bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of liver metastases in patients with neuroendocrine tumors: A National Comprehensive Cancer Network analysis.
Authors: Choti Michael A. , Bobiak Sarah , Bloomston Mark , Zornosa Carrie C. , Bergsland Emily K. , Strosberg Jonathan R. , Benson Al Bowen , Kulke Matthew , Shah Manisha H. , Nakakura Eric K. , Yao James C.
Published: March 2020

4143

Background: The choice of therapy in patients with hepatic metastases from neuroendocrine tumors is controversial. The purpose of this study was to describe the utilization of liver resection and other locoregional therapies in the management of NET hepatic metastases in NCCN centers. Methods: The National Comprehensive Cancer Network (NCCN) Neuroendocrine Tumor Database tracks longitudinal care for patients treated at seven specialty cancer centers in the U.S. from 2004 to 2010. Patient and tumor characteristics, as well as the use of liver-directed therapy (LDT) in patients with neuroendocrine liver metastases (NELM) were evaluated. Results: Among 907 patients presenting with metastatic disease, 606 patients presenting with newly diagnosed disease or previously diagnosed disease with first distant recurrence of NELM were evaluated. LDT was used during some component of the patient care in only 43% of patients with NELM, the remainder received only systemic or no therapy. LDT varied by extent of disease (p=0.002) with a higher proportion of patients with liver-only disease receiving LDT (45%) compared to those with liver and extrahepatic disease (26%). There was a significant difference in LDT by functional tumor status (Χ2=6.84, p=0.03) and primary site of disease (Χ2=14.95, p=0.001) where a higher proportion of patients with hormonally functional tumors received LDT when compared to non-functional tumors (48% vs 42%) as well as those with primary small bowel carcinoid vs pancreatic NET (56% vs 39%). Among those treated with LDT, 39% underwent surgical resection, 57% intra-arterial therapy (IAT), and 4% ablation alone. Major hepatectomy was performed in 21%, multiple resections in 13%, and resection combined with ablation in 24% of patients receiving surgical therapy. Among the 147 patients treated with IAT, 52% received standard chemoembolization, 23% bland embolization, and 18% yttrium-90 therapy. Conclusions: Even at specialty centers less than half of patients received LDT, among which one-fifth had a hepatic resection. Future studies on this cohort will measure outcomes based on type of LDT.
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]
Adoptive immunotherapy with autologous cytotoxic T lymphocytes (CTLs) pulsed ex vivo with patient-derived tumor cells in heavily pretreated, advanced renal cell carcinoma (aRCC) patients: A feasibility study.
Authors: Porta Camillo , Montagna Daniela , Paglino Chiara , Secondino Simona , Bregant Cristina , Ganini Carlo , Perotti Cesare , Turin Ilaria , Pedrazzoli Paolo
Published: March 2020

4575

Background: Immunotherapy still remains the only treatment which proved able to induce long-lasting complete responses in aRCC. The aim of the present study was to evaluate the feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous CTLs pulsed with patient-derived tumor cells in heavily pre-treated subjects with aRCC. Methods: This study was performed in accordance with local regulations on the production of cell derivatives; local Ethical Committee approval was obtained on a named patient basis, after obtaining each patient’s informed consent. CTLs were generated stimulating CD8-enriched lymphocytes with dendritic cells (DCs) pulsed with fresh autologous tumor cells in the presence of IL-12 and IL-7; these specific anti-tumor CTLs were expanded and then reinfused after a lymphodepleting chemotherapy with CTX and fludarabine, followed by s.c. administration of low-dose IL-2. Disease status was assessed after every two re-infusions. Eight patients were enrolled, 6 with a clear cell RCC, 1 with a papillary RCC, and 1 with a mixed, papillary and collecting ducts, RCC. All patients have been previously treated with a median of 5 prior treatment lines; the median time between diagnosis of aRCC and tumor biopsy was 55 months (15-185). Results: Six of the 8 enrolled patients have produced suitable tumor cell lines, and 5 of them had been already re-infused with tumor-specific CTLs. All patients received at least 2 CTL infusions (range: 2-5+); mean of totally infused CTLs was 10.7 x 109(range: 4-26.6). All CTLs infusions were well tolerated, with no evidence of autoimmune reactions. In terms of antitumor activity, one patient achieved a partial response, 3 had a slowly progressing disease, and one patient is still not evaluable; furthermore, in 3 patients disease-related symptoms improved. Conclusions: Our preliminary results suggest that immunotherapy with autologous CTLs pulsed ex-vivo with patient-derived tumor cells is feasible and safe in heavily pre-treated aRCC patients. Signs of activity were recorded, suggesting the need to further expand this cohort of patients.
Randomized phase II study of first-line everolimus plus bevacizumab (E+B) versus interferon α-2a plus bevacizumab (I+B) in patients (pts) with metastatic renal cell carcinoma (mRCC): Record-2 final overall survival (OS) and safety results.
Authors: Ravaud Alain , Barrios Carlos H. , Alekseev Boris Y. , Tay Miah Hiang , Agarwala Sanjiv S. , Yalcin Suayib , Lin Chia-Chi , Shkolnik Michail , Matveev Vsevolod , Anak Ozlem , Gogov Sven , Pelov Diana , Louveau Anne-Laure , Vaury Alexandra , Melichar Bohuslav
Published: March 2020

4576

Background: RECORD-2 (NCT00719264) primary analysis demonstrated similar median progression-free survival (PFS) for pts with mRCC treated with E+B and I+B (Dec 2011 cut-off). The primary objective was not met; median PFS in E+B/I+B was 9.3/10.0 mo (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P=0.485) and probability of success (PoS) of a subsequent phase III trial was 5.1%. Here we present final OS and safety/exposure results (Aug 2012 cut-off). Methods: Untreated pts with clear cell mRCC and previous nephrectomy were randomized 1:1 to B 10 mg/kg every 2 weeks and either E 10 mg/day or I (9 MIU 3 times/week). The primary objective was treatment effect on PFS per central review based on an estimation of PoS (≥50%) of a subsequent phase III study. Secondary objectives included OS and safety. Results: In E+B (n=182) and I+B (n=183) arms, median age was 60/60 years and 76/72% of pts were men, respectively. In both arms, most pts (93%) were of favorable/intermediate MSKCC risk. Median follow-up was 33 mo. In E+B and I+B arms, 51/52% of pts died, respectively. Median OS (95% CI) was 27.1 mo (19.9-35.3) in the E+B arm and 27.1 mo (20.4-30.8) in the I+B arm. After discontinuing study treatment, 64/60% of pts in E+B and I+B arms, respectively, received antineoplastic therapy. Median exposure duration in E+B and I+B arms was 8.5/8.3 mo, respectively; AEs resulted in treatment discontinuation for 23/25% of pts, respectively. The most frequent AEs (%) were stomatitis (63), proteinuria (50), diarrhea (40), hypertension (38), and epistaxis (35) in the E+B arm and decreased appetite (45), fatigue (42), proteinuria (38), asthenia (35), and pyrexia (35) in the I+B arm. The most frequent grade 3/4 AEs (%) were proteinuria (24), stomatitis (11), and anemia (11) for E+B and fatigue (17), asthenia (14), and proteinuria (10) for I+B. Conclusions: OS of E+B and I+B was similar. OS results are consistent with PFS primary analysis. First-line treatment with mTOR inhibitor-based therapy did not impair chance of survival relative to standard therapy. No new safety issues were identified and E+B remained generally well tolerated. Clinical trial information: NCT00719264.
First-, second-, third-line therapy for metastatic renal cell carcinoma (mRCC): Benchmarks for trials design from the International mRCC Database Consortium (IMDC).
Authors: Heng Daniel Yick Chin , Rini Brian I. , Lee Jae-Lyun , Kroeger Nils , Srinivas Sandy , Harshman Lauren Christine , Knox Jennifer J. , Bjarnason Georg A. , MacKenzie Mary J. , Wood Lori , Vaishampayan Ulka N. , Agarwal Neeraj , Pal Sumanta Kumar , Tan Min-Han , Rha Sun Young , Yuasa Takeshi , Donskov Frede , Bamias Aristotelis , North Scott A. , Choueiri Toni K.
Published: March 2020

4586

Background: Limited data exists on outcomes for mRCC patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counseling and clinical trial design. Methods: Outcomes of mRCC patients from the IMDC treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared and adjusted by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) benchmarks were calculated using different population inclusion criteria. OS and PFS are calculated from the line of therapy under consideration unless otherwise specified. Results: 2,705 patients were treated with TT of which 1,533 (57%) received only 1st-line TT, 734 (27%) received 2 lines of TT, and 438 (16%) received 3+ lines of TT. The median OS of patients that received 1, 2 or 3+ lines of TT starting from initial TT was 14.9, 21.0, and 39.2 months, respectively (p<0.0001). On multivariable analysis adjusting for baseline Heng prognostic factors, the use of 2nd-line and 3rd-line therapy were each independently associated with better OS (HR=0.738 and 0.626, respectively, both p<0.0001). Survival benchmarks derived from patients in the IMDC using selected inclusion criteria as seen in contemporary mRCC clinical trials are shown below. Conclusions: Patients that are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing new clinical trials. [Table: see text]
Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer.
Authors: Carey Lisa A. , Berry Donald A. , Ollila David , Harris Lyndsay , Krop Ian E. , Weckstein Douglas , Henry Norah Lynn , Anders Carey K. , Cirrincione Constance , Winer Eric P. , Perou Charles M. , Hudis Clifford ,   Alliance
Published: March 2020

500

Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2+ BrCa and were randomized to receive T (80mg/m2/week IV) + H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T + L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dose-dense AC and 1 year H was recommended. Tumors were biopsied for research before therapy; post-Rx samples of residual disease were requested. The primary endpoint was in-breast pCR rate; the study had 85% power to detect an increase from 30% (TH) to 50% (THL). Results: 305 patients were randomized (118 THL, 120 TH, 67 TL); 68% were clinical stage II and 59% hormone receptor-positive. Grade 3+ toxicity was higher among L-containing arms, including neutropenia (12% TL, 7% THL, 2% TH), rash (15% TL, 14% THL, 2% TH), and diarrhea (20% TL, 20% THL, 2% TH). Breast pCR rates with 95% confidence limits were: 51% (42-60%) THL, 40% (32-49%) TH, 32% (22-44%) TL. pCR rate in the TH arm was higher than previous studies, and was not significantly different from THL (p=0.11). We will present molecular subtype, sequence and gene copy number abnormalities in primary tumors and residual disease. Conclusions: pCR rate was higher with combined THL compared with standard TH but did not reach statistical significance. These results are qualitatively similar to other neoadjuvant studies in HER2+ BrCa, and contribute to estimates of pCR rates after these agents. Tissue-based studies may illuminate which patients benefit from HER2-targeting using these agents. Clinical trial information: NCT00770809.
Metformin use and all-cause and prostate-cancer-specific mortality among diabetic men.
Authors: Margel David , Urbach David R. , Lipscombe Lorraine , Bell Chaim , Kilkarni Girish , Austin Peter , Joshua Anthony Michael , Fleshner Neil Eric
Published: March 2020

5007

Background: To evaluate the association between cumulative duration of metformin use after prostate cancer diagnosis and all-cause and prostate cancer-specific mortality among diabetic patients. Methods: We used a population-based retrospective cohort design. Data were obtained from several Ontario health care administrative databases. Within a cohort of men over the age of 66 with incident diabetes who subsequently developed prostate cancer, we examined the effect of duration of anti-diabetic medication exposure, after prostate cancer diagnosis, on all-cause and prostate cancer-specific mortality. Crude and adjusted hazard ratios were calculated using a time-varying Cox proportional hazard model to estimate effects. Results: The cohort consisted of 3,837 patients. Median age (interquartile range IQR) at diagnosis of prostate cancer was 75 (72-79) years. During a median (IQR) follow up of 4.64 (2.7-7.1) years, 1,343 (35%) died, and 291 patients died of prostate cancer (7.6%). Cumulative duration of metformin treatment, after prostate cancer diagnosis, was associated with a significant decreased risk of prostate cancer-specific and all-cause mortality in a dose-dependent fashion. The adjusted hazard ratio, for prostate cancer-specific mortality was 0.76 (95% confidence interval, 0.64-0.89) for each additional six months of metformin use. The association with all-cause mortality was also significant but declined over-time from a HR of 0.76 in the first 6 months to 0.93 between 24-30 months. There was no relationship between cumulative use of other anti-diabetic drugs and either outcome. Conclusions: Increased cumulative duration of metformin exposure after prostate cancer diagnosis was associated with decreases in both all-cause and prostate-cancer-specific mortality among diabetic men.
A double-blind, placebo RCT evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer: The U.K. National Cancer Research Network (NCRN) Pomi-T study.
Authors: Thomas Robert J. , Williams Madeleine M A , Sharma Harbiner , Chaudry Aasem , Bellamy Patricia
Published: March 2020

5008

Background: Polyphenol-rich foods such as pomegranate, green tea, broccoli and turmeric have demonstrated anti-neoplastic effects in cell lines and animal models. Although some have been investigated in small phase II studies, this combination had never been evaluated within an adequately powered nationally certified RCT. Methods: 203 men, average age 74 yrs, had localised prostate cancer, 59% managed with active surveillance and 41% with watchful waiting (progressive PSA relapse following previous radical interventions). They were randomised to receive a b.d. oral capsule containing a blend of pomegranate seed, green tea, broccoli and turmeric or an identical placebo for 6 months. The groups were statistically balanced in terms of gleason grade, body mass index (BMI), treatment category and fasting cholesterol although there was a difference in average age at baseline; 71.8 yrs in the food supplement group (FSG) versus 76.4 years in the placebo group (PG). Four men withdrew after randomisation. Results: The median rise in PSA in the FSG was 14.7% (95% CI 3.4-36.7%) versus 78.5% in the PG (95% CI 48.1-115.5%) (63.8% difference, ANCOVA analysis of covariance, p=0.0008). 46% of men had stable or lower PSA at trial completion in the FSG versus 14% in the PG (32% difference, chi2, p=0.00001). There were no significant differences in PSA% change within the predetermined subgroups (age, gleason grade, treatment category, BMI). There were no differences in cholesterol, blood pressure, blood sugar or c-reactive protein. 24% men recorded events in the FSG and 34% in the PG (non significant). Mild gastro-intestinal effects were (17%) in the FSG but 8% of these reported an improvement in stool quality. Conclusions: This study found a statistically significant short-term favourable effect on the percentage rise in PSA in these men managed with observation following intake of this specific food supplement. Although many men would see this as useful addition to their self help strategies, future trials should look at the longer-term clinical benefits particularly in terms of preventing medical intervention. Clinical trial information: 81263.
A prognostic model for predicting overall survival in metastatic castrate-resistant prostate cancer (mCRPC) men treated with second-line chemotherapy.
Authors: Halabi Susan , Lin Chen-Yen , Small Eric Jay , Armstrong Andrew J. , Kaplan Ellen B. , Petrylak Daniel Peter , Sternberg Cora N. , Shen Liji , Oudard Stephane , De Bono Johann Sebastian , Sartor A. Oliver
Published: March 2020

5011

Background: Although several prognostic models for overall survival (OS) have been developed and validated in men with chemotherapy naïve mCRPC, this work sought to develop and validate a prognostic model to predict OS in men who had progressed following first-line chemotherapy, and were receiving second line chemotherapy. Methods: Data from a phase III trial of cabazitaxel plus prednisone compared to mitoxantrone plus prednisone in mCRPC men who had developed progressive disease following first-line chemotherapy (TROPIC trial) were used. The TROPIC data was randomly split into training (n=507) and testing (n=248) sets. A separate data set consisting of 488 men previously treated with docetaxel who were randomly assigned to either satraplatin and prednisone or placebo and prednisone (SPARC trial), was used as a second testing set for external validation. Adaptive Lasso selected nine baseline prognostic factors of OS. A predictive score was computed from the estimated regression coefficients and used to classify patients into low (<-1.25) and high (≥-1.25) risk groups in the two testing sets. The model was assessed on the testing sets for its predictive accuracy using area under the curve (AUC). Results: The 9 prognostic variables in the final model included: ECOG performance status, time since last docetaxel use, measurable disease, presence of visceral disease, pain, duration of prior hormonal use, hemoglobin, prostate specific antigen and alkaline phosphatase. The median OS in the TROPIC testing set were 11 and 16 months in the high and low risks, respectively, with a hazard ratio (HR) 2.3 (p-value<0.0001). The median OS in SPARC were 11 and 20 months in the high and low risk groups, respectively (HR=2.0, p<0.0001). The AUC for this model was 0.73 (95 CI 0.68-0.72) and 0.70 (95 CI 0.72-0.74) on the two testing sets (TROPIC, and SPARC), respectively. Conclusions: A prognostic model of OS in the post-docetaxel second line chemotherapy mCRPC setting was developed and externally validated. This model can be used to select patients to participate in clinical trials on the basis of their prognosis. Prospective validation is needed.
A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results.
Authors: Antonarakis Emmanuel S. , Kibel Adam S , Adams George , Karsh Lawrence Ivan , Elfiky Aymen , Shore Neal D. , Vogelzang Nicholas J. , Corman John M. , Tyler Robert Claude , McCoy Candice , Wang Yang , Sheikh Nadeem A. , Drake Charles G.
Published: March 2020

5016

Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ≤12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAP-GMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFNγ, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P<.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P=.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.
Sulforaphane treatment in men with recurrent prostate cancer.
Authors: Alumkal Joshi J. , Slottke Rachel , Mori Motomi , Schwartzman Jacob , Graff Julie Nicole , Beer Tomasz M. , Ryan Christopher W. , Koop Dennis R , Cherala Ganesh , Munar Myrna , Flamiatos Jason Frederick , Gao Lina , Tucker Erin
Published: March 2020

5017

Background: Diets high in cruciferous vegetables are strongly associated with lower prostate cancer risk. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on pre-clinical evidence in multiple tumor models. Our own work demonstrates that sulforaphane inhibits HDAC function and suppresses AR signaling in prostate cancer cells (Gibbs, et al PNAS 2009). However, the anti-tumor efficacy and safety of sulforaphane in men with prostate cancer was unknown. Methods: In this single arm study, we treated patients with biochemical (PSA)-recurrence of prostate cancer with 200 µmol of sulforaphane extracts for up to 20 weeks. The primary endpoint was PSA response rate (>50% decline in PSA). Other efficacy endpoints included: maximal PSA decline and percent change in PSA from baseline to end of study. We also analyzed PSA doubling time changes using a mixed effects model. Genotyping for GSTM1 that contributes to sulforaphane metabolism, sulforaphane pharmacokinetics (PK), and pharmacodynamic (PD) measurements of HDAC inhibition in mononuclear cells (MCs) were also performed. Results: Twenty patients were enrolled, and 16/20 (80%) completed the pre-planned 20 weeks of treatment. One patient experienced a PSA decline >50%. Thirty-five percent of patients had lesser PSA declines (3% to 20%), and 15% of patients had a final PSA lower than baseline. There was a significant reduction in PSA doubling time (6 months pre-study vs. 9.4 months on-study, p=.013). Of note, testosterone levels remained non-castrate in all subjects. PK analysis demonstrated that GSTM1 null genotype correlated with longer sulforaphane T1/2 (half-life) (2.6 hours for GSTM1 null vs. 2.1 hours for GSTM1 intact, p=0.04). Sulforaphane treatment also increased histone acetylation in PD assays in MCs. Finally, no grade three adverse events were seen, and only one patient discontinued study treatment for toxicity (grade one GI discomfort). Conclusions: Treatment with 200 µmol per day of sulforaphane is feasible, safe, and inhibits HDAC function. This combined with the preliminary observation of PSA modulation, which may indicate biologic activity, provides the basis for dose escalation studies of sulforaphane in men with prostate cancer. Clinical trial information: NCT01228084.