gland, pelvic lymph nodes and comparative performance against MRI. Results: 84 pts were enrolled to date from 16 centers. Interim data is available for 54 pts. A majority (≥2/3) of SPECT/CT readers correctly identified the presence or absence of primary PCa in 51/54 (94%, 85-98 95% CI) patients including 2 true-negative cases treated with neoadjuvant enzalutamide. Sensitivity and specificity were 94% (84-98 95% CI) and 100% (34-100 95% CI) respectively. Conclusions: Based on the interim data available, trofolastat has accurately detected primary prostate carcinoma within the gland with high sensitivity and specificity in high-risk pts prior to surgery. Updated results, analyses of secondary endpoints, pelvic lymph nodes, and comparative performance vs. MRI from this ongoing study will be presented. Clinical trial information: NCT01667536. [Table: see text]

TPS5099 Background: Cbz 25 mg/m2 IV Q3W + P 10 mg PO QD has an established safety profile and significantly improves overall survival (OS) vs mitoxantrone + P in pts with mCRPC previously treated with a D-containing regimen (phase III TROPIC study; NCT00417079; median OS: 15.1 vs 12.7 mos; HR: 0.70; P < 0.0001). Pooled data on file suggest that lower Grade 3–4 neutropenia rates are observed with Cbz < 25 vs ≥ 25 mg/m2 (61% vs 74%). In an attempt to further improve the therapeutic index of Cbz in the second-line treatment of mCRPC, PROSELICA (NCT01308580) was designed to assess whether Cbz 20 mg/m2 is associated with lower hematologic toxicity and has non-inferior efficacy compared with the standard 25 mg/m2dose. Methods: PROSELICA is a randomized, open-label, multinational, phase III study comparing the efficacy and tolerability of IV Cbz 20 with 25 mg/m2, Q3W. Pts with a life expectancy > 6 mos, ECOG PS ≤ 2, confirmed mCRPC and prior therapy with a D-containing regimen are eligible. Pts are randomized 1:1 to Cbz dosing arms; all pts receive P 10 mg PO QD and are treated until disease progression, unacceptable toxicity or consent withdrawal (max. 10 cycles). Pts are stratified by ECOG PS, measurable disease and region of the world. The primary endpoint is OS (non-inferiority). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in subgroups. Planned enrollment is 1200 pts. The study started in May 2011; by 31 Dec 2012, 851 pts had been enrolled. 158 sites are enrolling pts. Based on a review of safety and efficacy endpoints, the last Data Monitoring Committee meeting (Dec 2012) recommended continuing the study without change. Clinical trial information: NCT01308580. [Table: see text]

4576 Background: RECORD-2 (NCT00719264) primary analysis demonstrated similar median progression-free survival (PFS) for pts with mRCC treated with E+B and I+B (Dec 2011 cut-off). The primary objective was not met; median PFS in E+B/I+B was 9.3/10.0 mo (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P=0.485) and probability of success (PoS) of a subsequent phase III trial was 5.1%. Here we present final OS and safety/exposure results (Aug 2012 cut-off). Methods: Untreated pts with clear cell mRCC and previous nephrectomy were randomized 1:1 to B 10 mg/kg every 2 weeks and either E 10 mg/day or I (9 MIU 3 times/week). The primary objective was treatment effect on PFS per central review based on an estimation of PoS (≥50%) of a subsequent phase III study. Secondary objectives included OS and safety. Results: In E+B (n=182) and I+B (n=183) arms, median age was 60/60 years and 76/72% of pts were men, respectively. In both arms, most pts (93%) were of favorable/intermediate MSKCC risk. Median follow-up was 33 mo. In E+B and I+B arms, 51/52% of pts died, respectively. Median OS (95% CI) was 27.1 mo (19.9-35.3) in the E+B arm and 27.1 mo (20.4-30.8) in the I+B arm. After discontinuing study treatment, 64/60% of pts in E+B and I+B arms, respectively, received antineoplastic therapy. Median exposure duration in E+B and I+B arms was 8.5/8.3 mo, respectively; AEs resulted in treatment discontinuation for 23/25% of pts, respectively. The most frequent AEs (%) were stomatitis (63), proteinuria (50), diarrhea (40), hypertension (38), and epistaxis (35) in the E+B arm and decreased appetite (45), fatigue (42), proteinuria (38), asthenia (35), and pyrexia (35) in the I+B arm. The most frequent grade 3/4 AEs (%) were proteinuria (24), stomatitis (11), and anemia (11) for E+B and fatigue (17), asthenia (14), and proteinuria (10) for I+B. Conclusions: OS of E+B and I+B was similar. OS results are consistent with PFS primary analysis. First-line treatment with mTOR inhibitor-based therapy did not impair chance of survival relative to standard therapy. No new safety issues were identified and E+B remained generally well tolerated. Clinical trial information: NCT00719264.

Background Study results demonstrated that IFN augments BEV activity and improves median PFS in pts with mRCC. Thus, combination BEV + IFN is a standard first-line treatment option for mRCC. Combining BEV with the mTOR inhibitor EVE may be an efficacious and well-tolerated treatment option. The open-label, phase II RECORD-2 trial compared first-line EVE + BEV and IFN + BEV in mRCC. Patients and methods: Therapy-naive pts with clear cell mRCC and prior nephrectomy were randomized 1:1 to BEV 10 mg/kg IV every 2 weeks with either EVE 10 mg oral daily or IFN (9 MIU SC 3 times/week, if tolerated). Tumour assessments were every 12 weeks. Primary objective was treatment effect on progression-free survival (PFS) per central review based on an estimate of the chance of a subsequent phase III trial success (50% threshold for phase II success). Results In EVE + BEV (n = 182) and IFN + BEV (n = 183) arms, median age was 60/60 years, 76/72% of pts were men, MSKCC risk was favourable/intermediate/poor in 36/57/7% and 36/57/7% of pts, and 43/46% of pts had >2 organs involved, respectively. For EVE + BEV and IFN + BEV, median treatment duration was 8.5/8.3 months, respectively; 23/26% of pts discontinued due to AEs. In EVE + BEV and IFN + BEV arms, median PFS by central review was 9.3/10.0 months (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P =0.485), respectively; probability of subsequent phase III success was 5.1%. Results of central and local PFS analysis were consistent. Objective response rate was 27/28% in EVE + BEV and IFN + BEV arms, respectively. Median overall survival (OS) was not reached in the EVE + BEV arm and was 25.9 months (95% CI: 21.1, 30.2) in the IFN + BEV arm. Most frequent AEs (%) were stomatitis (63), proteinuria (49), diarrhoea (39), hypertension (38), and epistaxis (35) in EVE + BEV arm and decreased appetite (45), fatigue (41), proteinuria (37), and pyrexia (35) in IFN + BEV arm. Conclusions In RECORD-2, PFS and tolerability were similar for first-line EVE + BEV and IFN + BEV. Final OS analysis will occur after 2-year follow-up. Disclosure A. Ravaud: Alain Ravaud is a member of global, European, and/or French boards on urological tumors for Pfizer, Novartis, GlaxoSmithKline, Bayer-Schering, and Dendreon, and has received institutional grant support from Pfizer, Novartis, and Roche. O. Anak: Ozlem Anak is an employee of Novartis Pharma AG. D. Pelov: Diana Pelov is an employee of Novartis Pharmaceuticals Corporation. A. Louveau: Anne-Laure Louveau is an employee of Novartis Pharma S.A.S. T. M-H: Tay M-H is a speaker for an advisory board for Novartis Pharmaceuticals Corporation. B. Melichar: Bohuslav Melichar has received honoraria from Novartis and Roche and served on an advisory board for Roche. All other authors have declared no conflicts of interest.

Background In the AVOREN trial, first-line BEV + IFN (9 MIU three times in a week [tiw]) was effective in patients (pts) with mRCC. A retrospective analysis found that efficacy was maintained and IFN-related toxicity was improved in pts with IFN dose reduced to 6 or 3 MIU. BEVLiN (MO21609) prospectively assesses the safety and efficacy of BEV with low-dose IFN (3 MIU) in mRCC. Methods BEVLiN is an open-label single arm, multinational phase 2 study. Nephrectomized, treatment-naive pts with clear cell mRCC and favourable/intermediate Motzer scores were treated with BEV 10mg/kg q2w + IFN 3 MIU tiw until disease progression. BEVLiN was designed to allow descriptive, cross-trial comparison with the BEV + IFN 9 MIU-treated favourable/intermediate Motzer score AVOREN subgroup. Primary end points are safety (specific grade [Gr] ≥3 IFN-associated adverse events [AEs]) and progression-free survival (PFS). Secondary end points are overall survival (OS); overall response rate (ORR); any Gr ≥3, overall, and serious AEs. Results 147 pts were enrolled in BEVLiN. Baseline pt characteristics were similar to the comparator AVOREN subgroup. The median follow-up was 29.4 months. Pts received a median of 22.5 cycles of BEV (18.0 in the AVOREN subgroup). Median PFS was 15.3 mos (95% CI: 11.7; 18.0) vs 10.5 mos (95% CI: 10.1; 12.9); median OS was 30.7 mos (95% CI: 25.7; not reached) vs 25.8 mos (95% CI: 22.7; 29.4); and ORR was 29% vs 36% in BEVLiN and the AVOREN subgroup, respectively. The rates of any-Gr and Gr ≥3 IFN-associated AEs were markedly lower in BEVLiN than in the AVOREN subgroup (Table). Overall rates of AEs of special interest were similar between studies, despite longer BEV duration in BEVLiN. AE, % (95% CI) BEVLiN n = 146 a AVOREN subgroup n = 283 a Any Gr Gr ≥3 Any Gr Gr ≥3 Any IFN-related AE 53 (45–62) 10 (6–16) 89 (85–92) 27 (22–32) · Asthenia/fatigue 37 (29–45) 10 (5–16) 63 (57–68) 21 (16–26) · Pyrexia 19 (13–27) 0 (0–2) 45 (39-51) 2 (1–4) · Nausea 9 (5–15) 1 (0–4) 29 (23–34) 1 (0–3) · Anorexia 0 (0–2) 0 (0–2) 36 (30–42) 3 (1–5) Any BEV-related AE of special interest b 59 (50–67) 23 (17–31) 60 (54–66) 23 (18–28) a Treated pts. b Includes hypertension, proteinuria, bleeding, and other AEs. Conclusions Use of low-dose IFN with BEV in BEVLiN resulted in a reduction in IFN-related AEs without compromising efficacy outcomes compared with a control AVOREN subgroup. Disclosure B. Melichar: Dr. Bohuslav Melichar has received honoraria for lectures from Roche and participated in an advisory board meeting. S. Bracarda: Dr. Sergio Bracarda is an Advisory Board Member for Novartis, Pfizer, GSK, Bayer, Aveo/Astellas, Jannsen &Jannsen and Sanofi-Aventis. He has received honoraria for lectures from Novartis, Sanofi-Aventis and Pfizer. R. Janciauskiene: Dr. Janciauskiene has been principal investigator in a Hoffmann-La Roche sponsored trial and has been an invited speaker for Hoffmann-La Roche. B. Lutiger: Beatrix Lutiger is an employee of F. Hoffmann-La Roche AG. M.E. Gore: Dr. Martin Gore has participated advisory board meetings and is on the speaker's bureau for Roche. G. Mickisch: Dr. Gerald Mickisch is a member of the BEVLiN Steering Committee. J. Bellmunt: Dr. Joaquim Bellmunt has participated in an advisory board meeting, and received a lectures fee from Roche. All other authors have declared no conflicts of interest.