bluuebunny/crossref_metadata_2025_split huggingface dataset:
Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC).
Authors: Motzer Robert John , Barrios Carlos H. , Kim Tae Min , Falcon Silvia , Cosgriff Thomas , Harker W. Graydon , Pittman Kenneth B. , Sabbatini Roberto , Rha Sun Young , Flaig Thomas W. , Page Ray D. , Bavbek Sevil E. , Beck J. Thaddeus , Patel Poulam M , Schiff Edward , Vaury Alexandra , Niolat Julie , Gogov Sven , Anak Ozlem , Knox Jennifer 
Published: March 2020

4504 Background: Sequential SUN (tyrosine kinase inhibitor, TKI) until progression of disease (PD) followed by EVE (mTOR inhibitor) is standard therapy for patients with mRCC. This open-label, multicenter, phase II trial compared 1st-line EVE to 1st-line SUN (NCT00903175). Sequential EVE→SUN was also compared with standard SUN→EVE. Methods: Patients with mRCC (clear or non-clear cell) naive to prior systemic therapy were randomized 1:1 to either 1st-line EVE 10 mg/day or SUN 50 mg/day (4 weeks on, 2 weeks off) until PD. Patients then crossed over and continued on the alternate drug until PD. Primary objective was to assess PFS noninferiority of 1st-line EVE to 1st-line SUN; defined as an observed hazard ratio (HR)1st EVE/SUN ≤1.1. Overall survival (OS), combined 1st-line and 2nd-line PFS, and safety were secondary end points. Results: From10/09 to 6/11, 471 patients enrolled (EVE→SUN, n = 238; SUN→EVE, n = 233). Median age was 62 years, 85.4% had clear-cell RCC, and MSKCC favorable/intermediate/poor risk was 30/56/14%. Median follow-up was 22.7 months. A total of 53.7% of patients who discontinued 1st-line EVE entered into 2nd-line SUN and 51.6% of patients who discontinued 1st-line SUN entered into 2nd-line EVE. Median PFS (95% CI) was 7.9 (5.6-8.2) months for 1st-line EVE and 10.7 (8.2-11.5) months for 1st-line SUN. HR1st EVE/1st SUN (95% CI) was 1.43 (1.15-1.77). Median OS (95% CI) was 22.4 (19.7-NA) months for EVE→SUN and 32.0 (20.5-NA) months for SUN→EVE; HREVE-SUN/SUN-EVE (95% CI) was 1.24 (0.94-1.64). A trend in favor of SUN→EVE for OS was observed, but will need to be confirmed with final OS analysis. Additional efficacy results for secondary end points are forthcoming. Common treatment-emergent adverse events for 1st-line EVE vs SUN, respectively, were stomatitis (53% vs 57%), fatigue (45% vs 51%), and diarrhea (38% vs 57%). Conclusions: Noninferiority of PFS for 1st-line EVE compared with SUN was not achieved in this randomized phase II trial of mRCC patients. The treatment paradigm remains SUN→EVE since the sequence achieved optimal clinical benefit. Clinical trial information: NCT00903175.
ARISER: A randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC—Results and implications for adjuvant clinical trials.
Authors: Belldegrun Arie S. , Chamie Karim , Kloepfer Pia , Fall Barbara , Bevan Paul , Störkel Stephan , Wilhelm Olaf , Pantuck Allan J. 
Published: March 2020

4507^ Background: cG250 (Rencarex) is a chimeric monoclonal antibody that binds to the CAIX cell-surface antigen present on 95% of ccRCC. Its safety and activity in phase II studies provided the rationale to investigate its use as an adjuvant monotherapy in subjects with clinically localized high-risk ccRCC—50% of whom progress to metastatic disease. Methods: We performed an international, prospective, multicenter, phase III trial of the efficacy and safety of adjuvant cG250 vs placebo (randomized 1:1) by assessing disease-free (DFS) and overall survival (OS) in 864 RCC patients after nephrectomy. Inclusion criteria were: 1) T3/T4 N0/M0; 2) any T stage and N+/M0; or 3) T1b/T2 N0/M0 high-grade ccRCC. Treatment consisted of a 50 mg loading dose followed by 23-weekly infusions of 20 mg. DFS and CAIX antigen expression were quantified by an independent radiological review and a central pathologist. CAIX score was derived by multiplying the intensity of staining (1–3) by the fraction of positive of cells (0–1), yielding a range of 0.0–3.0. Results: Baseline demographics were well balanced across groups. Treatment demonstrated an excellent safety profile. There were 360 confirmed recurrences and 181 deaths during follow up. When compared with the placebo group, cG250-treated subjects did not enjoy a statistically significant DFS (HR=0.99, p=0.74) or OS advantage (HR=1.01, p=0.94). Median DFS and OS were over 6 years and never reached irrespective of treatment, respectively. However, on subset analysis, subjects with high CAIX expression (>2.0) who received cG250 experienced a statistically significant treatment effect with improved DFS (HR=0.55; p=0.01). Conclusions: While cG250 appears not to have clinical benefit in the adjuvant treatment for all high-risk patients, cG250-treated patients with a high CAIX score appeared to have a significantly improved DFS. The CAIX score may help in stratifying patients who may benefit from cG250 adjuvant therapy. Notwithstanding this benefit, the surprising median DFS of over 6 years and outstanding OS in high-risk patients represent a significant challenge to adjuvant ccRCC drug development. Clinical trial information: NCT00087022.
A first-in-human study of the oral selective androgen receptor down-regulating drug (SARD) AZD3514 in patients with castration-resistant prostate cancer (CRPC).
Authors: Omlin Aurelius Gabriel , Jones Robert J. , van der Noll Ruud , Graham Janet , Ong Michael , Finkelman Richard D. , Schellens Jan HM , Zivi Andrea , Crespo Mateus , Clack Glen , Alumkal Joshi J. , Dymond Angela , Dickinson Andrew , Ranson Malcolm , Malone Michael D , De Bono Johann Sebastian , Elliott Tony 
Published: March 2020

4511 Background: AZD3514 is a first in class, orally bio-available drug that inhibits androgen-dependent and –independent androgen receptor (AR) signaling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels. Methods: A rolling six design was employed initially using a once a day (QD) schedule (A). PK assessments led to a change to twice daily (BD) dosing (B) to increase exposure. PK profiles were studied over 96 hours after a single dose and over 24 hours at start of/following 21 days continuous dosing. PD analyses included PSA and CTC quantification. Results: 49 CRPC patients (pts) have been treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000mg (QD). 2000mg BD was considered non-tolerable due to multiple grade 2 toxicities (nausea [N], vomiting [V], fatigue). No adverse events (AEs) met the DLT definition. The most frequent drug-related AE’s were N; G1/2 36/49 (73%), G3 2/49 (4%) and V; G1/2 24/49 (49%) & G3 3/49 (6%). N/V were managed with oral anti-emetics. Dose proportional increases in plasma concentrations were observed following a single dose. Geometric mean (%CV) Cmax and AUC at MTD were 9,608 (38.5) ng/mL and 61,734 (40.6) ng.hr/mL, respectively. Compared with single dose continuous dosing led to a mean decrease of 26% in exposure. Maximum PSA and CTC declines are summarized below. Objective soft tissue responses per RECIST1.1 were observed in 2/26 (8%) pts. One pt with abiraterone resistant disease remained on study for 19 months. At 6 and 12 months 21 (43%) and 8 (16%) pts remained on study without evidence of bone or soft tissue progression, respectively. Conclusions: AZD3514 has antitumor activity in patients with advanced CRPC. Clinical trial information: NCT01162395. [Table: see text]
Gene expression profiling in bladder cancer to identify potential therapeutic targets.
Authors: Hussain Syed A. , Palmer Daniel H. , Syn Wing Kin , Sacco Joseph J , Lloyd Bryony , Jithesh Puthen , Arrand John R. , Barton Darren , Ansari Jawaher , Sibson David R , James Nicholas David 
Published: March 2020

4518 Background: Characterization of gene expression patterns in bladder cancer (BC) allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Methods: Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Results: Hierarchical clustering defined signatures, which differentiated between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, g1 and g3. Pathways associated with cell cycle and proliferations were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer as compared to normal tissue. Conclusions: This study contributes to a growing body of work on gene expression signatures in BC. The data support an important role for osteopontin in BC, and identify several pathways worthy of further investigation. [Table: see text]
Phase II study of gemcitabine, oxaliplatin, and paclitaxel (GOT) on a 2-weekly schedule in patients (pts) with refractory germ cell tumor (rGCT): Final results.
Authors: Sadeghi Sarmad , Quinn David I. , Tsao-Wei Denice D , Hamid Omid , Hu James , Schuckman Anne K. , Daneshmand Siamak , Groshen Susan G. , Raghavan Derek , Dorff Tanya B. 
Published: March 2020

4531 Background: Modern therapy (Tx) for GCC has transformed the disease but challenges remain in managing rGCT. Methods: 30 men with GCC progression ≤4 weeks after a standard (7), salvage (17), or stem cell (6) regimen were enrolled in the trial. PS<=2, Age>16, PD by RECIST/markers (Tm) criteria. Growing teratoma syndrome excluded. Regimen: paclitaxel 170mg/m2/3h; gemcitabine 800mg/m2/80min; oxaliplatin 100mg/m2/90min, increased to 125mg/m2 in cycle 2 if no major toxicity. Mg2+ and Ca2+infused before oxaliplatin. The regimen was designed to maximize Oxaliplatin density with full dosing of pts with recovering marrow and dose escalation for pts with limited toxicity in cycle 1. Retreatment if ANC ≥1000 or 700 with monocytosis, platelets >75K. Pts with normalized Tm had 3 further cycles. Primary endpoint: Response (RR); 2nd: OS, PFS, toxicity. Results: Median GOT cycles 6 [1-14].Dose escalation in 9 pts correlated with improved OS (p=0.03). Tm normalized in 23.3%. 5 pts (4 PR, 1 SD) became NED after definitive surgery. No link between ethnicity and RR or OS. Conclusions: 2-weekly GOT for rGCC produced high rates of Tm and RECIST response and rendered 5 pts resectable. Dose escalation was associated with better OS and will be explored with GCSF in a trial extension. The median OS of 18.3 mos compares favorably with 6-13.5 mos in other series (Oechsle K Eur Urol 60: 850, 2011). Clinical trial information: NCT00183820. [Table: see text]
Phase I/II study of paclitaxel plus ifosfamide (TI) followed by high-dose paclitaxel, ifosfamide, and carboplatin (TIC) with autologous stem cell transplant (ASCT) for salvage treatment of germ cell tumors (GCT).
Authors: Jia Xiaoyu , Feldman Darren Richard , Glezerman Ilya , Van Alstine Lindsay Joy , Bajorin Dean F. , Fischer Patricia , Hughes Amanda , Sheinfeld Joel , Bains Manjit S. , Reich Lilian , Bosl George J. , Motzer Robert John , Patil Sujata 
Published: March 2020

4534 Background: High-dose chemotherapy (HDCT) can achieve durable remissions in 30-60% of GCT patients (pts) requiring salvage treatment. This Phase I/II study investigated safety and efficacy of a novel high-dose regimen (TI-TIC) in this population. Methods: Pts age ≥18 with GCT and progression after ≥1 cisplatin-based regimen were eligible. TI-TIC consists of 1-2 cycles of conventional-dose paclitaxel plus ifosfamide (TI) q14-21 days followed by 3 cycles of high-dose TIC with ASCT q21-28 days. TI dosing was constant. In Phase I, high-dose TIC was administered in 1 of 5 cohorts (I: 6, 8 or 10g/m2; T: 200 or 250mg/m2; C: AUC=21 or 24) using a standard 3+3 dose escalation design to determine the maximal tolerated dose (MTD). In Phase II, Simon’s 2-stage optimal design was used to estimate the complete response (CR) rate at MTD. Results: Of 26 pts (25 male; median age 31; 21 nonseminoma, 5 seminoma) enrolled, 23 received ≥1 cycle of high-dose TIC. Primary sites included testis (n=15), mediastinum (n=6), other (5). In Phase I, 0/18 pts had dose-limiting toxicity (DLT) during TIC cycle 1, making cohort 5 (T 250mg/m2, I 10g/m2, C AUC=24) the MTD. Toxicities were similar to those reported with TI-CE (Feldman JCO 2010) with little variation across cohorts. However, 2/18 pts in Phase I (1 in cohort 4, 1 in cohort 5) developed grade 3 acute renal insufficiency after cycles 1 and 2 (cycle 3 not given). Both later developed chronic renal insufficiency with 1 pt requiring dialysis 10 months after TI-TIC. A third pt treated in Phase II developed a similar acute and then chronic renal insufficiency pattern with TIC cycles 1 and 2. In Phase II, 7/11 evaluable pts (64%, 90% one-sided CI 40%-100%) achieved a CR, 1 had a partial response with negative markers, and 3 had incomplete responses. Although the CR rate was sufficient to move to the second Simon’s stage, renal toxicity led to premature trial closure. Conclusions: Although there was preliminary evidence of efficacy, high dose TI-TIC was associated with acute and chronic renal insufficiency. TI-CE remains the standard high dose regimen for salvage treatment of GCT at MSKCC. Clinical trial information: NCT00423852.
First-salvage treatment in patients with recurrent or refractory advanced germ-cell cancer after cisplatin-based chemotherapy: A database of the German Testicular Cancer Study Group.
Authors: Oechsle Karin , Berger Lars Arne , Lorch Anja , Hentrich Marcus , Kopp Hans-Georg , Gauler Thomas Christoph , Beyer Joerg , De Wit Maike , Honecker Friedemann , Bokemeyer Carsten 
Published: March 2020

4559 Background: About 20-30% of patients (pts) with advanced germ-cell cancer (GCC) relapse after cisplatin-based chemotherapy. This database evaluates first salvage treatment and the prognostic categories at first relapse according to the International Prognostic Factors Study Group (= IPFSG; JCO 2010). Methods: A total of 144 pts (78% nonseminoma) with relapsed or refractory GCC undergoing 1st salvage treatment with either conventional (CD-CX) or high-dose chemotherapy with autologous stem cell support (HD-CX) from 16 German centers were retrospectively analysed. Results: Subgroups according to the IPFSG prognostic categories, were: very low risk in 9/144 (6%), low risk in 26/144 (18%), intermediate risk in 78/144 (54%), high risk in 27/144 (19%), and very high risk in 4/144 pts (3%). 1st salvage treatment consisted of HD-CX in 96 (67%) and CD-CX in 48 pts (33%). Treatment response was CR/PR- in 60%, PR+/SD in 33%, and PD in 7%. After a median follow-up (mFU) of 21 months (mos) (range, 0 – 193), 53% of all pts had relapsed and 30% had died resulting in a median progression-free survival (PFS) of 7 mos (95%CI 0-16) and overall survival (OS) of 47 mos (95%CI 21-73). At subsequent relapses, 25/48 pts (52%) received HD-CX as > 2nd-salvage treatment. For the total cohort, PFS rate after 2 years was 35%, and OS rate after 5 years was 53%. Stratification according to IPFSG prognostic categories significantly correlated with PFS (p=0.001) and OS (p=0.004) after 1st salvage treatment. Even among high-risk and very high risk (n=31, mFU 12 mos) a PFS of 37 % at 2 years and an OS of 60 % at 2 years was observed, after 1st or 2nd salvage treatment, which might be due to patient selection and short follow-up. Conclusions: IPFSG prognostic categories highly correlated with observed PFS and OS after first salvage treatment in this cohort of pts with refractory or relapsed GCC. First salvage treatment with CD- or HD-CX resulted in overall 5 year-OS rates of about 50% across all prognostic categories. Even pts with high and very high risk achieved 2 year-OS rates of about 60% with salvage HD-CX at first or subsequent relapses.
Validation of an inverse association between programmed death ligand 1 (PDL1) and genes in the vascular endothelial growth factor (VEGF) pathway in primary clear cell renal cell (ccRCC).
Authors: Joseph Richard Wayne , Parasramka Mansi , Serie Daniel , Eckel-Passow Jeanette , Thompson E Aubrey , Lohse Christine M. , Ho Thai Huu , Castle Erik P. , Thompson Robert Houston , Leibovich Bradley C. , Cheville John , Parker Alexander S. 
Published: March 2020

4567 Background: Trials combining anti-PDL1 and anti-VEGF therapies for clear cell renal cell carcinoma (ccRCC) are underway; however the relationship between the expression of PDL1 and genes in the VEGF pathway is poorly understood. Using the Affymetrix platform, we observed an inverse association between the expression of PDL1 and key genes in the VEGF pathway. Herein, we validate this inverse association using an independent set of 100 primary ccRCC tumors. Methods: From our registry database we sampled 100 ccRCC tumors with varying PDL1 protein expression (0%-100%) determined by immunohistochemistry (IHC). We extracted RNA from FFPE slides and performed RT-PCR to quantify gene expression of PDL1, VEGF, VEGFR1, and VEGFR2. All genes were normalized to the POLR2a gene. We evaluated the association of PDL1 protein expression and VEGF gene expression using Spearman rank correlation. In addition, we employed a linear mixed effects model to compare the fold-change in expression of VEGF genes between PDL1 low (0-5%, n=68) and PDL1 high (>5%, n=32) tumors. Results: As expected, PDL1 protein expression positively correlates with PDL1 geneexpression (corr=0.42, p<0.001). Validating our array data, PDL1 protein expression inversely correlates with expression of key VEGF genes: VEGF (corr=-0.23, p=0.01), VEGFR1 (corr=-0.34, p<0.001), and VEGFR2 (corr=-0.23, p=0.01). In our dichotomized analysis, we noted significantly higher expression of VEGF genes in the PDL1 low compared to the PDL1 high group: VEGF (fold change=1.82, p<0.001), VEGFR1 (FC=2.63, p<0.001), and VEGFR2 (FC=2.13, p=0.001). Conclusions: We independently validate an inverse association between the expression of PDL1 and key genes in the VEGF pathway in primary ccRCC. If validated further in larger studies, the existence of an immune evasive and an angiogenic phenotype within ccRCC could inform current clinical trials targeting these two pathways. Ultimately, whether VEGF signaling affects PDL1 expression, or whether angiogenic or immune evasive phenotypes predict response to anti-PDL1, anti-VEGF, or a combination of the two therapies remains unclear.
A phase II trial assessing pazopanib (paz) as third-line therapy for metastatic renal cell carcinoma (mRCC): Clinical outcome and temporal analysis of molecular profile.
Authors: Pal Sumanta Kumar , Hossain Dewan Md Sakib , Zhang Qifang , Gao Chan , Frankel Paul Henry , Ruel Christopher , Jones Jeremy , Carmichael Courtney , Twardowski Przemyslaw , Figlin Robert A. , Kortylewski Marcin 
Published: March 2020

4571 Background: Paz, an oral vascular endothelial growth factor (VEGF) receptor inhibitor, was assessed in a phase III study conducted in patients (pts) with mRCC who were cytokine-refractory or treatment-naïve (Sternberg et al J Clin Oncol 2010). Clinical outcomes with paz have been associated with a molecular profile (Tran et al Lancet Oncol 2012). The activity of paz in the 3rd-line setting and temporal changes in molecular profile during paz therapy are poorly understood. Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received paz 800 mg/daily on a 28d cycle, and were assessed for response by RECIST 1.1 every 2 cycles. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error=10%). Molecular profiles were assessed on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen) at baseline, 6 mos and 12 mos. Results: 28 pts (20M, 8F) were enrolled, with a median age of 63 (range, 45-86). All patients received at least 2 lines of prior therapy, and 6 pts (21%) had received 2 prior lines of VEGF-directed therapy. In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. 8 pts (29%) had SD as a best response. Median PFS for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities were hypertension (46%) and proteinuria (14%). At baseline, IL-6 was marginally lower in patients who achieved PR/CR (responders) as compared to those who did not (non-responders; P=0.06). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, IL-2R, IL-6, IL-8, and VEGF (P<0.05 for each) at both time intervals. Conclusions: Paz demonstrated an ORR of 43%, representing the highest ORR observed to date in a 3rd-line trial in mRCC. At 6 and 12 months, differences in molecular profile emerged between responders and non-responders, potentially underscoring mechanisms of drug resistance. Clinical trial information: NCT01157091.
Effective monotherapy despite intratumor heterogeneity: Clonal convergence within the PI3K pathway and sensitivity to mTOR inhibitors in patients with advanced renal cell carcinoma (RCC).
Authors: Voss Martin Henner , Hakimi A. Ari , Chen Yingbei , Pham Can G. , Brannon Angela Rose , Scott Sasinya N. , Takeda Shugaku , Liu Han , Motzer Robert John , Berger Michael F. , Hsieh James 
Published: March 2020

4573 Background: Rapalogs, inhibitors of mTOR, are approved for treatment of advanced RCC. Recent reports of clonal heterogeneity challenge the concept of targeted monotherapy and the development of genomic biomarkers. Still, a subset of patients (pts) derives extended benefit from single agent rapalogs. This study analyzed such outliers so as to explore the genomic background of rapalog sensitivity in the setting of clonal heterogeneity. Methods: Cases were chosen based on time to treatment failure > 20 mos and tissue availability. DNA was extracted from spatially separate areas in primary tumors, metastases and the germline. Custom target capture and ultra-deep sequencing identified small indels, single base pair substitutions and copy number changes across all exons of 230 target genes. Results: 4 pts contributed 13 specimens (11 primary tumor samples, 2 metastases); mean exon coverage was 443X. Genomic alterations with activating effect on PI3K pathway signaling were seen in 11 of 13 specimens (Table). Clonal heterogeneity was present in all pts. For 2 pts, different mechanisms activated the pathway in separate sites, in 1 pt through separate genes. Conclusions: Pathway-activating genomic events across all sites explain rapalog benefit in 3 of 4 pts. Different disease sites in the same pt can harbor separate mechanisms activating the targeted pathway. This suggests that clonal convergence within the PI3K pathway can create an oncogenomic landscape sensitive to rapalogs despite branching clonal evolution. It supports the notion of sampling >1 disease site during future biomarker development. [Table: see text]