bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of changes in biomarkers with treatment with cabozantinib (Cabo) in metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the 100mg nonrandomized expansion cohort of a randomized discontinuation trial.
Authors: Leibowitz-Amit Raya , Pintilie Melania , Laird A. Douglas , Aftab Dana T. , Berger Raanan , Chi Kim N. , Joshua Anthony M.
Published: February 2017

196

Background: Cabo, an oral inhibitor of receptor tyrosine kinases (RTK) including MET and VEGFR2, showed activity in early clinical studies in mCRPC, and is being investigated in phase 3 trials. Our primary aim was to retrospectively study the potential association between plasma concentrations of known markers of hypoxia, RTK cell signaling, inflammation, bone metabolism, chemo-attraction and epithelial-mesenchymal transition with response to Cabo in patients (pts) who received 100mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225). Methods: Our cohort of mCRPC pts with available plasma samples comprised of 81 pts with bone lesions assessed for bone scan response (BSR, defined as ≥30% decrease in lesion area compared to baseline). Thirty three pts also had measurable disease and were assessed for RECIST response. Plasma samples were available for all pts at baseline, at 6 weeks and at time of best response. Levels of 27 plasma biomarkers were measured in duplicate using ELISA. Spearman correlation coefficients were calculated for the association between response and biomarker levels at each time point. Results: Sixty six of 81 pts (81%) had a BSR, and 6 of 33 pts (18%) had a partial response by RECIST. No significant associations were found between the levels of any of the biomarkers at baseline or subsequent time points and either BSR or response by RECIST. Over time, the plasma concentrations of soluble VEGFR2 were significantly decreased during treatment with Cabo, consistent with the known effects of VEGFR inhibition on soluble VEGFR2. The plasma concentrations of nine markers (VEGFA, CA9, clusterin, FLT3L, Gas6A, Bone Alkaline phosphatase, and the soluble forms of the RTKs MET, IGF1R and AXL) were significantly increased during treatment with Cabo irrespective of response. Conclusions: These results demonstrate that metabolic alterations occur following treatment with Cabo in pts with mCRPC. Changes in certain biomarkers during treatment with Cabo could suggest potential co-targeting approaches with Cabo or other RTK inhibitors in mCRPC.
Phenotypic characterization of circulating tumor cells (CTCs) from neuroendocrine prostate cancer (NEPC) and metastatic castration-resistant prostate cancer (mCRPC) patients to identify a novel diagnostic algorithm for the presence of NEPC.
Authors: Beltran Himisha , Jendrisak Adam , Landers Mark , Mosquera Juan Miguel , Kossai Myriam , Louw Jessica , Krupa Rachel , Nanus David M. , Tagawa Scott T. , Marrinucci Dena , Rubin Mark A. , Dittamore Ryan Vance
Published: February 2017

197

Background: NEPC is an aggressive variant of prostate cancer that most commonly arises in later stages of mCRPC, especially with visceral metastases in the setting of a low PSA. There are no reliable serum markers to identify patients that are transforming to NEPC and incidence of CTCs in these patients is unknown. Detection of NEPC has clinical implications as these patients are often treated with platinum chemotherapy rather than with androgen receptor (AR) targeted therapies such as abiraterone or enzalutamide. We sought to determine if phenotypic characterization of CTCs could differentiate NEPC from mCRPC. Methods: 24 pts (16 pts with tissue confirmed NEPC and 8 pts with mCRPC) had blood collection for CTC analysis utilizing the Epic Sciences platform. Epic analysis included identification of traditional CTCs (CK+, CD45- cells, with intact nuclei, morph distinct), CK- CTCs (CK-, CD45-, intact nuclei, morph distinct), small CTCs (CK+, CD45-, intact nuclei, small cell size), and CTC clusters. We examined CTCs at the single cell level for CTC size, shape, epithelial and AR expression. Advanced digital pathology algorithms measured size and shape measurements of CTCs. Results: CTCs from NEPC patients demonstrated strong statistical differentiation from mCRPC patients, with unique CTC morphology and protein chemistry that was not seen in mCRPC CTCs. NEPC CTCs had increase prevalence of unique CTC phenotypes including: small size, AR negativity, and presence of nucleoli. Unique cell types enabled a multivariate biomarker that is strongly associated with CTCs exclusive to tissue confirmed NEPC. Conclusions: CTCs from NEPC have unique phenotypes compared with those from mCRPC. If confirmed, the utilization of a liquid biopsy to diagnose NEPC may enable earlier identification of patients prone to visceral metastasis, and intervention to cytotoxic therapeutics. Additionally, identification of patients with NEPC could help for patient selection for AR vs. NEPC targeted therapeutics. [Table: see text]
Ferumoxytol enhanced MRI for lymph node staging in prostate cancer.
Authors: Brown Anna Mary , Sankineni Sandeep , Bernardo Marcelino , Daar Dagane , Weaver Juanita , McKinney Yolanda , Couvillon Anna , Gulley James L. , Pinto Peter A. , Dahut William L. , Madan Ravi Amrit , Choyke Peter L. , Turkbey Baris
Published: February 2017

208

Background: Conventional imaging methods of lymph node staging in prostate cancer are limited. The goal of this study is to determine the utility of ferumoxytol enhanced MRI in lymph node (LN) staging. Methods: This ongoing IRB-approved clinical trial enrolls prostate cancer patients at high risk for LN metastases. Patients first undergo baseline T2 and T2* weighted MRI scans followed by 7.5mg/Kg ferumoxytol injection. Repeat scans are acquired at 24 hr and 48 hr post-injection. The criterion for positive LNs was hyperintense signal indicating failure to take up ferumoxytol. Validation was determined on clinical grounds or by histopathology when available. Results: To date, 11 patients have completed the study. One patient was examined pre-operatively while the other 10 had suspected therapy failure. Median age and PSA were 65 yrs (36-75) and 5.6ng/dL (0.3-201). Of 16 LNs with median size 1.6 x 1.1cm, 10 were true positives, one was false positive and one was false negative with 4 nodes pending validation. The LN status was correctly identified in 8 of 11 patients [Table]. Conclusions: Ferumoxytol enhanced MRI shows promise in detecting malignant LNs with diameter >6mm in prostate cancer paients. This method is performed in a conventional MRI unit with off-label use of an FDA-approved agent and thus could be widely available. However, further validation is necessary before routine use. Clinical trial information: NCT02141490. [Table: see text]
Presence of myeloid-derived suppressor cells (MDSC) in patients with metastatic castration-sensitive and castration-resistant prostate cancer.
Authors: Autio Karen A. , Wong Phillip , Rabinowitz Angel , Yuan Jianda , Slavin Lauryn Michelle , Brennan Ryan , DerSarkissian Melineh , Mu Zhenyu , Scher Howard I. , Lesokhin Alexander M.
Published: February 2017

222

Background: MDSC contribute to an immune suppressive environment and have been implicated in cancer progression. Measurement (identification and enumeration) is challenged by the lack of analytically valid assays limiting data interpretation between groups. This impacts our understanding of rationale immune targets and design of clinical trials. We employed a novel biomarker based assay in whole blood to enumerate MDSC from patients with metastatic castration sensitive (CSPC) and castration resistant prostate cancer (CRPC). Methods: Whole blood was collected in Cyto-Chex (Streck) tubes. A published computational algorithm-based approach (developed by Memorial Sloan Kettering Cancer Center and commercialized by Serametrix) was employed to determine the %MDSC-monocytic and coefficient of variance (CV=ratio of SD and geometric mean fluorescence intensity) to assess HLA-DR spread on CD14+CD11b cells. Samples were performed in duplicate. Clinical variables including clinical state, past and current treatment, metastatic sites, PSA, and standard prognostic markers were collected. Results: 36 pts with metastatic prostate cancer (29 CRPC; 7 CSPC) were included. Median (SD) %MDSC in 29 CRPC pts was 21.15 (5.33) and median (SD) CV was1.29 (0.25); 7 CSPC demonstrated a median (SD) %MDSC 19.15 (4.86) and median (SD) CV 1.22 (0.25). MDSC did not differ between chemotherapy exposed (n=13) and chemotherapy naive (n=16) CRPC (23.3 vs 19.5, p=ns). MDSC were not significantly higher in those with visceral mets, though a trend existed (20.3 vs 24.0, p=0.076). PSA did not appear to correlate with MDSC or CV. Conclusions: Understanding the distribution and characterization of MDSC in various clinical states in prostate cancer is relevant to the development of immune targets in this disease. MDSC were quantifiable in both CSPC and CRPC. There was a trend for higher MDSC values in patients with visceral metastases, which historically are associated with worse prognoses. Presence of MDSC in metastatic CSPC and CRPC has important therapeutic and trial implications. Further discovery in larger cohorts and earlier disease states is underway.
Previous enzalutamide therapy and response to subsequent taxane therapy in metastatic castration-resistant prostate cancer.
Authors: Gizzi Marco , Baciarello Giulia , Flechon Aude , Beuzeboc Philippe , Angelergues Antoine , Roubaud Guilhem , Bompas Emmanuelle , Le Moulec Sylvestre , Latorzeff Igor , Delva Remy , Voog Eric , Priou Frank , Duclos Brigitte , Laguerre Brigitte , Vassal Cecile , Gross Goupil Marine , Patrikidou Anna , Fizazi Karim , Loriot Yohann
Published: February 2017

227

Background: Cross-resistance between taxanes and androgen receptor axis targeted agents is a matter of debate in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data about response to taxanes after prior enzalutamide suggest some level of cross-resistance (van Soest et al, Eur J Cancer 2013) though this was not confirmed in other models (Al Nakouzi N, Eur Urol 2014). The first objective of this study was to assess the impact of previous enzalutamide therapy on the efficacy of subsequent taxane-based chemotherapy. The second objective was to investigate the prognosis of patients when chemotherapy was initiated in enzalutamide-pretreated patients. Methods: Data from 96 enzalutamide- and placebo-treated patients enrolled in the Prevail phase III trial were retrospectively collected from 14 centers in France. Changes in prostate specific antigen (PSA) levels, progression free survival (PFS) and RECIST criteria v 1.1 were used to determine the activity of docetaxel (n=89) or cabazitaxel (n=7) treatment. The Halabi model was used to predict survival probabilities for the enzalutamide- or placebo-pretreated patients when chemotherapy was initiated (Halabi et al, J Clin Oncol 2014). Results: Overall, 96 patients were included in this analysis (58 in the placebo arm vs. 38 in enzalutamide arm). PSA response to taxanes (defined as a decline of ≥50% from baseline) was marginally lower in enzalutamide-vs. placebo-pretreated patients (34% vs. 53%, p=0.10). PSA response in enzalutamide-pretreated patients was not different from that observed with docetaxel given every 3 weeks in TAX 327 trial (Tannock et al, NEJM 2004) (45%, p=0.20, binomial test). Median PFS and objective response rates were similar between the two groups (4.8m vs 6.7 m;p=0.14 and 45% vs 43%;p=0.83 respectively). Halabi score was well-balanced between the two groups (p=0.30). Conclusions: Taxanes retain efficacy in enzalutamide-pretreated mCRPC. At the time of first-line taxane-based chemotherapy initiation, the prognosis of enzalutamide-treated patients according to the Halabi score was not different from that of enzalutamide-naïve patients.
Radium-223 dichloride (Ra-223) in U.S. expanded access program (EAP).
Authors: Vogelzang Nicholas J. , Fernandez Daniel Celestino , Morris Michael J. , Iagaru Andrei , Brown Alan , Almeida Fabio , Sweeney Christopher , Smith Matthew Raymond , Dicker Adam , Wong Yu-Ning , Shore Neal D. , Bangerter Keith , Petrenciuc Oana , Sartor A. Oliver
Published: February 2017

247

Background: The ALSYMPCA study (Parker, NEJM, 2013) was the basis for regulatory approval of Ra-223 for the treatment of castrate-resistant prostate cancer (CRPC) patients (pts) with symptomatic bone metastases. The aim of this prospective EAP was to monitor acute and long-term safety of Ra-223. Pt profiles and findings in the EAP setting are presented. Methods: In the EAP, CRPC pts with symptomatic bone metastases who either received or were not eligible for docetaxel received Ra-223 50 kBq/kg by injection q4wks for 6 cycles. Primary endpts: ECOG PS, symptomatic skeletal-related events (SSE), treatment-emergent adverse events [TEAEs], routine laboratory tests including PSA. Exploratory endpts: overall survival (OS), SSE rates, changes in total ALP (tALP)/PSA responses, time to tALP normalization, and to tALP and PSA progression. Descriptive statistics were used. Results: 184 pts entered treatment; baseline characteristics were similar as seen in ALSYMPCA (N=600) (exceptions in table); 67% had total ALP <220 U/L and 47% mild/moderate pain. 81/184 (44%) received all 6 injections; 26 (14%) had a dose interruption/delay, 18 due to AEs. Median OS was 17m (50/184; 27% pts). TEAEs occurring at ≥10% were anemia, fatigue, diarrhea, and nausea. The most common Grade 3/4 hematologic TEAE was anemia (11%). Majority of pts had no change in ECOG PS within each trt cycle. 19 (10%) pts had an SSE, 13 received EBRT for bone pain. 33% of pts had a ≥30% confirmed ALP decline from baseline and 16% had a ≥50% decline. Median time to ALP progression was not reached. Median time to PSA progression was 4m and 6% had a confirmed PSA response. Conclusions: In heavily pretreated patients with CRPC and bone metastases and in an EAP setting, Ra-223 was well tolerated with no new safety concerns and a positive effect on efficacy parameters. Clinical trial information: NCT01516762. [Table: see text]
Creation of a standardized set of patient-centered outcomes for advanced prostate cancer: An international effort.
Authors: Morgans Alicia Katherine , van Bommel Annelotte , Stowell Caleb , Penson David F. ,   Advanced Prostate Cancer Working Group of ICHOM
Published: February 2017

282

Background: Clinical trials and international registries assess outcomes considered relevant to men with advanced prostate cancer (CaP). However, we lack a single standardized set of outcomes, making direct comparisons between populations and quality of care assessments challenging. We sought to create a minimum standardized set of outcomes relevant to men with advanced CaP. Methods: The International Consortium for Health Outcomes Measurement assembled a multi-disciplinary working group to create a minimum set of measures to collect for men with advanced CaP. We used a modified Delphi method to establish pertinent measures and case-mix characteristics. Results: Approximately 24 experts, including clinicians and patient advocates, from North America, Europe, and Australia participated. We defined the included population as men with metastatic prostate cancer or biochemical recurrence who failed or were ineligible for salvage therapy. Outcomes important to all men with advanced CaP, such as overall survival, and measures specific to subgroups, such as time to metastasis, were identified. Measures gathered from clinical data include risk-stratification characteristics and measures of disease control. Patient-reported outcome measures, like pain control, depression, and erectile, urinary, and bowel dysfunction, were also identified. Conclusions: Standardized outcome measures are necessary to assess quality of care across different populations, and are critical to ensure value in health care. Our international, multi-disciplinary team identified clinical data and patient-reported outcomes to provide a basis for international health outcome comparisons and future assessments of quality of care for men with advanced CaP.
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.
Phase II clinical trial of axitinib in metastatic pheochromocytomas and paraganlgiomas (P/PG): Preliminary results.
Authors: Burotto Pichun Mauricio Emmanuel , Edgerly Maureen , Velarde Margarita , Bates Susan Elaine , Daerr Roland , Adams Karen , Pacak Karel , Fojo Tito
Published: February 2017

457

Background: Malignant pheochromocytoma/paraganglioma (P/PG) is a rare malignancy. Management of metastatic disease includes surgery, external radiation, 131I-MIBG and systemic chemotherapy. CVD (cyclophosphamide, vincristine and dacarbazine) is the only chemotherapy commonly used to treat metastatic disease. Putative anti-angiogenic agents such as the tyrosine kinase inhibitor (TKI) axitinib target a well-recognized pathway thought to be active in many tumors. Methods: Patients with histologically confirmed P/PG previously treated or naive to treatment received axitinib at initial dose of 5 mg BID. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival, response rate and safety. Results: Between January and September 2014 nine patients have been enrolled. The median age was 54.7 years, (range 42.5 – 70.5); median number of previous systemic treatments was one (range 0 – 3). Three of the nine patients achieved a partial response. An additional 5 patients have had tumor shrinkage insufficient to qualify as a partial response with only one patient response scored as progression. Tumor shrinkage has been observed in lymph node, soft tissue and lung metastases; and has been associated with reductions in circulating cathecholamines. Median time to progression has not been reached. A total of 50 cycles have been administered. Toxicity has led to a reduction of the dose of axitinib from a starting dose of 5 mg BID to 3 mg BID in six and 2 mg BID in two patients. The axitinib dose could be increased to 7 mg BID in only one patient Principal grade 3-4 toxicities included hypertension (6 patients), fatigue (4 patients), diarrhea (1 patient) and mucositis (1 patient). Conclusions: Preliminary data shows axitinib can result in tumor shrinkage in patients with a diagnosis of malignant P/PG. The high rate of dose reduction related to toxicity may reflect a different pharmacokinetic profile of the drug in these patients a possibility now under investigation. Clinical trial information: NCT01967576.
Can Gleason 7 prostate cancer ever be low-risk? Results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.
Authors: McGinley Kathleen F. , Sun Xizi , Howard Lauren E. , Aronson William J. , Terris Martha K. , Kane Christopher J. , Amling Christopher L. , Cooperberg Matthew R. , Freedland Stephen J.
Published: February 2017

57

Background: Overtreatment of low-risk prostate cancer (PC) is a major issue. Increasing use of active surveillance (AS) will ease this burden. Limited data are available on including men with intermediate risk PC (i.e. Gleason 7) into AS protocols. We examined if a subset of men with Gleason 7 (3+4) PC could be reasonable AS candidates. Methods: We used SEARCH to identify men who had radical prostatectomy from 2001-13 with >8 cores on biopsy and complete data. We compared men who fulfilled low-risk disease criteria (cT1c/T2a; biopsy Gleason ≤6; PSA ≤10 ng/mL) with the exception of biopsy Gleason 7 (3+4) vs. men who met all 3 low-risk criteria. Logistic regression models were used to test the association between biopsy Gleason 3+4 vs. ≤6 and pathological features. Biochemical recurrence (BCR) was examined using multivariable Cox hazards analysis adjusted for clinical and demographic features. To examine if there was a subset of men with low-volume Gleason 7 who would have comparable outcomes to low-risk men, we repeated all analyses limiting the percent positive cores to ≤ 33% and positive cores to ≤ 4, ≤ 3, or ≤ 2. Results: 885 men met inclusion criteria: 505 had low-risk PC and 380 had Gleason 7 low-risk PC. Overall, the Gleason 7 low-risk men had increased risk of pathological Gleason ≥4+3 (p<0.001), positive margins (p=0.069), extracapsular extension (p<0.001), and seminal vesicle invasion (p<0.001) on univariable analysis. Men in the Gleason 7 low-risk group had significantly higher BCR risk (HR 1.65, p=0.004). Analyses were repeated using increasingly strict definitions of low-volume PC. With the exception of higher pathological Gleason score (p<0.001), at ≤3 positive cores, there was no difference in adverse pathological features between groups (all p>0.1). Among men with ≤3 positive cores who met the other low-risk criteria (cT1c/T2a; PSA ≤10 ng/mL), BCR risk was similar in men with Gleason 6 or Gleason 7 (3+4) (HR 1.30; p=0.347) PC. Conclusions: Among men with PSA≤10 ng/mL and stage cT1c/T2a, those with Gleason 7 (3+4) PC in ≤3 positive cores have similar rates of adverse pathology and BCR as men with Gleason ≤6 PC. This finding may expand inclusion criteria of AS protocols to reduce PC overtreatment.
Impact of CCP test on personalizing treatment decisions: Results from a prospective registry of newly diagnosed prostate cancer patients.
Authors: Shore Neal D. , Boczko Judd , Kella Naveen , Moran Brian Joseph , Crawford E. David , Hamilton Stephanie A. , Kaldate Rajesh R. , Roundy Kirstin M , Brawer Michael K. , Gonzalgo Mark L.
Published: February 2017

63

Background: The cell cycle progression (CCP) test is a validated molecular assay that assesses risk of prostate cancer−specific disease progression and mortality when combined with standard clinicopathologic parameters. PROCEDE−1000 is the largest prospective registry to evaluate CCP test impact on personalizing prostate cancer treatment. Results of an interim analysis are presented. Methods: Untreated patients with newly diagnosed (≤6 months), clinically localized prostate adenocarcinoma were enrolled (n=816). The physician’s initial therapy recommendation (pre−CCP) was recorded on the first questionnaire. The CCP test was then conducted on prostate biopsy tissue. Three post−CCP questionnaires recorded the physician’s revised treatment recommendation, physician/patient treatment decision, and actual treatment administered. Changes in treatments between the pre-CCP and post−CCP questionnaires demonstrated the impact of CCP testing on treatment decisions at each stage. Results: Visual analog scale measurements indicated a significant increase (p=0.0125) in the physician’s likelihood of recommending non−interventional treatment post−CCP test; there was an increase in active surveillance from the initial interventional therapy recommendation. From pre−CCP therapy recommendation, the CCP score caused a change in actual treatment administered in 44% of patients; 72% of changes were reductions in treatment. Reductions occurred in radical prostatectomy (27%), radiation therapy (44% primary; 56% adjuvant), brachytherapy (46% interstitial; 66% HDR) and hormonal therapy (33% neoadjuvant; 68% concurrent) treatments. While 35.9% of patients were recommended for conservative management pre−CCP testing, there was a 6.5% increase in non−interventional treatments during actual follow−up. Overall, there was a significant reduction in the number of treatment options at each successive evaluation (p<0.0001). Conclusions: The CCP risk assessment score has a significant impact in helping physicians and patients reach consensus on an appropriate personalized treatment decision, often with major reductions in interventional treatment burden. Clinical trial information: NCT01954004.
Sector analysis to provide additional spatial information on the permanent prostate brachytherapy learning curve.
Authors: Mohamed Yoosuf Ahamed Badusha , Jonnada Sai , Napier Eoin , Byrne Monica M. , Flynn Margaret A. , Workman Geraldine , Mitchell Darren M. , Jain Suneil
Published: February 2017

93

Background: To evaluate the spatial pattern of permanent prostate brachytherapy (PBT) learning curve using post-implant multi-sector dosimetric analysis. Methods: Two hundred patients treated with I-125 PBT at a single institution were assessed. A 12 sector analysis of post-implant CT was created for each case by dividing the prostate base, mid gland and apex into 4 sectors each. Dosimetric analysis was evaluated for whole prostate and individual sectors assessing: minimum dose to 90% of prostate (D90) and dose to 0.1 cm3 of the rectum (D0.1cc). Linear regression analysis and Pearson’s correlation co-efficient were used to investigate changes in D90with case number. Results: Global prostate analysis demonstrated a post-implant learning curve with significant improvement in D90 (p<0.01) in the last 50 cases (157.0 Gy ± 9.7) when compared to the initial 50 (141.6 Gy ± 14.5). Linear regression confirmed a significant improvement in global D90 with case number (r2=0.19, p=0.0001) at a rate of 0.11 Gy/case. Sector analysis demonstrated greatest improvement in base sectors with increasing case number with an improvement of 0.16 Gy/case (Table; p=0.049 when compared to global D90). Further, D90 in posterior mid-gland reduced with case number and correlated with reduced rectal D0.1cc. Conclusions: Sector analysis demonstrated increased spatial information on the PBT learning curve which may enable on-going improvements in implant quality. [Table: see text]