bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ with UGT1A1 polymorphisms.
Authors: Johnson Toby , Xu Chun-fang , Choueiri Toni K. , Deen Keith C. , Xue Zhengyu , Bartlett-Pandite Arundathy N. , Carpenter Christopher , Motzer Robert John 
Published: March 2020

4569 Background: A phase III randomized clinical trial (COMPARZ) comparing pazopanib vs sunitinib for treatment of advanced renal cell carcinoma demonstrated similar efficacies but different safety profiles for the two therapies. Elevations in serum total bilirubin have been observed in patients receiving either therapy. UGT1A1 polymorphisms are associated with elevated bilirubin in the general population (Gilbert’s syndrome). This study investigated the association between functional UGT1A1 polymorphisms and on-therapy serum total bilirubin in the COMPARZ study. Methods: Patients homozygous or compound heterozygous for UGT1A1 *28, *37, and *6 alleles were predicted to have reduced UGT1A1 function. Logistic regression adjusted for ancestry principal components was used to compare patients with on-therapy hyperbilirubinemia (≥1.5 × upper limit of normal [ULN]; pazopanib, N = 62; sunitinib, N = 34) against patients exposed to treatment and with maximum on-therapy bilirubin ≤1 × ULN (pazopanib, N = 213; sunitinib, N = 215), excluding patients with maximum on-therapy bilirubin between 1 and 1.5 × ULN (pazopanib, N = 96; sunitinib, N = 104). Results: Patients with predicted reduced UGT1A1 function had higher baseline bilirubin and also were more likely to experience hyperbilirubinemia when receiving either pazopanib (P = 6.9×10–8) or sunitinib (P = 1.8×10–3). After adjusting for baseline bilirubin, patients with predicted reduced UGT1A1 function remained more likely to experience hyperbilirubinemia when receiving pazopanib (P = 0.015) or sunitinib (P = 0.026), with odds ratio (95% CI) 3.53 (1.28–9.76) and 4.41 (1.23–15.75), respectively. Conclusions: The data suggest that some instances of hyperbilirubinemia in patients treated with pazopanib or sunitinib may be benign manifestations of Gilbert’s syndrome. Bilirubin fractionation or, if not available, UGT1A1 genotyping, would enable further characterization of liver safety risk and help in making treatment decisions.
Multiplexed tissue protein assay as a predictor of response to targeted therapy in advanced renal cell carcinoma.
Authors: Vaishampayan Ulka N. , Derrien-Colemyn Alexandrine , Hong Ye , Sethi Seema , Chen Wei , Dickow Brenda , Gillespie John Williams , Smith Daryn W. , Tunon Peter 
Published: March 2020

4577 Background: A number of prognostic biomarkers have been explored in advanced renal cancer, but to date none have been useful in therapeutic outcome prediction. Methods: Following regulatory approval, formalin-fixed paraffin embedded (FFPE) pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The FFPE tissue was analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Multiplexed panels of protein biomarkers were used to probe tissue sections for proteins along the PI3K/AKT/mTOR and/or the VEGFR/PDGFR signaling pathways. Expression of biomarkers in tumor tissue was scored and predictive scores which correlated with the pt’s clinical outcome status generated. Results: Tissue samples of 51 pts treated with sunitinib (S)were analyzed. A predictive score was generated by combining the scores assigned to VEGFR1 and VEGFR2 and multiplying the sum with the score of VEGFA. A predictive score equal to or above 24, was associated with response or stable disease (SD) at 12 weeks. Patients with a score <24 were predicted to have progression (PD) on S. Using this scoring method, 27 of the 33 responders tested and 15 of the 18 non responders were accurately identified. The accuracy of the test was noted to be 82.6% and sensitivity and specificity were 81.8% and 83.3% respectively. Tissue samples of 33 pts treated with mTOR inhibitor were analyzed using the same technique. Three biomarkers in the mTOR pathway (pmTOR (Ser 2448), p4EBP1 (Ser 65), p4EBP1 (Thr 37-46)) were used to create a predictive score. Eight of 12 OR/SD pts (sensitivity 67%) and 17 of 21 PD pts (specificity 76%) were accurately predicted using a score cut-off of 6 for an accuracy of 71.5%. Statistical modeling, results of ongoing validation testing, and score correlation with time to progression will be presented. Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information to help guide therapy. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by NCI SBIR Contract No. HHSN261201000135C.
Overcoming sunitinib-induced resistance by dose escalation in renal cell carcinoma: Evidence in animal models and patients.
Authors: Pili Roberto , Adelaiye Remi , Miles Kiersten Marie , Ciamporcero Eric , Sotomayor Paula , Bjarnason Georg A. 
Published: March 2020

4582 Background: Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). However, despite the clinical efficacy, eventually tumors develop resistance and progress. Thus, we have tested the hypothesis whether sunitinib dose-escalation could overcome initial drug resistance. Methods: Human patient-derived ccRCC xenografts were implanted in SCID mice and were randomly assigned into two groups (sunitinib and vehicle). Mice were treated with sunitinib 5 days/week with a dose-escalation schema starting from 40 mg/kg to 60 mg/kg and 80 mg/kg. Tumor volumes and body weights were assessed weekly. Tumor tissues and blood were collected prior to dose increments. In selected patients treated with 50 mg sunitinib and presenting minimal toxicities, dose was escalated to 62.5 and 75 mg at the time of tumor progression. Results: Our preclinical results show that patient-derived tumors (RP-01 and RP-02), although initially responsive to sunitinib 40 mg/kg, eventually became resistant to treatment. Following dose increase to 60 mg/kg, we observed again tumor response but eventually the tumors became resistant. A similar effect was noticed when we further escalated sunitinib to 80 mg/kg. Immunohistochemistry analysis shows decreased tumor vascularization during response to sunitinib, but then hypervascularization at the time of resistance. Associated increase in expression of the methyltransferase EZH2, the histone marks H3K27me3, H3k4me2 and H3K9me2 in tumors resistant to sunitinib was observed. Analysis of sunitinib and VEGF/VEFGR2 blood and tumor levels will be reported. In parallel, our clinical experience shows that intra-patient sunitinib dose-escalation was safe and clinical benefit was observed. Details on tumor responses and toxicities will be reported. Conclusions: Overall, our results suggest that sunitinib-induced resistance may be overcome in part by increasing the dose of the VEGF receptor tyrosine kinase inhibitor in mouse models and ccRCC patients, and highlights the potential role of epigenetic changes associated with sunitinib resistance.
Phase II trial of vandetanib in Von Hippel-Lindau-associated renal cell carcinoma.
Authors: Stamatakis Lambros , Shuch Brian , Singer Eric A. , Nix Jeffrey , Truong Hong , Friend Julia C. , Fowler Sarah , Bratslavsky Gennady , Metwalli Adam R. , Shih Joanna H. , Linehan W. Marston , Srinivasan Ramaprasad 
Published: March 2020

4584 Background: Germline mutations in the von Hippel Lindau (VHL) gene are associated with the development of bilateral multifocal clear-cell renal cell carcinoma (RCC). VHL patients with localized disease are surgically managed, with nephron sparing resection recommended once tumors reach 3 cm. Patients typically undergo multiple surgeries with significant cumulative morbidity. In this phase 2 trial of vandetanib, a dual VEGFR2/EGFR inhibitor, a systemic approach to these tumors was explored. Methods: Patients with VHL-associated RCC were treated with 300 mg vandetanib daily until disease progression or unacceptable toxicity. Cross sectional imaging was performed at baseline and every 12 weeks. The primary endpoint was overall renal tumor response assessed by RECIST. Results: A total of 34 subjects were enrolled, with a mean age of 47 years (range 28 – 72). The median number of targeted lesions per subject was 2 (range 1 – 6) and the mean tumor diameter was 2.3 cm (range 1.2 – 4.0). Twenty-seven (80%) subjects had baseline imaging and at least one follow-up study to allow response evaluation. Median time on study was 6.1 months (range 1.0 – 23.3). Thirteen (38%) subjects demonstrated overall reduction in tumor burden with a median reduction of 6% (range 4-54%). One (3%) subject had a PR by RECIST and 26 (77%) had stable disease as their best response. Eleven (32%) subjects were taken off study due to growth of at least one lesion that met criteria for surgical resection or disease progression. Nine (27%) subjects required dose reductions due to toxicity. Although the majority of adverse events encountered on trial were grade 2 or less, 9 (27%) subjects were taken off trial due to drug-related toxicities and 9 (27%) withdrew due to intolerable side effects. Rash (71%), and QTc prolongation (41%) were the most common adverse events noted. Conclusions: In the largest phase II study of a systemic agent for VHL-related RCC, vandetanib demonstrated anti-tumor activity. Despite a reasonable safety profile, poor tolerability necessitated drug withdrawal in a significant proportion of patients. Newer agents that selectively target the VEGF receptors may offer a more tolerable alternative and might optimize clinical benefits in this population. Clinical trial information: NCT0056695.
Double-blind randomized trial of aflibercept versus placebo with docetaxel and prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tannock Ian , Fizazi Karim , Ivanov Sergey , Thellenberg-Karlsson Camilla , Flechon Aude , Skoneczna Iwona Anna , Orlandi Francisco Jorquera , Gravis Gwenaelle , Matveev Vsevolod , Bavbek Sevil E. , Gil Thierry , Viana Luciano S. , Aren Osvaldo , Karyakin Oleg , Elliott Tony , Birtle Alison J. , Magherini Emmanuelle , Petrylak Daniel Peter , Tombal Bertrand , Rosenthal Mark ,   VENICE Investigators
Published: March 2020

5002 Background: Docetaxel/prednisone is standard first-line chemotherapy for men with mCRPC. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of Vascular Endothelial Growth Factor and Placental-derived Growth Factors, thereby inhibiting angiogenesis. Methods: We performed an international double-blind randomized trial (known as VENICE) which recruited men with mCRPC, adequate organ function and no prior chemotherapy. Men were treated with docetaxel (75mg/m² intravenously every 3 weeks) and oral prednisone (5mg twice daily) and randomized 1:1 to receive aflibercept (6 mg/kg) or placebo, intravenously every 3 weeks. The primary endpoint was overall survival: 873 deaths were required to detect a hazard ratio (HR) of 0.8 with 90% power. Results: A total of 1,224 men were randomized, 612 in each arm. Median age was 68 years and baseline characteristics were well balanced between arms. Participants received a median of 8 (aflibercept) and 9 (placebo) cycles of therapy. Median relative dose intensity was >0.93 for aflibercept, placebo and docetaxel. At final analysis, median follow-up was 35 months and 873 pts had died. Median survival was 22.1 months (95.6% CI: 20.3-24.1 months) in the aflibercept arm and 21.2 months (95.6% CI: 19.6-23.8 months) in the placebo arm (stratified HR = 0.94; 95.6% CI: 0.82-1.08, p=0.38). Pre-defined secondary endpoints for aflibercept and placebo arms were similar, including PSA response rate (68.6% and 63.5%), time to first skeletal-related event (median: 15.3 and 15.0 months), and progression-free survival (median: 6.9 and 6.2 months). Quality of Life analysis using FACT-P and a trial-specific module will be reported. Higher incidence of grade 3-4 gastrointestinal disorders, hemorrhagic events, hypertension, fatigue, infections and fatal adverse events (5.6% vs. 3.3%) was observed in the aflibercept arm. Conclusions: Aflibercept in combination with docetaxel/prednisone given as first-line chemotherapy for men with mCRPC did not lead to an improvement in survival and added toxicity. Trial Registration: NCT00519285. Funding: Sanofi and Regeneron Pharmaceuticals, Inc. Clinical trial information: NCT00519285.
Correlation of 18F-fluoride PET response to dasatinib in castration-resistant prostate cancer bone metastases with progression-free survival: Preliminary results from ACRIN 6687.
Authors: Yu Evan Y. , Duan Fenghai , Muzi Mark , Gorelick Jeremy , Chin Bennett , Alumkal Joshi J. , Taplin Mary-Ellen , Herman Ben , Higano Celestia S. , Doot Robert K , Hartfeil Donna M , Febbo Phillip G. , Mankoff David A. ,   Department of Defense Prostate Cancer Clinical Trials Consortium and American College of Radiology Imaging Network
Published: March 2020

5003 Background: Dasatinib is a SRC kinase inhibitor that decreases bone turnover in men with metastatic castration-resistant prostate cancer (mCRPC). 18F-fluoride PET was used to evaluate differential response between normal and tumor bone to dasatinib. Methods: Patients with bone mCRPC underwent dynamic 18F-flouride PET imaging prior to and 12 weeks after dasatinib treatment. Up to 5 bone metastases with matching normal bone regions were selected for analysis by SUVmax, Ki, K1and Patlak flux. Their pre-treatment values and change from pre-treatment to post-treatment values were evaluated via generalized estimating equations to predict skeletal-related events (SRE) and via Cox proportional hazards modeling to predict progression-free survival (PFS) with Prostate Cancer Working Group 2 criteria, overall survival and time to SRE. Results: Eighteen patients treated with dasatinib underwent baseline 18F-flouride PET imaging; 12 had follow-up scans allowing assessment of changes due to therapy. Median age for all patients was 69 (range 48-86) years. Significant decrease in SUVmax (p=0.0002) occurred in bone metastases with dasatinib while significant increases in Patlak flux (p=0.0033) occurred in normal bone. Significant differences in changes from tumor bone compared to normal bone in response to dasatinib were noted for SUVmax (p<0.0001). Of 18 patients, 17 have either met progression criteria or death by the time of this analysis. Decrease in tumor bone SUVmax (p=0.019), Ki(p=0.022), and Patlak flux (p=0.034) from pre-treatment to post-treatment correlates with longer PFS. Conclusions: 18F-fluoride PET indicates differential effect of dasatinib on tumor compared to normal bone in men with mCRPC. In patients undergoing pre- and post-dasatinib 18F-fluoride PET imaging a decrease in bone mCRPC fluoride uptake in response to treatment correlates with PFS. Clinical trial information: NCT00936975.
Prolaris: A novel genetic test for prostate cancer prognosis.
Authors: Brawer Michael K. , Cuzick Jack M. , Cooperberg Matthew R. , Swanson Gregory P. , Freedland Stephen J. , Reid Julia E. , Fisher Gabrielle , Lanchbury Jerry S. , Gutin Alexander , Stone Steven , Carroll Peter ,   Transatlantic Prostate Group
Published: March 2020

5005 Background: The natural history of prostate cancer is highly variable and difficult to predict. Improved tools are needed to match treatment more appropriately to a patient’s risk of progression. Therefore, we developed an expression signature composed of genes involved in cell cycle progression (Prolaris) and tested its utility in prostate cancer. Methods: We developed an expression signature composed of 31 cell cycle progression and 15 housekeeper genes. An expression score (Prolaris score) was derived as the mean of all cell cycle progression genes. The signature was tested at disease diagnosis in two conservatively managed cohorts from the UK (N=337 and 349), after radical prostatectomy in two cohorts from the U.S. (N=366 Scott & White Hospital, TX and 413 USCF, CA), and after external beam radiation therapy (N=141) in a cohort from Durham VA Medical Center. All studies were retrospective. Results: The cell cycle progression signature was a highly significant predictor of outcome in all five studies. In conservatively managed patients, the Prolaris score was the dominant variable for predicting death from prostate cancer in univariate analysis (p = 6.1 x 10-22 after diagnosis by TURP, and p = 8.6 x 10-10 after diagnosis by needle biopsy). In both studies, the Prolaris score remained highly significant in multivariate analysis making it a stronger predictor of disease-specific mortality than other prognostic variables. After prostatectomy, Prolaris predicted biochemical recurrence (BCR) in univariate analysis (S&W p = 5.6 x 10-9; UCSF p= 2.23 x 10-6) and provided additional prognostic information in multivariate analysis (S&W p = 3.3 x10-6; UCSF 9.5 x10-5). After radiation therapy, Prolaris predicted BCR (Phoenix) in univariate (p=0.0017) and multivariate analysis (p=0.034). In all five studies the HR per unit change in the Prolaris score was remarkably similar, ranging from 1.89 to 2.92, indicating that the effect size for the Prolaris score is robust to clinical setting and patient composition. Conclusions: The Prolaris test predicts prostate cancer outcome in multiple patient cohorts and diverse clinical settings. In all cases, it provides information beyond clinicopathologic variables to help differentiate aggressive from indolent disease.
Effect of corticosteroid (CS) use at baseline (CUB) on overall survival (OS) in patients (pts) receiving abiraterone acetate (AA): Results from a randomized study (COU-AA-301) in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel (D).
Authors: Montgomery Robert B. , Kheoh Thian San , Molina Arturo , Li Jinhui , Bellmunt Joaquim , Ryan Charles J. , Tran Namphuong , Loriot Yohann , Efstathiou Eleni , Scher Howard I. , De Bono Johann Sebastian 
Published: March 2020

5014 Background: CS have been used to mitigate mineralocorticoid-related effects and restore sensitivity to AA (Attard et al., J Clin Oncol. 2008). Prednisone (P) was also used as an active comparator in the COU-AA-301 (de Bono et al., N Engl J Med. 2011) and COU-AA-302 (Ryan et al., N Engl J Med. 2013) AA pivotal studies. CUB has also been reported to adversely influence OS in the AFFIRM study, which may reflect an influence on disease biology or unrecognized factors that are not a part of clinically based prognostic models (Scher et al., Ann Oncol. 2012). This post hoc exploratory analysis investigated whether CUB is a prognostic factor for OS in mCRPC post-D pts treated with AA + P or P alone. Methods: COU-AA-301 is a randomized double-blind study of AA (1 g) + P (5 mg po BID) vs placebo + P in mCRPC post-D. The primary endpoint was OS. All pts had received CS with D therapy. CUB included P (n = 272), dexamethasone (n = 107), and others (n = 110). 797 pts were not on CUB. Median times were estimated by the product-limit method; Cox model was used to obtain the hazard ratio (HR) and associated confidence interval (CI). Results: Pts with CUB had worse baseline disease characteristics (including adverse ECOG PS, Gleason score, analgesic score, and LDH) (all p < 0.05). Pts receiving CUB had inferior OS; AA + P improved OS independent of CUB. (Table). CUB was an independent prognostic factor in multivariate analysis (p = 0.03; HR 1.22 [95% CI: 1.02-1.45]) that was associated with lower baseline androgen levels (p < 0.0001). In a stepwise selection model, CUB was not an independent prognostic factor. Conclusions: In this study, CUB was not a strong independent prognostic factor in mCRPC post-D pts treated with AA + P or P alone. CUB was associated with worse baseline disease characteristics and inferior OS in this study, in which all pts subsequently received CS. Clinical trial information: NCT00638690. [Table: see text]
Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer Clinical Trials Consortium Study.
Authors: Morris Michael J. , Hammers Hans J. , Sweeney Christopher , Antonarakis Emmanuel S. , Cho Steve Y. , Pandit-Taskar Neeta , Jacene Heather , Bloma Marianne , Aksnes Anne-Kirsti , O'Bryan-Tear C. Gillies , Carrasquillo Jorge A. 
Published: March 2020

5021 Background: Ra-223, a first-in-class α-emitting pharmaceutical, targets bone metastases (mets) with high-energy α-particles of very short range (< 100 µm). D is an approved chemotherapy with demonstrated survival benefit for patients progressing after castrating hormone therapy. We are exploring the hypothesis that simultaneously targeting the tumor and the bone is clinically superior to targeting either alone. We therefore conducted a phase I study of Ra-223 + D in patients with CRPC and bone mets to establish the safety of the combination. Methods: Eligible patients had confirmed symptomatic CRPC with ≥ 2 bone mets and were candidates for treatment with D. Dose escalation followed a 3 + 3 design, with no intrapatient dose escalation or overlapping of cohorts. Patients were to receive 2 combined doses of Ra-223 q6wk + D q3wk (cohort 1: Ra-223/D = 25 kBq/kg /75 mg/m2; cohort 2: Ra-223/D = 25 kBq/kg /60 mg/m2; and cohort 3: Ra-223/D = 50 kBq/kg /60 mg/m2). Dose-limiting toxicity was assessed 6 weeks after first Ra-223 + D injection. Long-term safety data were collected every 3 months after end of study treatment for up to 1 year after start of study treatment. Results: 17 patients were treated, 7 each in cohorts 1 and 3 (1 patient in each cohort discontinued early and was replaced), and 3 in cohort 2. There was no discontinuation or delay of Ra-223 due to adverse events, and so far no reports of long-term toxicity during follow-up. 4 cases of febrile neutropenia occurred during study treatment (12 wk): 3 occurred in cohort 1 (1 was 7 days after first Ra-223 + D, and 2 were in the same subject, both occurring 1 wk after first and second doses of D alone [wk 4 and 10]); 1 occurred in cohort 3, 1 week after second Ra-223 + D (wk 7). Other safety data were as expected based on Ra-223 and D monotherapy data. Conclusions: The phase IIa regimen of Ra-223 + D utilizes a regimen of D 60 mg/m2 q3wk × 10 + Ra-223 50 kBq/kg q6wk × 5. The regimen is currently being explored in a randomized 2:1 open-label expanded safety cohort comparing Ra-223 + D versus D 75 mg/ m2 alone (standard dose). Clinical trial information: NCT01106352.