bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, dose tolerance, pharmacokinetics, and pharmacodynamics of fosciclopirox (CPX-POM) in patients with advanced solid tumors.
Authors: Patel Manish R. , Ulahannan Susanna Varkey , Weir Scott James , Wood Robyn , Ham Tammy , Casey Crista , Reed Greg , Dandawate Prasad , Ramamoorthy Prabhu , Baltezor Michael Jay , Jensen Roy A. , Woolbright Benjamin L. , Taylor John Arthur , Anant Shrikant , Dalton Michael , Zhukova-Harrill Valentina , McCulloch William , Jones Suzanne Fields , Burris Howard A. , Falchook Gerald Steven 
Published: February 2020

518 Background: Fosciclopirox (CPX-POM) is being developed for the treatment of non-muscle invasive and muscle invasive bladder cancer. CPX-POM selectively delivers its active metabolite, ciclopirox (CPX), to the entire urinary tract following systemic administration. In a chemical carcinogen mouse model of bladder cancer, CPX-POM treatment resulted in significant decreases in bladder weight, migration to lower stage tumors, inhibition of cell proliferation as well as Notch 1 and Wnt signaling pathways. Methods: Study CPX-POM-001 (NCT03348514) is US multi-site, Phase I, open-label, dose escalation study characterizing the safety, dose tolerance, pharmacokinetics (PK) and pharmacodynamics of IV CPX-POM in advanced solid tumor patients. The PK of CPX-POM, CPX and ciclopirox glucuronide (CPX-G), were characterized in plasma and urine. Circulating biomarkers of Wnt and Notch, IL-6, IL-8 and VEGF were determined. Results: Nineteen patients were enrolled in the study. The starting dose of 30 mg/m2 was administered once daily on Days 1-5 of each 21-day treatment cycle. Doses were escalated to 1200 mg/m2. The MTD was determined to be 900 mg/m2. Overall, the number of treatment-related AE's tended to increase in frequency with dose, nausea and vomiting being the most common. Grade 3 confusion was observed in the 1200 mg/m2 cohort. Four AE's of Grade 1 confusion at 600 and 900 mg/m2. There was no evidence of QTc prolongation or other ECG abnormality. One patient in the 240 mg/m2 dose cohort, with a diagnosis of indolent primary fallopian tube tumor, achieved a partial response per RECIST 1.1. Metabolism of CPX-POM was rapid and complete. The clearance of CPX was dose proportional and time-independent. At MTD, steady-state 24-hour urine CPX concentrations of 215 µM were achieved. Evidence of Notch and Wnt inhibition was observed. Conclusions: IV CPX-POM was well tolerated with treatment-related AEs primarily CNS-related. At MTD, systemic and urinary CPX exposures exceeding in vitro IC50 values by several-fold. The 900 mg/m2 dose is currently being evaluated in an expansion cohort study in cisplatin-ineligible muscle invasive bladder cancer patients scheduled for cystectomy. Clinical trial information: NCT03348514.
Sequencing chemotherapy and surgery in upper tract urothelial cancers.
Authors: Parasramka Saurabh , Cook Alex , Myint Zin , Xue Ding , Wu Jianrong , Wang Peng 
Published: February 2020

521 Background: Prognosis for high grade, non-metastatic upper tract urothelial carcinoma (UTUC) (renal pelvis or ureter) has not improved in past two decades. Given improvements in disease-free survival in phase III POUT study, adjuvant chemotherapy (AC) has been the preferred approach. Neoadjuvant chemotherapy (NAC) is favored based on median survival (OS) benefit seen in urothelial bladder cancer. We studied National Cancer Database (NCDB) to answer this question. Methods: We identified adults > 18 years with non-metastatic, high grade, UTUC. All patients received surgery of the primary site and chemotherapy in the neoadjuvant or adjuvant setting. Patient’s receiving radiation therapy or who died within 90 days of surgery were not included. Descriptive statistics, log-rank tests and cox-regression tests were performed. Patients achieving complete pathological response (pCR) defined as (pTis, pT0, pTa and N0) were assessed for OS. Results: 1191 patients with complete data were identified; 225 (19%) received NAC and 966 (81%) received AC. 60% were males, median age was 68 and 73% had Charlson score (CS) of ‘0’. Median follow-up time for alive patients was 30.4 and 36.7 months in the NAC and AC groups respectively. Renal pelvis was the primary in 760 cases (63%) and ureter in 441 (37%). On univariate analysis receiving NAC, age < 75 years and CS score ‘0’ was associated with significant survival benefit (p < 0.05). Similarly on multivariate analysis receiving NAC and having CS of ‘0’ had significantly better survival with HR 0.75 (CI 0.58-0.96) and 0.8 (CI 0.65-0.96) respectively. Age > 75 years had worse survival HR 1.34 (CI 1.08-1.66). Thirty-seven patients (17%) in the NAC group achieved pCR with OS > 71.6 months which was significantly better than AC group and non-responders in the NAC group (p < 0.05). There was a trend towards more benefit with NAC compared to AC in Stage 1 and 2 UTUC than in Stage 3 and 4. Conclusions: Our study indicates that subset of early stage UTUC benefit more from NAC comparing to AC. However, randomized prospective study is warranted to further explore the role of NAC in UTUC.
Racial and sex differences in somatic mutations in bladder cancer patients: An analysis of the cBioPortal for Cancer Genomics.
Authors: Nyame Yaw A. , Baker Kelsey K. , Montgomery Robert B. , Grivas Petros , Redman Mary Weber , Wright Jonathan L. 
Published: February 2020

556 Background: Disparities in bladder cancer outcomes exist by race/ethnicity and sex. However, limited data exists on differences in tumor biology by race/ethnicity and sex. Methods: This is a retrospective analysis of non-synonymous mutational data from the cBioPortal open access platform. A total of eight unique cohorts were identified. The cohort was divided into groups by sex and race. Somatic mutations were selected from those with frequency > 7% from TCGA and DNA damage repair (DDR) genes. Univariable analysis was performed using Student’s t-test and Fischer’s exact test. For those genes with significant differences, multivariate Cox regression analysis was performed, including a test for interaction for genes significantly associated with race or gender. Results: A total of 917 unique patients were identified from cBioPortal for this analysis. Median age for the cohort was 68 years (range: 25-98) and 227 (25%) were identified as female. The cohort was majority white (85%). TP53 (54% vs. 31%, p < 0.001), ARID1A (29% vs. 7%, p < 0.001), ERBB3 (12% vs. 3%, p = 0.01) and CDKN1A (8% vs 18%, p = 0.02) were differentially mutated in white tumors compared to non-white tumors. ERBB2 was more common among male (13%) compared to female (6%) patients in the cohort (p < 0.01). There were no differences in DDR genes by race/ethnicity and sex. The median age for those with ERCC2 (70.4 vs. 66.8 years) and RAD51 (76.3 vs. 67.0 years) mutations was higher compared to those without the mutations, respectively. On multivariable analysis, ERCC2 (HR 0.45, 95% CI 0.25, 080), SPTAN1 (HR 0.50, 95% CI 0.29, 0.84), and EP300 (HR 0.60, 95% CI 0.39, 0.92) were associated with survival. There was a significant interaction between white race and CDKN1A in the survival analysis, with non-white patients with CKDN1A mutations having increased hazard for mortality (HR 3.1, 95% CI 1.14, 8.42). Conclusions: Somatic mutational differences existed by both race and gender in a large cohort of patients with bladder cancer. These findings are limited by poor representation of non-white patients and retrospective design; advocating for representative patient cohorts to assess tumor biology in bladder cancer disparities research.
NIVOREN GETUG-AFU 26 translational study: Association of PD-1, AXL, and PBRM-1 with outcomes in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) treated with nivolumab (N).
Authors: Vano Yann-Alexandre , Rioux-Leclercq Nathalie , Dalban Cécile , Sautes-Fridman Catherine , Bougoüin Antoine , Chaput Nathalie , Chouaib Salem , Beuselinck Benoit , Chevreau Christine , Gross-Goupil Marine , Negrier Sylvie , Laguerre Brigitte , Borchiellini Delphine , Colina-Moreno Irelka , Fridman Wolf-Herman , Chabaud Sylvie , Tantot Florence , Barros Monteiro Janice , Escudier Bernard , Albiges Laurence 
Published: February 2020

618 Background: The NIVOREN GETUG-AFU 26 study reported safety and efficacy of N in mccRCC pts in a “real world setting”. A translationnal research program was launched to characterize immune cell populations in the tumor by immunohistochemistry (IHC) and correlate them with outcome on N. Methods: All pts treated with N in the GETUG AFU 26 NIVOREN trial who consented for translational program and with available archived paraffin- embedded (FFPE) tumor tissue samples were eligible. Tumor were centrally reviewed. Using IHC we quantified main immune populations (B-cells, CD8 T-cells, macrophages), and immune checkpoints receptors (TIM-3, LAG-3, PD-1) at the invasive margin (IM) and at the core of the tumor (CT). We also identified AXL and PBRM1/BAP1 expression. Results: Overall 324 pts were included. Pts had similar baseline characteristics (IMDC Good, Intermediate, Poor in 18%, 60% and 22%, respectively) and comparable outcomes than overall trial population (PFS/OS = 4.5 / 25.4 months). PD-1 (IM) expression was associated with better PFS whereas AXL expression by tumor cells (TC) was associated with worse PFS (table). LAG-3 expression tend to be associated with worse OS. PBRM-1 loss (15%) was associated with better OS and PFS and with a higher density of CD8 T-cells (p = 0.001) and CD163-macrophages (p = 0.01) (CT) and a higher expression of LAG-3 (CT) (p = 0.01) and PD-1 (CT) (p = 0.02). BAP-1 loss was not associated with PFS (p = 0.6) nor OS (p = 0.9) in this cohort. Conclusions: We report the largest translational analysis supporting that PD-1 and AXL expression are associated with PFS in pts with mccRCC receiving N. We further confirm that PBRM-1 loss is a strong prognostic factor in this setting.[Table: see text]
Factors associated with clinical trial participation for patients with renal cell carcinoma.
Authors: Shinder Brian , Kim Sinae , Srivastava Arnav , Patel Hiren V. , Mayer Tina M. , Saraiya Biren , Singer Eric A. 
Published: February 2020

670 Background: Clinical trials are critical for the development of new treatment paradigms for renal cell carcinoma (RCC). The primary objective of this study was to characterize the factors associated with clinical trial participation for patients with RCC. The secondary objective was to examine survival outcomes in the clinical trial and control cohorts. Methods: The National Cancer Database (NCDB) was queried for patients with RCC who were coded as having enrolled in a clinical trial. Trial patients were matched in a 1:5 ratio to controls from the same institution based on clinical stage. Sociodemographic variables were compared between the two groups and univariate and multivariate logistic regression models evaluated factors associated with clinical trial participation. Kaplan-Meier product limit estimate was used to compare overall survival (OS) between the groups. Results: From 2004-2015, 681 patients enrolled in clinical trials were included for analysis. The mean age of trial patients was 56.4 compared to 62 in the matched cohort (p<0.0001). More patients in the trial group had a Charlson-Deyo comorbidity score of 0 (81.6% vs. 73.9%, p<0.0001). On multivariate analysis, male patients (OR 1.27; 95%CI 1.06-1.54, p=0.012) and white patients (OR 1.88, 95%CI 1.23-2.87; p=0.003) were more likely to participate in a trial. Having Medicaid (OR 0.42; 95%CI 0.27-0.64; p<0.0001) or Medicare (OR 0.6; 95%CI 0.46-0.77; p<0.0001) was negatively associated with clinical trial participation. Median OS was greater among clinical trial participants than that the control cohort (106.61 vs 87.62 months, p<0.0001). Conclusions: In this contemporary analysis of RCC patients from a national hospital registry database, we found that patient sociodemographic factors remain associated with clinical trial participation and that clinical trial participants experienced superior OS. Further work, both qualitative and quantitative, is necessary to identify clinical and non-clinical barriers to research participation in order to improve the validity of RCC trials.
A phase II study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma (nccRCC).
Authors: Hutson Thomas E. , Michaelson M Dror , Kuzel Timothy M. , Agarwal Neeraj , Molina Ana M. , Hsieh James J , Vaishampayan Ulka N. , Xie Sharon , Bapat Urmi , Jain Rohit K. , Fishman Mayer N. 
Published: February 2020

685 Background: Non-clear cell renal cell carcinoma (nccRCC) is an umbrella term that encompasses multiple RCC histological subtypes, including papillary, chromophobe, and undetermined RCC. Both increased expression of the vascular endothelial growth factor (VEGF) and dysregulation of the mammalian target of rapamycin (mTOR) pathway occur in nccRCC. Lenvatinib (LEN) is a multitarget tyrosine kinase inhibitor that inhibits the VEGF receptor and other targets; everolimus (EVE) is a mTOR inhibitor. LEN + EVE is approved for the treatment of patients with advanced RCC following 1 prior antiangiogenic therapy. This phase 2 study examined the efficacy and tolerability of LEN + EVE in patients with nccRCC. Methods: This single-arm, multicenter, phase 2 trial assessed the safety and efficacy of LEN (18 mg once daily) + EVE (5 mg once daily) in patients with unresectable advanced or metastatic nccRCC who had not received any chemotherapy for advanced disease. The primary objective was objective response rate (ORR) as assessed by investigators using RECIST v1.1. Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety assessments. Results: At the time of data cutoff (July 17, 2019), 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2) were enrolled and treated. The ORR was 25.8% (95% confidence interval [CI]: 11.9–44.6%); 8 patients achieved a partial response (PR; papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) and no patients had a complete response (CR). The median duration of response was not reached. Additionally, 18 patients (58.1%) had stable disease (SD) and the clinical benefit rate (CR + PR + durable SD [duration ≥ 23 weeks]) was 61.3% (95% CI: 42.2–78.2%). The median PFS was 9.23 months (95% CI: 5.49- not estimable [NE]) and median OS was 15.64 months (95% CI: 9.23–NE). The safety profile observed in this study was similar to the established profile of the study drug combination (LEN + EVE). Conclusions: The combination of LEN + EVE showed promising antitumor activity as first-line therapy in patients with advanced nccRCC. The ORR was 25.8%, which compares favorably to historical reports with EVE monotherapy. Clinical trial information: NCT02915783.
Clinical correlation of circulating tumor cell (CTC) PD-L1 and HLA I expression in metastatic renal cell carcinoma (mRCC) using exclusion-based sample preparation technology.
Authors: Emamekhoo Hamid , Schehr Jennifer L. , Bade Rory M. , Wei Xiao X. , McKay Rana R. , Choueiri Toni K. , Lang Joshua Michael 
Published: February 2020

721 Background: Despite therapeutic advancement in Vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) for mRCC treatment, there is currently no reliable predictive biomarkers of response or resistance. Single site biopsies provide limited information given the heterogenous nature of mRCC. Liquid biopsies may overcome these limitations; however, prior CTC capture platforms lacked sufficient sensitivity and specificity to achieve clinically useful detection rates. Methods: Given the prevalence of VEGF dependency, and its reliance on hypoxia, we aimed to increase sensitivity and specificity of capturing and identifying mRCC CTCs using carbonic anhydrase IX (CA IX) and CA XII. In addition, traditional markers for cell capture and identification with epithelial cellular adhesion molecule (EpCAM) and cytokeratin (CK) were included. Exclusion-based Sample Preparation technology was used to maximize cell yield. CD45/34/66b positive blood cells were excluded to ensure high specificity in evaluation of PD-L1 and HLA I expression on CTCs. Results: In a preliminary cohort of 21 mRCC pts (treatment: TKI=12, ICI=5, TKI+ICI=2, baseline=2), we identified heterogeneous populations of CTCs with differential expression of CA XII and CK. We detected CK+ CTCs in 20/21 pts (mean= 5/mL; range 0-53), CAXII+ CTCs in 21/21 pts (mean= 1/mL; range 1-9), and CK+/CAXII+ CTCs in 19/21 pts (mean=7/mL; range 0-102). In pts with multiple CTC samples on treatment, there was a high correlation between the number of CK+ CTCs and treatment response (ROC AUC 0.88). PD-L1 expression in CAXII+ CTCs correlated with response to ICI (ROC AUC 0.77) and TKI (ROC AUC 0.73). HLA I expression in CAXII+ CTCs correlated with response to TKI (ROC AUC 0.73) better than ICI (ROC AUC 0.59). Conclusions: Assessment of CTC heterogeneity may provide valuable molecular insights and diversify tools for early detection of therapeutic response and resistance that may guide treatment decision making. This assay is being tested in ongoing Phase II clinical trials.
The effect of docetaxel, enzalutamide, abiraterone, and radium-223 on cognitive function in older men with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Alibhai Shabbir M.H. , Breunis Henriette , Timilshina Narhari , Hansen Aaron Richard , Joshua Anthony M. , Warde Padraig Richard , Gregg Richard William , Fleshner Neil Eric , Tomlinson George , Hotte Sebastien J. , Emmenegger Urban 
Published: February 2020

73 Background: Older adults are at greater risk of cognitive decline with various oncologic therapies. Emerging data suggest cognitive effects of various therapies for mCRPC but study populations are highly selected and published data are limited and focus mostly on self-reported cognitive function. We evaluated the effects of treatment with docetaxel chemotherapy (CHEMO), abiraterone (ABI), enzalutamide (ENZA), and radium 223 (Ra223) on cognitive function in older men with mCRPC. Methods: Men age 65+ with mCRPC starting any of the 4 treatments for mCRPC were enrolled in this multicenter prospective cohort study. Three short yet reliable and sensitive measures in older adults were administered at baseline and final visit (6 months with CHEMO and Ra223, mean 14-16 months with ENZA and ABI) using the Montreal Cognitive Assessment (MoCA), Trails A, and Trails B to assess global cognition, attention, and executive function, respectively. Absolute changes in cognitive scores over time were analyzed using multivariable linear regression, and the percentage of individuals with a decline of 1.5 SD in each domain were calculated. Higher scores on MoCA are better but worse for Trails A/B. Results: A total of 51, 26, 49, and 21 men starting CHEMO, ABI, ENZA, and Ra223 with complete data were included. Mean age, education, and baseline cognition were similar between groups (Table). Most patients demonstrated stable cognition or slight reductions. Executive function was the most sensitive of the 3 cognitive domains, and declined by at least 1.5 SD in about one-fifth of each cohort. Although ABI had numerically smaller declines than ENZA, differences were generally small and clinically unimportant. Conclusions: Most older men do not experience significant cognitive decline while on treatment for mCRPC regardless of treatment used.[Table: see text]
The use of intermittent enzalutamide dosing in the treatment of metastatic castrate-resistant prostate cancer.
Authors: Rowe Michael , Hidayat Ayesha , Walter Stuart , Pollard Adam , Norris Timothy , Victor Deborah , McGrane John , Thomson Alastair 
Published: February 2020

81 Background: Intermittent hormone manipulation in castrate-sensitive prostate cancer can improve quality of life whilst maintaining comparable disease outcomes with continuous scheduling. Enzalutamide is effective in metastatic castrate-resistant prostate cancer (mCRPC) treatment but can have significant side-effects. We conducted a retrospective analysis of patients treated with intermittent enzalutamide compared with continuous dosing. Methods: Patients prescribed enzalutamide for mCRPC at Royal Cornwall Hospital from September 2011 to February 2018 were included. Data was collected from electronic medical records, selecting patients with at least a 1 month treatment break. Kaplan-Meier analysis of overall survival from enzalutamide start (OS), time to PSA failure (TTF) and total enzalutamide treatment time (TTT) was calculated for intermittent and continuous responders (>50% PSA drop), assigned significance level of 0.05. Results: 243 patients received enzalutamide, 110 (45%) were continuous responders and 29 (12%) had intermittent dosing. All patients treated intermittently had a PSA response prior to first treatment break, which was most commonly for fatigue (60%). 25% were still receiving enzalutamide. Median number of breaks was 1 (range 1-7), time on treatment was 70% and time to first break was 5 months. The intermittent group had significantly improved OS with median not reached, median OS for continuous responders was 19 months (HR 2.39, 95% CI 1.53-3.76, p=0.002). The intermittent group had prolonged TTF (median 13 vs 6 months, p=0.001) and TTT (median 30 vs 10 months, p=0.0003). Conclusions: Intermittent dosing of enzalutamide in these mCRPC patients does not adversely impact OS, increasing time patients remain on treatment. However, this was a small, retrospective, single-centre study; prospective trials are necessary to clarify the role of intermittent enzalutamide.[Table: see text]
Single-arm, phase II study to evaluate the safety and efficacy of sacituzumab govitecan in patients with metastatic castration-resistant prostate cancer who have progressed on second generation AR-directed therapy.
Authors: Lang Joshua Michael , Kyriakopoulos Christos , Slovin Susan F. , Eickhoff Jens C. , Dehm Scott , Tagawa Scott T. 
Published: February 2020

TPS251 Background: In patients with mCRPC, androgen receptor (AR) pathway inhibitors such as enzalutamide or abiraterone acetate are often used as first-line systemic therapy. After progression on either of these inhibitors, the likelihood of response to the other is significantly lower than in the first-line setting. Multiple resistance mechanisms have been identified, including the emergence of AR splice variants. Trop2 is a cell-surface antigen that is expressed in > 70% of prostate cancers and is enriched in mCRPC expressing AR splice variants. Sacituzumab govitecan (SG; IMMU-132) is a novel antibody drug conjugate composed of humanized anti-Trop2 antibody conjugated to SN-38 payload by hydrolyzable linker. SG has potential to be an effective therapy after progression on initial AR pathway inhibitors to meet this significant unmet clinical need. Methods: This is a single-arm, open-label, multicenter phase 2 trial (NCT03725761) to determine the efficacy and safety of SG. The primary endpoint is PSA response rate (≥50% PSA decline at or within 9 weeks of starting treatment); secondary endpoints include rPFS and overall survival. 55 subjects with mCRPC who have progressed on second-generation AR-directed therapy in either the hormone sensitive or CRPC setting will be included. Fresh or archived metastatic site biopsy is required. Subjects will be treated with SG IV at 10 mg/kg on Day 1 and Day 8 of 21-day cycles until disease progression. Subjects who receive ≥1 SG dose and have ≥1 PSA post-dose assessment will be included in final efficacy analysis. Circulating tumor cell biomarker studies will be performed throughout treatment and at progression to investigate potential mechanisms of response/resistance to SG. Tumor biopsies at baseline and after 3 therapy cycles will evaluate genomic alterations that predict treatment response. Subjects who remain progression free will undergo repeated evaluations of extent of disease every 9 weeks. The trial is actively accruing. Managed by: Prostate Cancer Clinical Trials Consortium; Funding: Immunomedics; Support: Prostate Cancer Foundation. Clinical trial information: NCT03725761.