bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma.
Authors: Sheng Xinan , Yan Xieqiao , Tang Bixia , Chi Zhihong , Cui Chuanliang , Si Lu , Mao Li Li , Lian Bin , Li Si Ming , Zhou Li , Wang Xuan , Bai Xue , Kong Yan , Dai Jie , Guo Jun 
Published: September 2018

4575 Background: CM082 is an oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination with other therapies. This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM082 in combination with everolimus in patients with metastatic renal cell carcinoma. Methods: A 3+3 dose escalation design with expansion cohort was utilized to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of CM082 plus everolimus at 5 mg PO daily for patients with metastatic clear cell renal cell carcinoma. Eligibility include PS 0-1, age ≥18 y, measurable disease, adequate organ function. Results: 22 patients (M/F: 16/6; median age: 55 y [range 32-69]; 21/22 pts [95.5%] had received prior anti-VEGF treatment (tx); 2/22 pts [9.1%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of CM082 (100 mg [n = 4]; 150 mg [n = 3]; 200 mg [n = 15]) in combination with everolimus 5 mg. One patient in cohort 1 was not evaluable for DLT due to consent withdrawal. DLT were observed in one patient: G4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, but was chosen as the optimal biological dose regimen. Median duration of tx was 24 wk (range 1-57, 7/22 [32%] pts ongoing. The most common tx-related adverse events (AEs), all grades, were proteinuria 96% (G3, 5%); leukopenia 77% (G3, 9%); neutropenia 59%, hypercholesterolemia 64%, anemia 50% (G3, 9%), hypertension 46% (G3, 14%), raised aspartate aminotransferase 41%, fatigue 45%, diarrhea 32%, hypertriglyceridemia 32% (G3, 5%) and thrombocytopenia 20% (G4, 5%). At 200mg, partial response (PR) was observed in 5/14 (36%) patients, durable stable disease (SD) (≥24 week) or PR were achieved in 10/14 (71%) patients. Median PFS was 170 days (5.7 months) at this cohort. Conclusions: CM082 200mg in combination with everolimus 5 mg appeared to be well tolerated when administered to pretreated patients with advanced RCC in this Ph1 study. The preliminary efficacy warrant further evaluationand and the follow-up Ph 2/3 study is underway. Clinical trial information: NCT02577458.
The association of tumor infiltrating CD8+ and Foxp3+ cells with overall response rate (ORR) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose aldesleukin (HD IL-2).
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Novak Jesse , Mahoney Kathleen Margaret , Mier James Walter , Freeman Gordon J. , Atkins Michael B. , Catalano Paul J. , Signoretti Sabina , McDermott David F. 
Published: September 2018

4576 Background: In the prospective, biomarker validation HD IL-2 “Select” study, durable remissions and prolonged survival were seen in both proposed “good” and “poor-risk” patients, based on clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining. Given the toxicity and limited efficacy of HD IL-2, efforts to improve its therapeutic index are warranted. Since the high-affinity receptor of IL2 is expressed on both T regulatory cells and activated effector T lymphocytes, we explored the association between HD IL-2 response and tumor infiltration of CD8+ T and FoxP3+cells. Methods: Archival tumor tissue was collected for pathologic analysis on 120 mRCC patients enrolled in the HD IL-2 “Select” trial.Density of tumor infiltrating CD8+ T cells and Foxp3+ cells (cell/mm2) were evaluated in the invasive margin (IM) and the tumor center (TC) by IHC and automated image analysis using Aperio algorithms. The association between ORR and immune cell density was assessed using Fisher exact test. Results: Tumor specimens of 89 patients were available for analysis. 24 pts experienced response (R, including 2 CR and 22 PR) and 65 pts did not respond (NR, including 11 SD and 54 PD). Baseline patient characteristics were similar between R and NR groups. A very high density of CD8+ cells in the IM, or a high density of Foxp3+ cells in the TC were significantly associated with ORR. A stronger association with ORR was found for patients having both high density of CD8+ cells in the IM and Foxp3+ cells in the TC. Conclusions: In this prospective, biomarker validation study, response to HD IL-2 was associated with a high density of CD8+ cells in the invasive margin, and a high density of Foxp3+cells in the tumor center. Independent validation is ongoing. To improve the predictive value of Foxp3, characterization of Foxp3 expressing cells (Tregs vs activated effector T cells) in highly infiltrated tumors is underway. [Table: see text]
Outcomes based on age in the phase 3 METEOR trial of cabozantinib (cabo) vs everolimus (eve) in patients with advanced renal cell carcinoma (RCC).
Authors: Donskov Frede , Motzer Robert J. , Voog Eric , Hovey Elizabeth J. , Grüllich Carsten , Nott Louise M. , Cuff Katharine Ellen , Gil Thierry , Jensen Niels Viggo , Chevreau Christine , Negrier Sylvie , Depenbusch Reinhard , Bergmann Lothar , Cornelio Izzy , Champsaur Anne , Escudier Bernard J. , Pal Sumanta K. , Powles Thomas , Choueiri Toni K. 
Published: September 2018

4578 Background: The incidence of RCC increases with age with the highest incidence at ~75 years of age (Znaor, Eur Urol 2015). The Phase 3 METEOR trial (NCT01865747) showed a significant improvement in progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.74; P < 0.0001), overall survival (OS; HR 0.66, 95% CI 0.53–0.83, P = 0.0003), and objective response rate (ORR; 17% vs 3%; P < 0.0001) for cabo compared with eve in patients with advanced RCC previously treated with VEGFR TKIs (Choueiri, NEJM 2015, Lancet Oncol 2016). Here we present outcomes by 3 categories of age for the METEOR trial. Methods: 658 patients were randomized 1:1 to cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Endpoints included PFS, OS, and ORR. Subgroup analyses by age ( < 65, 65 to 74, and ≥75 years) are presented. Results: At baseline, 60% of patients were < 65 years old, 31% were 65 to 74 years old, and 10% were ≥75 years old. Subgroups by age generally had similar baseline characteristics in both arms. The HRs for PFS favored cabo for all age groups (HR 0.53, 95% CI 0.41–0.68 for < 65 years old; 0.53, 95% CI 0.37–0.77 for 65 to 74 years old; and 0.38, 95% CI 0.18–0.79 for ≥75 years old). ORR per independent radiology committee for cabo vs eve was 15% vs 5% for < 65 years old, 21% vs 2% for 65 to 74 years old, and 19% vs 0% for ≥75 years old. HRs for OS also favored cabo (HR 0.72, 95% CI 0.54–0.95 for < 65 years old; 0.66, 95% CI 0.44–0.99 for 65 to 74 years old; and 0.57, 95% CI 0.28–1.14 for ≥75 years old). Median OS for cabo vs eve was 21.4 mo vs 17.1 mo for < 65 years old, not reached vs 18.0 mo for 65 to 74 years old, and 18.4 mo vs 14.0 mo for ≥75 years old. Older patients more frequently had dose reductions (60% with cabo and 22% with eve for < 65 years old vs 85% with cabo and 36% with eve for ≥75 years old). Grade 3 or 4 adverse events were generally consistent with the safety profiles in the overall population although some events such as fatigue and hypertension occurred at a higher rate in older patients. Conclusions: Treatment with cabo improved PFS, ORR, and OS compared with eve in patients with advanced RCC irrespective of age. Adverse events in older patients were more frequently managed with dose reductions. Clinical trial information: NCT01865747.
Development and clinical validation of circulating tumor cell (CTC) biomarkers in clear cell renal cell carcinoma (ccRCC) for the OMNIVORE clinical trial.
Authors: Arafat Waddah , Desotelle Joshua , Rodems Tamara , McKay Rana R. , Abel Jason , Choueiri Toni K. , Lang Joshua Michael 
Published: September 2018

4579 Background: New therapeutic strategies and biomarkers of treatment resistance are needed for metastatic ccRCC patients (pts) progressing on Nivolumab (Nivo). The upcoming OMNIVORE phase II clinical trial will evaluate whether adding Ipilumimab improves rPFS for pts with SD or PD on Nivo alone. We report development and clinical validation of predictive CTC biomarkers that will be evaluated in the OMNIVORE trial. Methods: We tested blood samples from ccRCC pts collected on biomarker trials at Dana Farber and U. of Wisconsin. Carbonic Anhydrase (CA) IX was used to capture CTCs in the VERSA platform to compare protein and gene expression signatures of resistance to Nivo. HLA and PD-L1 expression on CTC was quantified with independent confirmation with multicolor flow cytometry (FC). Results: We identified CTCs in 26/27 pts using RCC-specific CA IX antibody. Staining with CAXII and PAX8 confirmed CTC were of renal origin. The range of captured CK+/CAXII+/CD45- CTCs was 3-279 (median 15) from 18 pts. Multicolor FC found 8/9 pts with triple positive events for renal specific markers CAIX/CAXII/PAX8 [0-14.9%, median 0.32]. PDL1 and HLA staining was validated in cell line and pts samples with high reproducibility. PDL1 was expressed in < 10% of CTCs while HLA expression had high intra- and interpatient heterogeneity. Three pts had CTCs positive for both HLA and PDL1 that correlated with a high frequency of CTCs that were positive for 3 RCC markers (1.3, 5.1 and 14.9% of events) for an R² value of 0.92 (p < 0.0001). In 3 pts with ongoing response to Nivo (9-13 moths) triple positive events were 0, 0.2 and 0.3% (median 0.25%) and absent expression of PDL1/HLA. In 3 pts with early progression on Nivo ( < 5 mo), triple positive CTCs ranged 0.33-14.9% (median 5.05%) with CTCs from 2/3 pts positive for PDL1/HLA. Conclusions: We report the first identification of ccRCC CTCs using CAIX, CAXII and PAX8 as confirmatory markers. CTC frequency and PDL1/HLA expression is lower in Nivo responders versus pts with early progression. High but variable HLA expression suggests variant resistance mechanisms. The utility of theses predictive and pharmacodynamic biomarkers will be tested in the OMNIVORE trial.
Association of circulating tumor DNA (ctDNA) detection in metastatic renal cell carcinoma (mRCC) with tumor burden.
Authors: Maia Manuel Caitano , Bergerot Paulo Gustavo , Dizman Nazli , Hsu JoAnn , Jones Jeremy , Choueiri Toni K. , Sonpavde Guru , Lanman Richard B. , Banks Kimberly , Pal Sumanta K. 
Published: September 2018

4582 Background: In a series of 224 pts with advanced RCC, we have previously reported ctDNA detection in 79% of pts (Pal SK et al ASCO GU 2017). Clinical factors associated with detection are unknown. Methods: Data was obtained from pts with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIAA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of Heng risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions. Results: 32 pts were assessed (M:F 19:13) with a median age of 62 (range, 34-84). 25 pts, 4 pts and 3 pts had clear cell, sarcomatoid and papillary histology, respectively. Heng risk was good, intermediate and poor in 13, 18 and 1 pt, respectively. Pts received a median of 2 lines of prior tx. Specifically, 4 pts were not on active therapy (tx), 16 pts were receiving VEGF-directed tx, 6 pts were receiving checkpoint inhibitors (CPIs) and 6 pts were receiving combined VEGF/CPI tx. ctDNA was detected in 16 pts (50%) with a median of 2 genomic alterations (GAs) per pt. No associations were found between Heng risk, histology or tx type and presence/absence of ctDNA. However, pts with detectable ctDNA had a higher SLD compared to pts with no detectable ctDNA (99.6 vs 50.0 mm; P = 0.041). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P = 0.023). TP53 and VHL alterations were the most frequent GAs in this series, each occurring in 25% of the cohort. All 3 pts with brain metastases had ctDNA detected. Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC pts with detectable ctDNA, and increasing SLD may be associated with a higher number of GAs. Further validation of these findings may help identify appropriate pts for ctDNA assessment and maximize yield in clinical practice.
T cell infiltration (TCI) in matched renal biopsy (bx) and nephrectomy (nx) samples in renal cell carcinoma (RCC).
Authors: Zahoor Haris , Pavicic Paul G , Przybycin Christopher , Elson Paul , Diaz-Montero C. Marcela , Finke James , Rayman Patricia A. , Gilligan Timothy D. , Grivas Petros , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I. 
Published: September 2018

4587 Background: TCI in tumors has been investigated as a biomarker of response to checkpoint inhibitors. A neo-adjuvant trial of checkpoint inhibition in locally-advanced RCC is ongoing at Cleveland Clinic, where TCI in pre-treatment renal mass bx will be compared to post-treatment nx specimens. However, there are no data regarding the association of TCI in matched bx and nx samples without intervening treatment. Understanding this association will enable further study of this potential biomarker in future studies. Methods: Matched bx and nx samples (without intervening systemic therapy) were identified from patients with non-metastatic RCC. Selected tissue sections from bx and nx samples were reviewed, and marked for intra-tumoral lymphocytes by the Pathologist. Immunohistochemistry (IHC) was utilized to stain these selected tissue sections for T cell markers (CD3, CD4 and CD8), and additional immune markers including PD-1, PDL-1 and CD11b. Intra-tumoral staining was then quantified in the pre-marked tissue sections as counts per total tumor area surveyed. Spearman correlation (ρ) was used to measure the strength of association. Results: 30 matched pairs were investigated. The median interval between bx and nx was 2.8 (0.2-87.7) months. Clear cell was the most common histology (29/30; 97%). There was a positive correlation between the frequency of CD8+T cells between matched bx and nx samples (ρ= 0.39; p=0.03). CD3, CD4 and CD11b did not show significant correlation. (Table) PD-1 (bx 4/29, nx 16/29) and PDL-1 (bx 5/28, nx 10/28) expression was positive in the minority of samples. Conclusions: Bx material can potentially be used to assess the degree of CD8+ TCI in RCC nx samples. However the utility of bx evaluation for CD4+TCI and expression of PD-1, PDL-1 and CD11b requires further study. [Table: see text]
Impact of perioperative chemotherapy and radiation for locally advanced penile squamous cell carcinoma (PSCC).
Authors: Hathaway Amanda Redden , Morgan Charity , Yang Eddy Shih-Hsin , Diorio Gregory , Spiess Philippe E. , Sonpavde Guru 
Published: September 2018

4589 Background: While neoadjuvant chemotherapy preceding radical surgery (S) for PSCC appears to provide the most optimal outcomes, there are no randomized studies. The impact of triple-modality S plus perioperative chemotherapy (C) plus radiation (XRT) for PSCC is unclear. The differential outcomes provided by perioperative XRT vs. perioperative C are also unclear. Given the absence of prospective trials, we retrospectively analyzed the U.S. National Cancer Database (NCDB) to study this issue. Methods: Data from the NCDB was obtained for pts with locally advanced PSCC from 1998-2011. Patients who underwent S for PSCC pathologic stage ≥1 with data for receipt of perioperative C and/or XRT and follow-up were eligible for analysis. The following variables were evaluated: pathologic stage, age, Charlson Comorbidity Index (CCI), race, overall survival (OS), socioeconomic status based on median income of area of residence and therapy (S+C, S+XRT, S+C+XRT). Treatment patterns were described. Multivariate analyses (MVA) were conducted to determine the impact of factors on OS with P < 0.05 considered significant. Results: A total of 418 pts were evaluable including 132 in the S+XRT group, 166 in the S+C group and 120 in the S+C+XRT group. The number of pts with stages 1, 2, 3, 4 and unknown were 26, 78, 146, 137 and 31, respectively. In the MVA, stage was independently significantly prognostic (p = 0.002), while age (p = 0.056) and CCI (p = 0.057) were trending significant. S+C+XRT was not statistically better than S+XRT (HR 1.37 [95% CI: 0.935 - 2.007]) or S+C (HR 0.834 [95% CI: 0.589 - 1.180]). Additionally, S+C was not associated with significantly different OS compared to S+XRT (HR 1.142 [95% CI: 0.790 - 1.652]). Limitations of a retrospective analysis apply. Conclusions: This is the largest retrospective study of perioperative therapy for locally advanced PSCC. Triple modality therapy (S+C+XRT) did not extend OS compared to dual modality therapy (S+C or S+XRT). Additionally, the analysis did not identify whether C or XRT should be preferred in pts receiving dual modality therapy. The phase II International Penile Cancer Adjuvant Trial (InPACT) will investigate these conundrums for this orphan malignancy.
Post hoc analysis of a phase III study to test the association between circulating methylated glutathione s transferase (mGSTP1) DNA levels and response to docetaxel (DTX) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Mahon Kate Lynette , Qu Wenjia , Lin Hui-Ming , Spielman Calan , Cain Daniel , Jacobs Cindy , Chi Kim N. , De Bono Johann S. , Higano Celestia S. , Clark Susan J. , Horvath Lisa 
Published: September 2018

5014 Background: GSTP1 inactivation is associated with CpG island hypermethylation in > 99% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to DTX and overall survival (OS) in phase I/II mCRPC cohorts. This post hoc analysis of a phase III study aims to test the association between circulating mGSTP1 DNA levels and outcomes. Methods: The phase III SYNERGY study tested DTX +/- custirsen as 1st line chemotherapy in mCRPC (n = 1022) with no OS benefit in the experimental arm. Serum samples were taken at baseline (BL) and preC3 of DTX +/- custirsen from 600 patients (pts) enrolled on the SYNERGY study. mGSTP1levels in free DNA were measured using a sensitive methylation specific PCR assay and correlated with PSA response, time to PSA progression (TTP) and OS. Results: On interim analysis of 300 pts, serum mGSTP1 was detectable at BL in 80% and preC3 in 44%. Undetectable preC3 mGSTP1 correlated with a ≥30% fall in PSA within 3m of starting DTX (p < 0.001). Detectable BL and preC3 mGSTP1 predicted shorter TTP after DTX (BL; HR 1.6 95%CI 1.1-2.3; p = 0.01 and preC3 HR 2.2 95%CI 1.6-2.9; p < 0.001). Detectable mGSTP1 at both time points predicted shorter OS (BL; median OS 18.4 vs 33.1m, HR 2.4 95%CI 1.6-3.7; p < 0.001 and preC3; median OS 13.9 vs 29m, HR 2.7 95%CI 2.0-3.6; p < 0.001). In those with detectable BL mGSTP1, 50% had undetectable preC3 mGSTP1 predicting > 30% fall in PSA within 3m (p < 0.001), improved TTP (HR 0.40 95%CI 0.29-0.57; p < 0.001) and improved OS (25.2 vs 13.9 m HR 0.38 95%CI 0.28-0.51; p < 0.001). On multivariable analysis including Hb, Karnofsky PS, LDH, PSA and visceral metastases, detectable preC3 mGSTP1 independently predicted shorter TTP (HR 1.9 95%CI 1.4-2.6; p < 0.001). Detectable mGSTP1at both time points independently predicted OS (BL; HR1.8 95%CI 1.2-2.8; p = 0.006 and preC3; HR 2.2 95%CI 1.6-3.0; p < 0.001). Results from the full cohort of 600 pts will be available for presentation at the meeting. Conclusions: This study should validate circulating mGSTP1 DNA as a marker of therapeutic benefit and prognosis in men with mCRPC receiving DTX and could be utilized for clinical management.
Development and validation of a prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer (mCRPC) from the phase 3 prevail clinical trial.
Authors: Armstrong Andrew J. , Lin Ping , Higano Celestia S. , Sternberg Cora N. , Sonpavde Guru , Tombal Bertrand F. , Templeton Arnoud J. , Fizazi Karim , Phung De , Wong Elaine K , Krivoshik Andrew , Beer Tomasz M. 
Published: September 2018

5022 Background: Prognostic models require updating to reflect contemporary medical practice. In a post hoc analysis of the phase 3 PREVAIL trial (enzalutamide vs placebo), we identified prognostic factors for overall survival (OS) in chemotherapy-naive men with mCRPC. Methods: Patients were randomly divided 2:1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined candidate prognostic factors (including treatment) were analyzed in a multivariable Cox model with stepwise procedures and in a penalized Cox proportional hazards model using the adaptive least absolute shrinkage and selection operator (LASSO) penalty (data cutoff June 1, 2014). A multivariable model predicting OS was developed using the training set; the predictive accuracy was assessed in the testing set using time-dependent area under the curve (tAUC). The testing set was stratified based on risk score tertiles (low, intermediate, high), and OS was analyzed using Kaplan-Meier methodology. Results: Demographics, disease characteristics, and OS were balanced between the training and testing sets; median OS was 32.7 months for both datasets. There were no enzalutamide treatment-prognostic factor interactions (predictors). The final multivariable model included 11 prognostic factors: prostate-specific antigen, treatment, hemoglobin, neutrophil-lymphocyte ratio, liver metastases, time from diagnosis to randomization, lactate dehydrogenase, ≥ 10 bone metastases, pain, albumin, and alkaline phosphatase. The tAUC was 0.74 in the testing set. Median (95% confidence interval [CI]) OS for the low-, intermediate-, and high-risk groups (testing set) were not yet reached (NYR) (NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0). The hazard ratios (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Conclusions: Our validated prognostic model incorporates factors routinely collected in chemotherapy-naive men with mCRPC treated with enzalutamide and identifies subsets of men with widely differing survival times. Clinical trial information: NCT01212991.