bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interim results of a randomized phase 2 study of docetaxel with ramucirumab versus docetaxel in second-line advanced or metastatic urothelial carcinoma.
Authors: Petrylak Daniel Peter , Tagawa Scott T. , Kohli Manish , Tang Shande , Zhang Hui , Hamid Oday , Kauh John S. , Walgren Richard A. , Chi Kim N. 
Published: February 2017

295 Background: Patients (pts) with metastatic urothelial carcinoma (UC) progressing after first-line chemotherapy have limited treatment options. Ramucirumab (Ram), a human VEGFR2-targeted mAb, has demonstrated clinical activity in several solid tumors. Preclinical testing supports a role for Ram-taxane combinations in UC. Study JCDC is an open-label, multicenter, randomized phase 2 study of docetaxel (Doc) alone or combined with Ram or icrucumab (Icr) in locally advanced or metastatic platinum-resistant UC. We report on a planned interim analysis for Doc + Ram vs Doc; Icr results will be reported later. Methods: Eligible pts with advanced UC and ECOG PS 0-1 who relapsed ≤ 1 year from a platinum-regimen were randomized to receive Doc 75 mg/m2IV alone or with Ram 10mg/kg IV on Day 1 of repeating 21-day cycles. A sample size of 46 pts per arm enabled 71% power to demonstrate statistical significance of 4.5 mo (Doc + Ram) vs 3 mo (Doc) at a 1-sided α= 0.1. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed PFS with RECIST v1.1, analyzed by K-M methods. A planned interim analysis was performed after 75% of the PFS events. Results: 44 pts received Doc and 46 received Doc + Ram. Study arms were well matched with a mean age of 67 yr (29-84), and a 4:1 male to female ratio. 58.7% (Doc + Ram) vs 61.4% (Doc) had ECOG PS 1. 58.7% (Doc + Ram) vs 52.3% (Doc) had visceral metastases. Doc + Ram reduced the risk of disease progression, stratified HR = 0.388; 95% CI: 0.222, 0.677; log-rank p = 0.0005, improving median PFS (5.1 vs 2.4 mo). The ORR for Doc + Ram was 19.6 vs 4.5% for Doc (p= 0.0502), and the disease control rate was 67.4 vs 43.2%. OS maturity is pending. The most common adverse events in the Doc + Ram arm (all grades) were fatigue (80.4% Doc + Ram v 75.0% Doc), decreased appetite (54.3 v 43.2%), nausea (54.3 v 25.0%), and neuropathy (50.0 v 38.6%). Grade (G) ≥3 febrile neutropenia (19.6 v 11.4%), pneumonia (13 v 9.1%), hypertension (4.3 v 0%) were higher with Doc + Ram. One G3 hematuria was observed in each arm. Conclusions: Results support a statistically significant improvement in PFS for Doc + Ram in second-line UC. Final results are expected in 2015. Clinical trial information: NCT01282463.
Urine cystatin C (uCyC) as a predictor for acute kidney injury (AKI) in urothelial cancer (UC) patients (pts) treated with cisplatin (CDDP).
Authors: Jelinek Michael J , Wyche Alicia J , Wing Claudia , Koyner Jay L , Stadler Walter Michael , Murray Patrick T , O'Donnell Peter H. 
Published: February 2017

317 Background: CDDP-based treatment is limited by AKI. We aimed to test whether a novel AKI biomarker, uCyC, measured before and immediately after CDDP administration could permit earlier identification of UC pts at risk for AKI. Methods: In a nested case-control study, pts treated with CDDP were prospectively enrolled. uCyC was measured 2 hours pre- and 3 hours post-CDDP doses, with values normalized to urine creatinine. AKI was defined as an increase in serum creatinine (sCr) by ≥50% (severe cases) or ≥0.3 mg/dL above pre-CDDP baseline. Controls were pts with no significant sCr rise (sCr change <25% and <0.3 mg/dL). A sample size of 98 patients provided 80% power to detect a true difference in biomarker change pre- and post-CDDP between cases and controls. Results: 102 pts were enrolled: 47 had UC, and 55 had other cancers; 76 were male; 82 Caucasians/15 African Americans. 4 pts not providing urine samples were excluded from analysis. For the entire cohort, average pre-CDDP sCr was 0.98 mg/dL and mean cumulative CDDP dose was 220 mg/m2. Controls were younger (mean 59.2 vs 65.9 yrs, p=0.01). 25 pts (26%) developed AKI; 15 (15%) were severe cases. UC pts had a significantly increased risk of AKI compared with non-UC pts (UC n=17 [37%] vs non-UC n=8 [16%], Relative Risk 2.2, 95% CI 1.08-4.73; p=0.03). AKI risk did not correlate with total CDDP dose received. In AKI pts, uCyC increased temporally in accordance with sCr and did not increase in controls, but immediate uCyC changes (3 hrs post-CDDP) were not detectable in cases or controls. However, in UC severe cases, pre-CDDP uCyC was consistently higher than in UC controls (183 ng/mg vs 109 ng/mg, p=0.04). Additionally, in UC AKI pts compared to UC controls, average maximum (peak) uCyC was higher (1812 ng/mg vs 244 ng/mg, p=0.04). Baseline uCyC did not correlate with age, and there were no significant differences in age or baseline sCr between UC cases and controls. Conclusions: UC pts are over two times more likely to develop AKI with CDDP chemotherapy than pts with other cancers, even when pre-CDDP sCr is normal. Pre-treatment uCyC levels may have value in predicting which UC pts are at highest risk of developing CDDP-induced renal injury.
Defects in DNA repair genes and sensitivity to cisplatin based neoadjuvant chemotherapy (NAC) for bladder cancer.
Authors: Plimack Elizabeth R. , Dunbrack Roland , Brennan Timothy , Andrake Mark D. , Zhou Yan , Serebriiskii Ilya , Dulaimi Essel , Hoffman-Censits Jean H. , Bilusic Marijo , Wong Yu-Ning , Kutikov Alexander , Viterbo Rosalia , Greenberg Richard E. , Chen David Y. T. , Lallas Costas D. , Trabulsi Edouard John , Yelensky Roman , Miller Vincent A. , Golemis Erica , Ross Eric A 
Published: February 2017

320 Background: Cisplatin based NAC prior to cystectomy is standard of care for MIBC, with 40-50% expected to respond with ≤pT1N0M0. Biomarkers predictive of response are lacking. Methods: MIBC pts who received 3 cycles of cisplatin based NAC on 1 of 2 prospective multicenter clinical trials were included. Pts treated with accelerated methotrexate, vinblastine, doxorubicin + cisplatin (AMVAC) provided the discovery set [n=34, 15/34 (44%) ≤pT1N0M0]. Pts treated with dose dense gemcitabine + cisplatin (DDGC) provided the validation set [n=24, 11/24 (46%) ≤pT1N0M0]. DNA from pre-treatment tumor tissue underwent sequencing for all coding exons of 287 cancer related genes and was analyzed for presence of base substitutions, indels, copy number alterations, and selected re-arrangements. The mean number of variants and variant status for each gene were correlated with response using two-sample t-test and Fisher’s exact tests. Variant data were used to create a classification tree to discriminate responders vs. non-responders in the AMVAC discovery cohort. The resulting decision rule was then tested in the independent DDGC validation set. Overall survival analysis was performed using Kaplan-Meier. Results: Pts with pT0 had significantly more alterations than those with residual tumor in both the AMVAC discovery (p=.024) and DDGC validation (p=0.018) set. In the AMVAC discovery set, alteration in ≥1 of the three DNA repair genes ATM, RB1 or FANCC predicted for ≤pT1N0M0 (p<0.001, 87% sensitivity, 100% specificity) and improved overall survival (OS) (p=0.007). This test remained predictive for ≤pT1N0M0 in the DDGC validation set (p=0.033), with a trend towards improved OS (p=0.07) at short median follow up of 14.3 mo. Conclusions: Alterations in ≥1 of ATM, RB1 and FANCC predict response to cisplatin based chemotherapy defined as ≤pT1N0M0 in both our AMVAC discovery and DDGC validation sets. We hypothesize that defects in these genes, which are important for maintenance of chromatin structure and DNA repair, confer sensitivity to DNA damaging chemotherapy and explain the accumulation of alterations seen among pts with pT0. External validation in collaboration with the cooperative groups is planned.
Phase 2 study of the pan-isoform PI3 kinase inhibitor BKM120 in metastatic urothelial carcinoma patients.
Authors: Iyer Gopa , Tully Christopher Michael , Garcia-Grossman Ilana Rebecca , Scott Sasinya N. , Boyd Mariel Elena , McCoy Asia S. , Berger Michael F. , Al-Ahmadie Hikmat , Solit David B. , Rosenberg Jonathan E. , Bajorin Dean F. 
Published: February 2017

324 Background: PI3 kinase (PI3K) pathway alterations are found in 39% of urothelial carcinoma (UC) (TCGA). Prior reports have shown significant responses in metastatic UC patients (pts) whose tumors harbor PI3K pathway alterations treated with mTOR inhibitors, providing a rationale to investigate BKM120 in mUC. Methods: This phase II study enrolled mUC pts progressing on platinum-based chemotherapy (up to 4 prior agents). The primary and secondary endpoints were proportion of pts progression-free at 2 months and response rate (RR) by Response Criteria in Solid Tumors (RECIST) v1.1, respectively. A Simon 2-stage design was used to discriminate between a 2 month PFS rate of <60% (at which point the trial would be halted) vs. >80%. Pts received 100 mg drug once daily. To identify predictors of response/resistance to BKM120, targeted exon capture sequencing was performed to define the mutation status of PIK3CA, PTEN, AKT1, TSC1, and additional genes within tumors from all treated pts. Results: 13 of 15 enrolled pts were eligible for the primary endpoint. Median age was 65 (53-82). Pts had received an average of 3 agents (2-4) before enrollment. The median progression-free survival (PFS) was 2.77 months (95% CI: 1.83-3.71) with 6 pts displaying stable disease (SD) and 1 partial response (PR) at 2 months (PFS rate 54%). Sequencing identified 2 pts with PIK3CA mutations (E542K, H1047R) who experienced progression as best RECIST response. Tumor from the pt with a 16 month PR harbored a TSC1 R500* nonsense mutation. 1 pt with SD lasting 3.7 months had a TSC1 L330fs truncation. Conclusions: While BKM120 therapy did not display a significant improvement in 2-month PFS rate compared to standard chemotherapy in the second-line setting, 2 pts, one with a durable PR and one with SD, had tumors with inactivating mutations in TSC1. Based upon these results, an expansion cohort is accruing in which select mUC pts whose tumors harbor PI3K pathway alterations receive BKM120. Clinical trial information: NCT01551030.
Sequential chemotherapy with gemcitabine plus carboplatin, followed by additional docetaxel for aged patients with advanced upper-tract urothelial cancer.
Authors: Yoneyama Takahiro , Tobisawa Yuki , Yoneyama Tohru , Yamamoto Hayato , Imai Atsushi , Mori Kazuyuki , Hatakeyama Shingo , Hashimoto Yasuhiro , Koie Takuya , Ohyama Chikara 
Published: February 2017

344 Background: Gemcitabine + cisplatin may be a promising regimen for advanced upper-tract urothelial carcinoma (UTUC) as well as for advanced bladder cancer. However, cisplatin is proved to be too toxic for the patients with impaired renal function and aged patients. Majority of aged patients with UTUC have impaired renal function. There is no standard regimen for such patients. We assessed the effectiveness and adverse events (AEs) of a sequential chemotherapy with Gemcitabine plus carboplatin(GCarbo) followed by GCcarbo plus docetaxel (GCarboD) for advanced UTUC. Methods: We treated 86 patients with advanced UTUC at our clinic between August 2004 and December 2013. 45 patients (31 men and 14 women) with the age of 65 years or older were enrolled. Mean age was 73.0 (65–89), and mean Ccr was 47.9 (11.6–99.2) ml/minute. Mean observation period was 22.9 (3–87.2) months. The therapeutic regimen consisted of 2 lines: GCarbo therapy as the first line, with two courses as a set; GCarboD therapy as the second line if the response in the first line was insufficient. If this regimen was effective, another 2 courses of GCarbo was performed. If this regimen did not induce any tumor size reduction, we switched to GCarboD. Results: GCarbo regimen yielded 1 cases (2.2%) of CR, 20 (44.4%) of PR, and the mean duration of response of 11.0(3–51) months. GCarboD treatment was administered in 12cases, and yielded one (8.3%) PR and a duration of response was 7.0 months. The median survival period was 14.0 months with GCcarbo/GCarboD regimens. As for ARs with GCcarbo regimen, there were 23 (52.2%) of G3/4 blood toxicity. In GCarboD regimen, there were 11 (91.7%) of blood toxicity and 7 (58.3%) of gastrointestinal AEs. Conclusions: Although the present study is small and preliminary, the present sequential chemotherapy is safe and active for advanced UTUC of the patients sixty-five years or older. GCarbo regimen achieved relatively high response rate (46.6%) in advanced UTUC. The median overall survival of 14.0 months is acceptable when average age of 73.0 year for the subjects is took into consideration. However, GCarboD had limited effectiveness for non-responder of GCarbo.
Cardiovascular disease (CVD) risk factors among cisplatin-treated testicular cancer survivors (TCS): A multicenter clinical study of U.S. and Canadian patients.
Authors: Fung Chunkit , Feldman Darren Richard , Hamilton Robert James , Case-Eads Somer , Vaughn David J. , Beard Clair , Moore Malcolm J. , Sahasrabudhe Deepak M. , Brames Mary J. , Fossa Sophie D. , Sesso Howard D. , Einhorn Lawrence H. , Travis Lois B. ,   for The Platinum Study Group
Published: February 2017

391 Background: The remarkable success of cisplatin-based chemotherapy in curing metastatic TC has been accompanied by potential life-threatening sequelae, including CVD. Most prior studies, however, have been conducted in Europe and included older chemotherapy regimens. We examined CVD risk factors in an ongoing multi-center clinical study of TCS given modern cisplatin-based chemotherapy (CHEM) at centers in North America (NCI 1R01 CA157823-02). Methods: TCS aged ≤49 years at time of first-line CHEM were eligible to undergo clinical examination and complete a questionnaire regarding co-morbidities, lifestyle behaviors, and prescription drug use. Results: We evaluated the first 443 consecutively enrolled TCS (23% seminoma; 77% nonseminoma) with most having stage II (52%) or III (28%) disease. The median age at time of TC diagnosis was 32 years (range 15-49 years) and median time since completion of chemotherapy was 59 months (range 1-24 years). Patients were largely white (90%), married (62%), and had full-time employment (82%) and health insurance (88%). 8% of TCS were current smokers. 48% of TCS had gained >10 lbs after CHEM with 29% having a ≥102 cm (40 inch) waist circumference, and 43% and 31% having a body mass index of 25 to <30 kg/m2 (overweight) and ≥ 30 kg/m2 (obese), respectively. A sizable proportion of men had abnormal systolic (21% with 130-139 mm Hg and 17% with ≥140 mm Hg) and diastolic (35% with 80-89 mm Hg and 13% with ≥90 mm Hg) blood pressure. 14%, 11%, and 5% TCS indicated that they currently used medications for hypertension, cholesterol and diabetes, respectively. Cardiac conditions were reported by 32 TCS (7%), including angina (N=2), angioplasty/stent placement (N=1), myocardial infarction (N=1), transient ischemic attack (N=1), stroke (N=2), peripheral vascular disease (N=12), deep vein thrombosis (N=23), and pulmonary embolism (N=15). Conclusions: A number ofCVD risk factors are present in a contemporary North American cohort of TCS after CHEM. Future analytic studies should focus on mechanistic investigations to facilitate the development of screening and preventive efforts for CVD in high-risk patients.
DART Study: A phase II randomized trial of dalantercept plus axitinib versus placebo plus axitinib in advanced clear cell renal cell carcinoma (RCC): Results from Part 1.
Authors: Voss Martin Henner , Plimack Elizabeth R. , Rini Brian I. , Atkins Michael B. , Alter Robert , Bhatt Rupal Satish , Beck J. Thaddeus , Pappas Kristen M. , Wilson Dawn , Zhang Xiaosha , Sherman Matthew L. , Pandya Shuchi Sumant 
Published: February 2017

407 Background: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis involved in blood vessel maturation and stabilization. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in dual angiogenic blockade and augmented inhibition of tumor growth in RCC xenograft models. Dalantercept (Dal) is an ALK1 receptor-fusion protein that acts as a ligand trap and has demonstrated monotherapy activity with an acceptable safety profile in a completed phase I study. Methods: Part 1 of this study evaluated the safety, tolerability, and preliminary activity of escalating dose levels of Dal plus fixed dose axitinib in pts with advanced RCC. 3-6 pts each received Dal (0.6, 0.9, or 1.2 mg/kg) SC Q3W and axitinib 5 mg PO BID. Key eligibility: predominantly clear cell RCC, 1 prior VEGFR TKI, ≤3 prior tx. Results: As of September 12, 2014, 29 pts were enrolled in three cohorts (n=6, 9, 14) at dose levels of 0.6, 0.9 and 1.2 mg/kg, respectively. At the 1.2 mg/kg dose level, 1 DLT of grade 3 abdominal and back pain occurred (n=1) in addition to more Dal associated edema events including peripheral edema (n=6), fluid overload (n=1), ascites (n=1), and pleural effusion (n=1). The 0.9 mg/kg dose level was well tolerated (3 pts with low grade edema; no pleural effusions or ascites) and selected for Part 2. Frequent AEs regardless of attribution: fatigue, diarrhea, dysphonia, nausea, peripheral edema, creatinine rise, epistaxis, hypertension, arthralgia, hand-foot rash, and cough. 28 pts were evaluable for response by RECIST 1.1. The ORR was 25% (n=7) and 31.3% (n=5) among pts who received ≥ 2 prior txs (n=16), including VEGF targeted tx, mTOR inhibitors, and immune tx. Of those evaluable for disease control at 6 mos. (n=25, 3 active pts have not reached 6 mos.), 52% (n=13) remained progression free. PFS data are maturing and will be presented. Conclusions: The combination of dalantercept and axitinib is well tolerated and associated with encouraging activity in pts with prior VEGF, mTOR, and immune therapies. Part 2 of this study randomizes pts to dalantercept + axitinib vs. placebo + axitinib and is actively accruing patients. Clinical trial information: NCT01727336.
A randomized phase II study of AZ2014 versus everolimus in patients with VEGF refractory metastatic clear cell renal cancer (mRCC).
Authors: Powles Thomas , Wheater Matthew James , Din Omar , Geldart Thomas R. , Boleti Ekaterini , Stockdale Andrew , Sundar Santhanam , Robinson Angus , Ahmed Imtiaz , Sarker Shah-Jalal , Hussain Syed A. , Ralph Christy 
Published: February 2017

409 Background: Dual TORC1 and 2 inhibitors such as AZD2014 have theoretical advantages over isolated TORC1 inhibitors such as everolimus in the treatment of mRCC. In this study we compare the activity of these drugs in patients with vascular endothelial growth factor (VEFG) refractory mRCC. Methods: Patients with measurable VEGF refractory mRCC were randomised (1:1) to AZD2014 or everolimus stratified by MSKCC prognostic score and 1st line targeted therapy. Progression free survival (PFS) measured by RECIST v1.1 was the primary endpoint. Adverse events (AE) (CTCAE v4.03), response rates (RR) and overall survival (OS) were reported. This was an investigator led study and had appropriate ethical approval. Results: The study was stopped early (May 2014) with the recommendation of the IDMC. At this point 48 patients were recruited and 40 (AZD2014 23 :everolimus 17) patients were assessable for efficacy. Patient’s demographics were similar in the 2 groups. The median PFS was shorter for AZD2014 than everolimus (2.0 [95% CI 1.6-3.2] months vs. 5.8 [95% CI 2.8-11.2] months: stratified HR [2.4 95% CI:1.0-5.7; p<0.05]). Progression of disease as a best response was higher for AZD2014 than everolimus (65% vs. 18%: p=0.03). Response rates for AZD2014 and everolimus were 0% and 12% respectively. There were 9 deaths in this patient group, 7 in AZD2014 and 2 in everolimus group, all were due to disease progression. Grade III-IV adverse events (AEs) occurred with AZD2014 and everolimus in 30% and 59% of patients respectively. Discontinuation for AEs did not occur with AZD. PK analysis revealed AZD2014 doses within therapeutic window. Results for the 48 patient will be presented along with the survival data. Conclusions: The PFS for AZD2014 is inferior to everolimus in this setting despite excellent tolerability. These results are consistent with previous results with broader spectrum mTOR inhibitors in VEGF refractory mRCC (GDC0890: HR2.04 [Powles et al ASCO 2014]). This approach appears to be flawed. Clinical trial information: NCT01793636.
Stool bacteriomic profiling in patients with metastatic renal cell carcinoma suggests an etiology of VEGF TKI-related diarrhea.
Authors: Pal Sumanta Kumar , Li Sierra Mi , Wu Xiwei , Pinnamaneni Manasvi , Hsu JoAnn , Carmichael Courtney , Frankel Paul Henry 
Published: February 2017

421 Background: Vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF TKIs) remain a mainstay of therapy for patients with metastatic renal cell carcinoma (mRCC). Diarrhea represents a pervasive toxicity, with all grade diarrhea affecting roughly 50% of patients receiving VEGF TKIs. The underlying cause of diarrhea in these patients is poorly understood. Methods: Patients with mRCC receiving an FDA-approved VEGF TKI therapy for mRCC were consented. Stool was collected in a standardized fashion and total genomic DNA was isolated using the PowerSoil DNA isolation kit (Mo Bio, USA). A standard PCR protocol was used to amplify bacterial 16S rRNA genes from all samples. PCR primers were used to amplify the V4 and V5 regions of the 16S rRNA. Paired-end of sequencing 2X100bp was performed by Illumina HiSeq 2000, and sequences were clustered using the CD-HIT clustering algorithm. Taxonomy was then assigned using the RDP-II classifier. Non-clustered analyses were also performed, stratifying patients by the presence or absence of diarrhea at the time of stool collection. Results: Of 26 patients consented, 23 patients submitted stool specimens and 20 had sufficient data for the current analysis. Amongst these 20 patients, the median age was 63 and the majority of patients (60%) were intermediate risk by Heng criteria. Eight patients (40%) received VEGF TKI therapy in the first-line setting. Across all lines of therapy, the most commonly used VEGF TKI was sunitinib (44%). A total of 141 bacterial species were identified. With respect to differences in patients who did and did not have diarrhea, the Mann-Whitney U-test identified 7 species with a p value of <0.1. The largest difference was seen in two Bifidobacterium species, B. animalis and B. bifidum, with both bacteria more abundant in patients with no diarrhea. Conclusions: This is the first effort to use stool bacteriomic profiling to ascertain the etiology of VEGF TKI related diarrhea in patients with mRCC. Two Bifidobacterium spp identified in this analysis are commonly found in probiotics. Studies to use probiotics enriched with Bifidobacterium spp to prevent or ameliorate VEGF TKI-related diarrhea are currently in development.