bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study of the x-linked inhibitor of apoptosis (XIAP) antisense AEG35156 in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Lee Ann Sing , Zee Benny C.Y. , Cheung Foon Yiu , Kwong Philip , Cheng Ashley Chi Kin , Lai Maria , Kwok Chloe , Chong Marc , Jolivet Jacques , Chiang C L , Leung K C , Siu Steven , Lee Conrad , Tung Stewart Yuk 
Published: March 2020

4105 Background: XIAP inhibits caspases which are proteases responsible for apoptotic cell death. It is highly expressed in HCC. AEG35156 is a second generation antisense oligonucleotide targeting XIAP mRNA, thus lowers the apoptotic threshold of cancer cells. It also accumulates in the liver. This study is designed to assess the added benefit of combining AEG35156 with sorafenib. Methods: Patients with histologically or clinically diagnosed (AASLD criteria) HCC who had failed or were unsuitable for resection or ablative therapies were randomized (2:1) to receive either weekly injection of AEG35156 300mg in combination with sorefanib 400mg BID or sorefanib alone. The primary end point was progression-free survival (PFS). Other endpoints were overall survival (OS), response rates and safety. Results: 51 patients were recruited. 48 patents were evaluable. There were 31 patients in the combination arm and 17 in the control arm. The median age was 60. 88% of patients were male. 81% of patients were hepatitis B carrier. 90% of patients belong to Child-Pugh class A. The median follow-up was 16.2 months. The PFS for the combination arm was 4.0 months (95% CI: 1.2-4.1) and 2.6 months for control arm. The OS for the combination arm was 6.5 months (95% CI: 3.9-11.5) and 5.4 months for the control arm. There were 3 partial responders (Choi’s criteria) in the combination arm (10%, 95% CI: 3-27%) and none (0%) in the control arm. Patients who had the study treatment interrupted (PFS 4.0, 95% CI: 2.4-5.4) or had dose modification (PFS 4.45, 95% CI: 1.0-6.5) according to protocol did significantly better than those who had no dose reduction (PFS 1.2, 95% CI: 1.2-4.0) and those in the control arm (PFS 2.6, 95% CI: 1.2-5.4). This also applies to OS. Regarding toxicities, there were one AEG35156 related serious adverse event (SAE) of hypersensitivity and two sorafenib related gastrointestinal SAE. Conclusions: AEG35156 in combination with Sorafenib was well tolerated in patients with advanced HCC. Dose reduced AEG35156 in combination with sorafenib have shown more activity than sorafenib alone and warrants further investigation.
Treatment of advanced or metastatic hepatocellular cancer (HCC): Final clinical results of a single-arm phase II study of bevacizumab and everolimus.
Authors: Treiber Gerhard , Wex Thomas , Schneider Guenther , Roecken Cristoph , Dufour Jean-Francois , Geisel Juergen , Hardikar S. ,   German Multicenter BEVARAD Study Group
Published: March 2020

4107 Background: mTOR inhibitors are emerging drugs for treatment (Tx) of advanced hepatocellular cancer (HCC), their therapeutic effects may be potentiated by combination with anti-VEGF partners (Treiber G, Expert Rev Anticancer Ther 2009). Methods: Pts with histologically confirmed advanced HCC were included. Tx consisted of RAD001 in a daily start dose of 5 mg orally and bevacizumab 5mg/kg iv every 2 weeks, up to 24 weeks. Primary endpoint was TTP, secondary endpoints were OS, RR, changes in biomarkers, and safety and tolerability besides PK analysis. Pts with either a CPT Score > 9, a CLIP score > 3, or a Performance Status of ECOG > 2 were not eligible. Radiological TTP was centrally evaluated by both, conventional(c)-, and modified(m)-RECIST criteria on a PP basis. Additionally, we included a combined endpoint (TTPcomb: time to either clinical or radiological progression leading to termination of treatment) as assessed by the local centers in all recruited patients. Results: 33 pts (ITT) were recruited (26 with Child A, 7 with Child B; median CLIP score was 2, mean age 67 y, and mean BMI 28). 17/33 pts. had previous Tx (including sorafenib < 3 months). Drop out other than PD was due to consent withdrawl, lost to FU, and AE (n=5), therefore 28 patients had received study medication >2 wks (PP). There were 65 CTC-AE grade 3/4 events occuring in 22 pts. Median Tx duration was 69 days on RAD001, and a median of 5 cycles of bevacizumab were applied. Dose adjustements for RAD001 were performed in 20 pts, mean cumulative individual RAD dose was 334 mg, there was no association between Cmin of RAD and TTP or OS. On ITT, median TTPcomb was 2.0 mo and median OS was 9.0 mo. On PP, median TTP approached 3.8 mo (conventional RECIST) and median OS 9.7 mo. Using (m)RECIST, 5 pts. achieved PR within the first 8 wks, and this was accompanied by a significant VEGF plasma decrease (median of -65%), on (c)RECIST best response seen was SD. Conclusions: Combination Tx of RAD001 and bevazicumab is tolerated acceptably. TTP and OS in our 1°/2°-line HCC patients on Tx is comparable to sorafenib monotherapy in the SHARP trial (1° line only).
Biliary tract cancer: A large institutional experience.
Authors: McNamara Mairead Geraldine , Horgan Anne , Walter Thomas , McKeever Elizabeth , Min Trisha , Riga Anne , Hedley David W , Cleary Sean P , Gallinger Steven , Greig Paul David , Serra Stefano , Dawson Laura A. , Knox Jennifer J. 
Published: March 2020

4109 Background: Biliary tract cancers (BTCs) encompass both cholangiocarcinoma (CC), arising in intrahepatic, perihilar (klatskin), or distal biliary tree, ampulla of vater and gallbladder carcinoma (GBC). Prognosis is poor for majority of these patients (pts). Aim: To retrospectively review outcomes of pts, as practices/treatments evolve, who presented to a multidisciplinary team at tertiary referral center Princess Margaret Hospital, Toronto, with a diagnosis of BTC. Methods: 1057 pts were followed from 01/87 - 09/11. Complete demographics, performance status (PS), disease site, histological diagnosis, percentage receiving surgery with curative intent, chemotherapy (CT), radiotherapy (RT), recurrence patterns and overall survival (OS) were analyzed. Results: The cohort includes 549 (52%) males, PS of 0-1 in 850 (80%), 2-3 in 87 (8%) pts. A histological diagnosis of adenocarcinoma was confirmed in 885 (84%), 106 (10%) non diagnostic, 66 (6%) other. Definitive surgery was performed in 41% and adjuvant CT or concurrent CT/RT given in 20% and 8% respectively. CT or CT/RT was given for unresectable/metastatic disease in first line palliative setting in 395 (37%) and 18 pts (5%) respectively. Response to first line CT in GBC was 33% vs. 24% in CC (p=0.005) and med survival was 8.4 and 13.1 mo respectively (p=0.001). The OS for entire cohort of 1057 pts was 19.3 mo with survival for breakdown of tumor type, stage detailed in the table. At this time, 207 (20%) are still alive, 609 (58%) deceased, status unknown/pending in 241 (22%). Conclusions: This represents a large biliary cancer cohort with survival benchmarks obtained in modern era of multidisciplinary care. Different subsites clearly present at different stages and have different prognosis with treatments. Despite better responses for advanced disease on CT in GBC, survival was better in CC consistent with reported literature. Therapeutic advancement mandates finding additional drug options and appropriate adjuvant care. [Table: see text]
Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors.
Authors: Fischer Christian , Pape Ulrich-Frank , Neumann Tabea , Detjen Katharina M , Hilfenhaus Georg , Hess Georg , Wiedenmann Bertram , Pavel Marianne E. 
Published: March 2020

4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. As antiangiogenic treatments are introduced in the management of neuroendocrine tumors (NETs), we addressed the expression and function of PlGF in NETs. Methods: Serum levels of PlGF were determined in two independent cohorts of NET patients collected retrospectively and prospectively (n=87 and n=84) using Roche Elecsys and correlated with clinical data. Expression of PlGF in tumors was evaluated by immunohistochemistry. PlGF effects on proliferation and migration were examined in vitro using NET cell lines. Results: Circulating and tumoral PlGF were found elevated in NET patients as compared to control sera and pancreatic tissues in a retrospective analysis restricted to patients with pancreatic NETs (pNETs). De novo expression of PlGF occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced proliferation and migration of NET cells, and elevated circulating PlGF levels correlated with advanced tumor grading, suggesting that PlGF supported a more aggressive phenotype. In line with this notion, circulating PlGF levels above median predicted reduced tumor related survival in pNET patients (p=0.012). Furthermore, pathologic PlGF levels were associated with poor prognosis within the subgroup of grade 2 tumors. Subsequent prospective PlGF determinations confirmed and extended our observation of elevated PlGF levels for both, pNETs (n=32, p<0.001) and midgut NETs (n=58, p<0.001). Since median follow up was too short to determine survival, time to progression (TTP) was analyzed instead. Most pNETs were progressive at the time of sample collection, precluding an informative evaluation of TTP in this subgroup. However, PlGF levels above median were correlated with shorter TTP in midgut NETs (p=0.0091; TTP 27 months versus undefined, HR 3.802). Conclusions: These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter in patients with NETs.
Efficacy of cabozantinib (XL184) in patients (pts) with metastatic, refractory renal cell carcinoma (RCC).
Authors: Choueiri Toni K. , Pal Sumanta Kumar , McDermott David F. , Ramies David A. , Morrissey Stephanie , Lee Yihua , Miles Dale , Holland Jaymes , Dutcher Janice P. 
Published: March 2020

4504 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). Anti-tumor activity was also evaluated. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Cabo was given daily at a dose of 140 mg free base (equivalent to 175 mg salt form) starting at Day 2. Rosi (4 mg) was given Day 1 and Day 22 to complete PK assessment for DDI. Cabo was continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts; 17/25 (64%) RCC pts had received ≥ 2 prior agents; 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. The majority of pts were in an intermediate (21/25) or poor (3/25) prognostic category (1/25 in favorable category) per Heng et al (JCO, 2009, v27, p5794). ORR by mRECIST: 7/25 (28%). Disease control rate (PR + SD): 72% at 16 weeks; 19/21 (90%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 - 63% reduction in measurements). 10/25 (36%) pts remain on cabo. Median PFS is 14.7 months (95% CI: 7.3, upper limit not reached) with a median follow-up of 7.7 months. AEs ≥ Grade 3 severity: hypophosphatemia (36%), hyponatremia (20%), and fatigue (16%). PK data suggest that clinically relevant doses of cabo do not alter the Cmax or AUC0-24h of rosi, consistent with no inhibition of CYP2C8. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated RCC pts with a toxicity profile similar to that of other VEGFR TKIs. PK data suggest no DDI between cabo and rosi (CYP2C8 substrate).
Time from prior chemotherapy (TFPC) as a prognostic factor in advanced urothelial carcinoma (UC) receiving second-line systemic therapy.
Authors: Pond Gregory Russell , Sonpavde Guru , Choueiri Toni K. , Qu Angela Q. , Vaughn David J. , Fougeray Ronan , Niegisch Guenter , Albers Peter , Wong Yu-Ning , Ko Yoo-Joung , Sridhar Srikala S. , Galsky Matt D. , Petrylak Daniel Peter , Beer Tomasz M. , Stadler Walter Michael , O'Donnell Peter H. , Sternberg Cora N. , Rosenberg Jonathan E. , Molins Joaquim Bellmunt 
Published: March 2020

4522 Background: Prognostic factors for overall survival (OS) in patients receiving second-line chemotherapy for advanced platinum-pretreated UC include ECOG performance status (PS) >0, hemoglobin (Hb) <10g/dL and the presence of liver metastasis (LM) (Bellmunt J, J Clin Oncol 2010). We hypothesized that time from prior chemotherapy (TFPC) independently impacts OS. Methods: Of 11 available phase II trials evaluating second-line therapy for advanced UC (n=698), 6 trials with available baseline Hb, PS and LM were utilized (n=534). The trials evaluated vinflunine (2 trials), docetaxel plus vandetanib or placebo, paclitaxel-gemcitabine, nanoparticle-albumin-bound paclitaxel and paclitaxel-cetuximab. The Kaplan-Meier method was used to estimate OS from date of starting second-line therapy. Cox proportional hazards regression stratified for trial was used to evaluate the prognostic effect of factors on OS. TFPC was evaluated as a continuous variable, and based on cutpoints of 3, 6, 9 and 12 months (mo) from prior chemotherapy to first study treatment. The choice of optimal cutpoint for TFPC was determined by the maximum likelihood ratio χ2 statistic. Results: Overall, 513 patients were evaluable. 64.1% received prior chemotherapy for metastatic disease. Median OS was 6.8 mo (95% CI: 6.1 to 7.4); range was 0 to 84.2 mo. Median OS was 5.2, 7.1, 8.8, 7.6 and 10.6 mo respectively for TFPC <3 (n=181), 3 to <6 (n=133), 6 to <9 (n=77), 9 to <12 (n=45) and >12 (n=77) mo, respectively. Shorter TFPC was independently prognostic for decreased survival. The optimal cutpoint for TFPC was <3 mo, but no well-defined plateau was observed. PS>0 (HR=1.72, p<0.001), LM (HR=1.41, p=0.002), Hb <10 g/dl (HR=1.59, p=0.001) and TFPC <3 mo (HR=1.67, p<0.001) were significantly prognostic in the multivariate model. Timing of prior chemotherapy (metastatic disease vs. perioperative) was not prognostic. Conclusions: A shorter duration of TFPC exhibited a significant negative prognostic impact on OS independent of known prognostic factors in patients receiving second-line therapy for advanced UC. If externally validated, TFPC should be a stratification factor in trials of second-line therapy for advanced UC.
Neoadjuvant chemotherapy with DD-MVAC and bevacizumab in high-risk urothelial cancer: Results from a phase II trial at the University of Texas M. D. Anderson Cancer Center.
Authors: Siefker-Radtke Arlene O. , Kamat Ashish M. , Corn Paul G. , Matin Surena F. , Grossman H. Barton , Millikan Randall E. , Dinney Colin P.N. 
Published: March 2020

4523 Background: DD-MVAC has shown an improved 5-year survival in metastatic urothelial cancer; however, there is no prospective data on its use in the neoadjuvant setting. Previous work suggested that over-expression of VEGF was associated with a high risk of relapse in our neoadjuvant patients, leading to the hypothesis that combining a VEGFR inhibitor with chemotherapy may improve patient outcomes. Methods: Between 8/07 and 12/10, 60 patients with urothelial carcinoma of the bladder or upper tract tumor were enrolled on a prospective phase II clinical trial. Eligibility requirements included at least one of the following: 3-D mass on EUA (cT3b disease), LVI, hydronephrosis, micropapillary features, tumor in a diverticula, and for upper tract tumors a high grade tumor or radiographically measurable sessile mass. The primary endpoint was pathologic down-staging to <=pT1N0M0. Results: Forty-four patients with bladder/urethral tumors and 16 patients with upper tract tumors were enrolled. Pathologic down-staging to <= pT1N0M0 occurred in 53% of patients overall (bladder/urethra 45%, upper tract 75%), and to <= pT0N0M0 in 38% overall (bladder/urethra 39%, upper tract 38%). At a median follow-up of 26 months, the 2-year OS and DSS was 78% and 82%, respectively (bladder 2-yr OS and DSS 75%, 78%; upper tract 93%, 93%). The median OS and DSS have not yet been reached. The most common grade 3 or greater toxicity was neutropenia in 27% of patients, followed by fatigue in 10%. The following grade 3 toxicities were observed in < 10% of patients: mucositis, DVT/PE, hypertension, nausea/vomiting, thrombocytopenia. One patient experienced cardiac ischemia. Conclusions: Neoadjuvant chemotherapy leads to pathologic down-staging in 45% of patients with bladder cancer. DD-MVAC appears an acceptable alternative to traditional M-VAC in the neoadjuvant setting. Although bevacizumab did not impact down-staging based upon historical expectations, determining the effect on recurrence requires longer follow-up.
Correlation of progression-free survival at 6 months (PFS6) with overall survival at 12 months (OS12) in an analysis of 10 trials of second-line therapy for advanced urothelial carcinoma (UC).
Authors: Maughan Benjamin , Boucher Kenneth M. , Agarwal Neeraj , Choueiri Toni K. , Qu Angela Q. , Vogelzang Nicholas J. , Fougeray Ronan , Niegisch Guenter , Albers Peter , Wong Yu-Ning , Ko Yoo-Joung , Sridhar Srikala S. , Galsky Matt D. , Petrylak Daniel Peter , Vaishampayan Ulka N. , Beer Tomasz M. , Sternberg Cora N. , Rosenberg Jonathan E. , Molins Joaquim Bellmunt , Sonpavde Guru 
Published: March 2020

4525 Background: Second-line therapy of advanced UC is a significant unmet need. While phase II trials have relied on response rate (RR) as a primary endpoint, response may not be suitable for assessing cytostatic agents and does not capture duration of benefit. We hypothesized that PFS6 correlates with OS12 and may be a robust intermediate endpoint for phase II trials. Methods: Ten trials with individual patient progression and survival data (n=646) evaluating chemotherapy and/or biologics following chemotherapy were combined. Progression was defined as tumor progression (RECIST 1.0 in 9 trials, WHO in 1 trial), or death from any cause. Unadjusted and adjusted binomial confidence intervals for PFS6, OS12 and response were reported, with adjustment for variability between trials using random effects models. The relationship between PFS6 and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression with larger studies having more influence. The relationship between PFS6 and OS12 at the individual level was assessed using Pearson chi-square test with Yates continuity correction. Statistical analyses employed “R” statistical computing software, version 2.8.0. Results: 59% had visceral metastasis and performance status was 0, 1 and 2 in 50, 39 and 8%, respectively. Median age was 65 years (31-88) and 77% were male. PFS6 was 22% (95% CI: 17-24%), and adjusted PFS6 was 23% (95% CI: 15-34%). The OS12 was 20% (95% CI: 17-24%), and adjusted OS12 was 21% (95% CI: 15-29%). The Pearson correlation between trial level PFS6 and OS12 was 0.66 (p = 0.037). The individual level agreement between PFS6 and OS12 was seen in 82% of patients (kappa = 0.45). Among 560 patients evaluable for response and OS, the RR was 22% (95% CI: 18-25%) and adjusted RR was 21% (95% CI: 13-32%). Trial level Pearson correlation between response and OS12 was 0.37 (p = 0.30), and individual level agreement was seen in 78% (kappa=0.36). Conclusions: PFS6 is associated with OS12 at the trial and individual levels in patients receiving second-line therapy for advanced UC. The association of response with OS was suboptimal. Validation of PFS6 is warranted.
Neoadjuvant accelerated MVAC (AMVAC) in patients with muscle invasive bladder cancer: Results of a multicenter phase II study.
Authors: Plimack Elizabeth R. , Hoffman-Censits Jean H. , Viterbo Rosalia , Greenberg Richard Evan , Chen David , Lallas Costas D. , Trabulsi Edouard John , Wong Yu-Ning , Kutikov Alexander , Lin Jianqing , Duncan Gail , Adair Beth , Cione Charlotte , O'Sullivan Conor , Kilpatrick Deborah , Ross Eric A , Boorjian Stephen A. , Uzzo Robert G. , Kelly William Kevin , Hudes Gary R. 
Published: March 2020

4526 Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) demonstrates a survival benefit in the neoadjuvant setting for patients (pts) with muscle invasive bladder cancer (MIBC). Compared with standard MVAC, AMVAC yielded higher response rates with less toxicity in the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with CrCl >=50 and adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) on day 1, with pegfilgrastim 6 mg day 2 or 3, every 2 weeks. Pts with CrCl < 60 could receive cisplatin split over 2 days. Radical cystectomy (RC) with lymph node dissection was performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month period. Median age 64 (range 45-83). Three withdrew from study early and are not evaluable for response (2 physician discretion, 1 withdrawal of consent). An additional 8 are currently receiving treatment on study with toxicity and response data pending. Of the 33 evaluable pts for whom final data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts received < 3 cycles due to grade 3 fatigue (1), low platelets (1), and disease progression precluding RC (1). 32/33 pts underwent RC, all within 8 weeks of last chemotherapy. Median time from start of chemotherapy to RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI, 22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non muscle invasive disease. For the intent to treat cohort (n=36) 8 pts had grade 3-4 AMVAC related adverse events, the most common being anemia (3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95% CI, 20.4-51.8%). All pts will have completed study treatment by April 2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is well tolerated and preliminary results show a pCR rate similar to that reported for standard 12-week MVAC, suggesting that AMVAC for three cycles (6 weeks) is a safe and efficient alternative.