bluuebunny/crossref_metadata_2025_split huggingface dataset:
A randomized phase II study of pazopanib in castrate-sensitive prostate cancer: A University of Chicago phase II consortium/DoD Prostate Cancer Clinical Trials Consortium study.
Authors: Ward J. E. , Limvorasak S. , Karrison T. , Chatta G. S. , Hussain M. , Shevrin D. H. , Szmulewitz R. Z. , Stadler W. M. , Posadas E. M. 
Published: February 2017

170 Background: Intermittent androgen suppression (IAS) has been studied as a way of minimizing toxicity from long term androgen deprivation therapy (ADT). Based on previous studies with similar agents, we hypothesized that inhibition of VEGFR would result in prolonged time to PSA progression (TTPP) and allow for longer periods off ADT. Methods: Men with biochemically recurrent, progressive prostate cancer and no evidence of macroscopic metastases were enrolled. They received 6 months of ADT. If at the end of that time the PSA was <0.5 ng/mL (with castrate testosterone levels), they were randomized to pazopanib 800 mg/d or observation. The primary outcome was TTPP, defined as time to a PSA >4.0 ng/mL, at which time they were restarted on ADT. Results: 37 pts met randomization criteria. 18 were randomized to pazopanib. Only 4 pts met the endpoint criteria of TTPP, whereas 13 (72%) pts went off study for other reasons with 1 pt on treatment at study closure. Reasons for discontinuation included drug toxicity (grade 1/2, 9 pts) and patient preference (2 pts). No grade 3/4 toxicity was noted. 1 pt was removed due to pulmonary embolus, 1 pt due to MD discretion and 1 pt due to noncompliance. 19 pts were randomized to observation of which 12 were off treatment when the study was stopped. Only 5 pts met criteria for TTPP, whereas 7 of 12 (58%) dropped out for other reasons, including the frequency of protocol related blood draws and visits (3 pts) and randomization to observation (2 pts), 1 pt was removed per MD discretion and 1 pt transferred care. Due to high dropout rates in both arms, accrual was halted as the primary endpoint could not be measured robustly. Conclusions: Minimizing the long term toxicities of ADT is an unmet need in prostate cancer therapy. Hence clinical interventions in concert with IAS represent an attractive area for drug development. This trial has outlined several barriers that exist in studying this patient population and might help to optimize future studies. Future trial design in this arena should investigate drugs with minimal toxicity and employ a design that maximizes patient convenience while anticipating the low threshold for patient drop out. No significant financial relationships to disclose.
Assessment of two prognostic risk group methods to predict outcomes with docetaxel-based therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pond G. R. , Armstrong A. J. , Wood B. A. , Brookes M. , Leopold L. H. , Burke J. M. , Caton J. R. , Fleming M. T. , Sonpavde G. 
Published: February 2017

185 Background: Threeprognosticrisk groups have been identified in men with mCRPC (good [GR]/intermediate [IR]/poor [PR]) based on 0-1, 2 or 3-4 factors (visceral disease, pain, anemia, bone scan progression). Prostate Cancer Working Group (PCWG)-2 defines clinical subtypes with visceral disease, bone metastases ± nodal metastases and nodal disease only. The prognostic ability of risk grouping or PCWG2 subtypes was evaluated in a large, independent phase II trial. Methods: A randomized phase IItrial of 221 men with mCRPC that received docetaxel-prednisone (DP) + AT-101 (Bcl-2 inhibitor) or DP + placebo was retrospectively analyzed using Cox regression and χ2 tests. Additional outcomes, tests and measures of discriminatory ability were assessed and will be presented. Patients from both groups were combined for analysis, as no significant differences in outcomes were observed. Results: 93, 81 and 38 men had GR, IR and PR disease. GR men were more likely than IR/PR men to be ECOG-PS 0 (48%, 27%, 21%) and had a lower median baseline PSA (63, 85, 193 ng/ml). Significant differences between risk groups were observed for progression-free survival (PFS, p=0.009) and overall survival (OS, p<0.001), while PCWG2 subtypes did not discriminate for these outcomes. Both risk groups and PCWG2 subtypes inconsistently predicted PSA declines (table). Conclusions: Prognostic risk groups significantly distinguished between outcomes in men with mCRPC receiving DP-based therapy, while PCWG2 subtypes did not. Risk groups may enhance stratification of patients in randomized trials and enable tailored drug development. Prognostic models that incorporate tumor molecular features may improve discriminatory ability. [Table: see text] [Table: see text]
The effect of pulmonary function testing on bleomycin dosing in germ cell tumors.
Authors: Houghton B. B. , Grimison P. S. , Toner G. C. , Chatfield M. , Thomson D. B. , Friedlander M. , Gebski V. , Rosenthal M. , Gurney H. , Stockler M. 
Published: February 2017

227 Background: Lung function testing (LFT) during chemotherapy with bleomycin is controversial. We describe the impact of LFT on bleomycin dosing in a phase II trial of accelerated BEP for advanced germ cell tumors. Methods: Patients had measurable disease and were stratified with the International Germ Cell Cancer Consensus Classification (IGCCC). The planned number of weekly bleomycin doses was 12 for intermediate risk (IR) and poor risk (PR) disease, and 9 for good risk (GR) disease. Clinical assessments, CXR, DLCO corrected for haemoglobin, and FVC were done 2-weekly. Bleomycin was to be stopped for: predefined clinical or CXR evidence of pulmonary toxicity; or a >25% reduction in DLCO or FVC; or GFR <35mL/min. We determined bleomycin doses planned, received, and omitted; and, patients receiving all, ≥2/3, or <2/3 of their planned bleomycin doses. Results: The first 30 patients had a median age of 28 (range 19-39) and 10 with lung metastases. 80% (259/324) of planned bleomycin doses were received; 75 doses (20%) were omitted in 15 pts, all for >25% reduction in DLCO. 16 patients had a 10 to 24% reduction in DLCO but none had >35%. In all patients the decline in FVC was < 10%. No patient developed other evidence of pulmonary toxicity. Patients with lung metastases were 2.5 times as likely to have a >25% reduction in DLCO (50% vs 20%, p=0.15), and 4 times as likely to receive <2/3 of their planned doses (40% v 10%, p=0.14). Conclusions: Asymptomatic reductions in DLCO caused 20% of bleomycin doses to be omitted and 20% of patients to receive < 2/3 of their planned doses. A 25% reduction in DLCO may be too cautious a threshold, particularly in those with lung metastases. [Table: see text] No significant financial relationships to disclose.
Defining “cisplatin ineligible” patients with metastatic bladder cancer.
Authors: Galsky M. D. , Hahn N. M. , Rosenberg J. E. , Sonpavde G. , Oh W. K. , Dreicer R. , Vogelzang N. J. , Sternberg C. N. , Bajorin D. F. , Bellmunt J. ,   Cisplatin Ineligibility in Bladder Cancer Working Group
Published: February 2017

238 Background: Cisplatin-based chemotherapy is standard first-line treatment for patients (pts) with metastatic urothelial carcinoma (UC). However, a large proportion of pts with UC are considered “unfit” for cisplatin, leading to clinical trials designed specifically for cisplatin-ineligible pts, with substantial variability in eligibility criteria. A clear and consistent definition of pts “unfit” for cisplatin-based therapy will aid in the development of standard eligibility criteria. Methods: We assembled a panel of GU medical oncologists and followed a three-fold approach. First, we surveyed 120 international GU medical oncologists. Subsequently, we reviewed the literature regarding ‘cisplatin ineligibility‘ in solid tumors. Finally, the panel reconciled the survey results and available literature and generated a consensus definition. Results: Responses were received from 65/120 (54%) of those surveyed. The survey results are shown in the Table . Reconciling the survey results with the available literature, the panel recommended the following be used to consistently define pts with metastatic UC “unfit” for cisplatin-based chemotherapy for clinical trial purposes: (1) ECOG performance status of 2 and/or (2) creatinine-clearance < 60 ml/min and/or (3) CTCAE Gr ≥ 2 hearing loss and/or (4) CTCAE Gr ≥ 2 neuropathy. Conclusions: Substantial variability exists in investigators' definitions of pts with metastatic UC “unfit” for cisplatin. A consensus definition is proposed for standardization of eligibility criteria. [Table: see text] No significant financial relationships to disclose.
Results of a phase II study of single-agent nab-paclitaxel in platinum-refractory second-line metastatic urothelial carcinoma (UC).
Authors: Sridhar S. S. , Canil C. M. , Mukherjee S. D. , Winquist E. , Elser C. , Eisen A. , Reaume M. N. , Zhang L. , Ko Y. 
Published: February 2017

241 Background: There is currently no standard second-line chemotherapy for platinum- refractory UC. Both paclitaxel and docetaxel are commonly used but response rates are < 20% and no survival advantage has been shown. In this multi-institutional phase II study, we evaluated the efficacy and tolerability of a new albumin-bound nanoparticle formulation of paclitaxel, known as Abraxane (ABI-007) as a single agent in patients with platinum-refractory metastatic UC. Methods: Patients with measurable UC, progressing on or after first-line platinum-based chemotherapy were enrolled onto this two-stage trial. ABI-007 was given at 260 mg/m2 IV q3weekly until progression. Clinical evaluation, CBC and blood chemistries were performed every cycle with restaging CT scans every 2 cycles. Results: Accrual is now complete with 48 patients enrolled. Baseline characteristics: Male: Female 40:8; median age 68; ECOG Performance Status 0:1:2, 15:24:8. 248 cycles were delivered: median 5.5 cycles/pt with 17/48 pts (35%) requiring dose reductions. Most frequent adverse events (AE) were alopecia (12%), fatigue (12%), pain (12%), neuropathy (9%) and nausea (4%). The most frequent grade 3+ AE were pain (45%), hypertension (14%), fatigue (8%), joint stiffness (5%), neuropathy (4%) and weakness (4%). Forty patients are evaluable for response: 1 (2.5%) complete response (CR), 11 (28%) partial responses (PR), 9 (23%) stable disease (SD) and 20 (49%) progressive disease. One patient was inevaluable for response, 7 patients are too early for evaluation. Conclusions: Single-agent ABI-007 was well tolerated with a response rate (CR+PR) of 33% (12/36) and a clinical benefit rate (CR+PR+SD) of 58% (21/36), representing one of the highest reported response rates to date in the second-line UC setting. These results suggest further study of ABI-007 in urothelial carcinoma is warranted. No significant financial relationships to disclose.
Phase II study of single-agent volasertib (BI 6727) for second-line treatment of urothelial cancer (UC).
Authors: Stadler W. M. , Vaughn D. J. , Sonpavde G. , Vogelzang N. J. , Tagawa S. T. , Rosen P. J. , Lin C. , Mahoney J. F. , Zhao C. , Carducci M. A. 
Published: February 2017

253 Background: Polo-like kinase 1 (Plk1) controls multiple essential steps of mitosis. Volasertib (BI 6727) is a first-in-class, selective inhibitor of Plk1. In vitro, Plk1 depletion in cancer cells leads to activation of the mitotic checkpoint, prolonged mitotic arrest, and eventually apoptosis. No standard therapy exists for metastatic urothelial cancer (UC) progressing after initial chemotherapy. Thus, there is an urgent need for novel treatment options. Interim efficacy and tolerability results are presented from an open-label, single-arm, multi-center phase II trial of volasertib in patients (pts) with previously treated advanced UC. Methods: Pts progressing after one prior systemic chemotherapy for locally advanced or metastatic UC or relapsing within 2 years of adjuvant/ neoadjuvant treatment received 300 mg volasertib (2-hour intravenous infusion) on day 1 every 21 days. If well tolerated, dose escalation to 350 mg in cycle 2 was encouraged. Primary endpoint was objective tumor response, defined by RECIST. The trial follows a modified Gehan-two-stage design with an early stopping rule based on the observed response rate of the first 20 pts receiving up to 4 courses of treatment. A minimum response rate of 10% (2/20) was required to recommend additional study. Results: This trial is ongoing: 31 pts (median age 67) were treated between December 2009 and August 2010. All pts were eligible for interim safety/efficacy analysis. As of August 2010, 6 pts (19%) demonstrated a partial response, 7 pts (23%) had stable disease and 16 (52%) progressed between 3-6 weeks after study initiation. Thirteen (42%) pts remain on trial between 13-41 weeks (median time on trial 5 months) without disease progression. Major grade 3 or 4 adverse events (irrespective of drug relatedness) were neutropenia (10 pts, 32%), thrombocytopenia (7 pts, 23%), anemia (5 pts, 16%), hyponatremia (3 pts, 10%), dehydration (2 pts, 7%), and urinary tract infection (2 pts, 7%). Conclusions: Single-agent volasertib was well tolerated and demonstrates clinical activity in the second-line treatment of pts with advanced UC. The early signs of clinical benefit allows proceeding per protocol to the second stage of the trial. [Table: see text]
Effect of recombinant human endostatin on antitumor efficacy of paclitaxel/gemcitabine/cisplatin (TGP) chemotherapy in the treatment of advanced urothelial carcinoma.
Authors: Guo J. , Sheng X. N. , Cui C. L. , Si L. , Chi Z. H. 
Published: February 2017

265^ Background: Rh-endostatin is a new recombinant human endostatin that can inhibit tumor endothelial cell proliferation, angiogenesis, and tumor growth in the pre-clinical studies. A phase III study revealed that rh-endostatin in combination with chemotherapy shows a synergic activity in advanced NSCLC patients. This study aims to evaluate the response, median progression-free survival (PFS), overall survival time (OS), and safety of the regimen, paclitaxel/gemcitabine/cisplatin (TGP) plus rh-endostatin, in patients with advanced urothelial transitional carcinoma. Methods: The phase II trial included 35 patients with histologically diagnozed advanced or metastatic urothelial carcinoma, ECOG performance status 0-1, and GFR>60ml/min. TGP chemotherapy plus rh-endostatin as a first line treatment included: paclitaxel (80 mg/m2, d1&8), gemcitabine (1000 mg/m2, d1&8), cisplatin (30 mg/m2, d1 to 3) and rh-endostatin (15mg, d1 to 14, every 21d). For every 2 cycles, patients were evaluated for progression or response. Patients who had achieved an objective response (complete or partial) or who had stable disease were further treated for two cycles. Results: The overall objective response rate was 62.8% (95% confidence interval [CI, 46.8% to 78.8%]), including 4 (11.4%) complete response (CR) and 18 (51.4%) partial responses (PRs). Six patients (17.1%) had stable disease (SD), and 7 (20.0%) had progression disease (PD). The disease control rate was 80.0%. The median progression-free survival and overall survival have not been reached. The most common adverse events included gastrointestinal reaction, alopecia, and myelosuppression. Grade 3/4 adverse events, including thrombocytopenia in 42.9% (15/35) of patients and leucopenia in 34.3% (12/35) of patients, were observed. Conclusions: The addition of rh-endostatin to TGP regimen for advanced urothelial carcinoma patients might have higher response rate. Rh-Endostatinin combination with TGP chemotherapy showed a synergic activityand a favorable toxic profile in advanced urothelial carcinoma patients. No significant financial relationships to disclose.
Development of a real-time multiplex PCR assay for the detection of FGFR3 mutations in urine.
Authors: Millholland J. , Patel S. G. , Fernandez C. A. , Shuber A. P. 
Published: February 2017

271 Background: We have recently reported the development of a Multi-Analyte Diagnostic Readout (MADR) non-invasive assay using urinary matrix metalloproteinases (MMPs) and FGFR3 as triage monitors in high-risk bladder cancer populations. This concept combines the marker performance characteristics of protein and DNA biomarkers into one assay for optimal performance. Eight common FGFR3 mutations in 3 exons have been associated with bladder cancer. Analysis of mutational status for each single mutation required 8 amplification steps, which were costly and time consuming. We have now developed a real-time multiplexed FGFR3 assay, generating a cost-effective, clinically applicable assay for the detection of FGFR3 mutations in urine. Methods: Our approach involves a two-step PCR amplification process. The initial round generates exon specific PCR products, which are then used as template for real-time PCR mutation detection utilizing locked nucleic acid (LNA) oligonucleotides. The LNA suppress wild-type DNA amplification. To convert our existing FGFR3 assay to a multiplex format, primary amplifications of exons 7, 10, and 15 were combined into a single real-time PCR assay for exon specific amplification and DNA quantitation. The LNA-mediated mutation detection was then converted from 4 reactions to 2 duplex amplifications. All multiplex assays were carried out on the Roche LC 480 real-time PCR platform. Results: To validate the new multiplex format, FGFR3 multiplex analysis was performed on DNA isolated from 50 Ta stage bladder tumors. FGFR3 mutations were detected in 90% (48/50) of the tumors. To directly compare performance with single mutation analysis, 40 urine samples previously analyzed using the singleplex format were again tested using the multiplex FGFR3 assay. 100% concordance was seen between the two assay formats. Conclusions: By multiplexing the FGFR3 mutation analysis we reduced the number of amplification steps, improving assay turnaround time and throughput, without compromising assay performance. The FGFR3 multiplex analysis provides a robust, cost-effective DNA assay that in combination with MMP protein analysis delivers a clinically applicable assay with optimal performance. [Table: see text]
A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical therapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013.
Authors: Klotz L. , O'Callaghan C. J. , Ding K. , Dearnaley D. P. , Higano C. S. , Horwitz E. M. , Malone S. , Goldenberg S. L. , Gospodarowicz M. K. , Crook J. M. 
Published: February 2017

3 Background: In men with PSA recurrence after radical radiotherapy (RRT), intermittent androgen suppression (IAS) has been suggested by phase II trials to improve quality of life (QoL) but effects on survival are unknown. In this Intergroup randomized phase III trial, we compared IAS vs continuous androgen deprivation (CAD) to test for non-inferiority of IAS with respect to overall survival (OS). Methods: Eligible men had rising PSA > 3.0 ng/ml >1 year post RRT, either initial or salvage, for localized prostate cancer. Patients could receive up to 1 year of neo/adjuvant androgen deprivation therapy (ADT) completed >1 year prior. Stratification factors were time since RRT (>1-3 vs >3 years), initial PSA (<15 vs >15), prior radical prostatectomy and prior ADT. IAS was delivered for 8 months in each cycle with restart when PSA reached >10 ng/ml off treatment. Primary endpoint was OS; secondary endpoints included time to hormone refractory state (HR), QoL, cholesterol/HDL/LDL, duration of treatment/non-treatment intervals, time to testosterone and potency recovery. The independent DSMC recommended halting the trial after a planned interim analysis demonstrated that a pre-specified stopping boundary for non-inferiority was crossed. Results: 1,386 patients were randomized to IAS (690) or CAD (696) arms. Arms were balanced for important baseline factors. Median follow up was 6.9 years. IAS patients completed a median of 2 x 8 month cycles (range: 1-9). 524 deaths were observed (268 on IAS vs 256 on CAD). Median OS was 8.8 vs 9.1 years on IAS and CAD arms, respectively (HR 1.02, 95%CI 0.86-1.21; p for non-inferiority [HR IAS vs CAD ≥ 1.25] = 0.009). The IAS arm had more disease related (122 vs 97) and fewer unrelated (134 vs 146) deaths. Time to HR was statistically significantly improved on the IAS arm (HR 0.80, 95%CI 0.67-0.98; p = 0.024). IAS patients had reduced hot flashes, but otherwise there was no evidence of differences in AEs, including myocardial events or osteoporotic fractures. Conclusions: In men with PSA recurrence after RRT IAS, given as described herein, is non-inferior to CAD with respect to OS. No significant financial relationships to disclose.
Association of genetic markers in angiogenesis- or exposure-related genes with overall survival in pazopanib (P) treated patients (Pts) with advanced renal cell carcinoma.
Authors: Xu C. , Ball H. A. , Bing N. , Sternberg C. N. , Xue Z. , McCann L. , King K. , Spraggs C. F. , Mooser V. E. , Pandite L. N. 
Published: February 2017

303 Background: Pazopanib, an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit, has been approved for the treatment of advanced renal cell cancer (RCC). Interindividual variability in response and survival is observed among advanced RCC pts treated with P. Our previous analyses showed that germline variants in angiogenesis (IL8, HIF1A, VEGFA)- and exposure (NR1IR)-related genes may predict progression free survival and/or response rate to P monotherapy (ASCO 2010 abstract 4520). This study sought to test the hypothesis that differences in overall survival (OS) can be explained, at least in part, by germline genetic variants in angiogenesis- and/or exposure-related genes. Methods: Twenty-seven functional polymorphisms within 13 genes were evaluated in 241 P treated pts with advanced RCC from a phase III study (ESMO 2010 abstract LBA22) and a single arm Phase II study. Genetic association with OS was analyzed using the Cox proportional hazards model. Results: Six polymorphisms in IL8, FGFR2, VEGFA, FLT4, and NR1I2 showed nominally significant association with OS (p≤0.05). A median OS of 29.6 months was observed in pts carrying wild-type IL8 2767 AA genotype (n=68, 31%), compared to 14.8 months in those with the TT variant genotype (n=36, 16%) (HR (95%CI) = 2.3 (1.4, 3.9) for TT vs. AA, p=0.002]. The median OS for pts who were heterozygous for this IL8 polymorphism was 23.9 months (n=119, 53%). The FGFR2 IVS2 + 906C>T variant TT genotype was associated with inferior OS compared with the wild-type CC genotype (median OS, 21.4 vs. 28.0 months, HR (95%CI) = 2.0 (1.2, 3.2), p=0.009). Similarly, shorter OS was observed for the VEGFA −1154G>A variant AA genotype compared with the wild-type GG genotype [median OS, 16.7 vs. 25.3 months, HR (95%CI) = 2.2 (1.3, 3.6), p=0.004]. The variant genotypes of the NR1IR (−25385C>T) and FLT4 (1480A>G) polymorphisms were also associated with reduced OS (p<0.05). Conclusions: Germline variants in angiogenesis- and exposure-related genes may be associated with survival outcome for P monotherapy in pts with advanced RCC. These associations are considered exploratory and require confirmation in an independent dataset. [Table: see text]