bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or placebo (P+O) among patients with advanced neuroendocrine tumors (NET).
Authors: Yao James C. , Hainsworth John D. , Wolin Edward M. , Pavel Marianne E. , Baudin Eric , Gross David , Ruszniewski Philippe , Tomassetti Paola , Panneerselvam Ashok , Saletan Stephen , Klimovsky Judith 
Published: March 2020

4014 Background: In this large phase III trial, median progression-free survival (PFS) improved by 5.1 mo with E+O compared to P+O in patients (pts) with NET associated with carcinoid syndrome. Baseline imbalances including WHO performance status (PS) and primary site favoring P+O confounded primary analysis. Chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA) are important biomarkers in NET. Analyses were performed to identify prognostic factors and adjust for baseline imbalances. Methods: Pts were randomized to E+O (n=216) or P+O (n=213). Potential prognostic factors including baseline CgA (≤2×ULN vs >2×ULN), baseline 5-HIAA (≤median vs >median at baseline), age (<65 vs ≥65), gender, race, WHO PS (0 vs 1, 2), primary site (lung vs other), prior somatostatin analog use (yes vs no), duration from diagnosis (<6 mo, 6-24 mo, 2-5 yr, >5 yr), and organs involved (liver, bone) were assessed in univariate analysis using the log rank test and stepwise regression using Cox proportional hazards model. Results: Median PFS (mo) was significantly longer for pts with nonelevated CgA (27 vs 11; p<.001) and nonelevated 5-HIAA (17 vs 11; p<.001). Analyses also indicated age (14 vs 12; p=.01), WHO PS (17 vs 11; p=.004), liver involvement (14 vs not reached; p=.02), bone metastases (8 vs 15; p<.001), and lung as primary site (11 vs 14; p=.06) as potentially prognostic. Multivariate analysis indicated that significant prognostic factors for PFS included baseline CgA (HR, 0.47; CI, 0.34-0.65; p<.001), WHO PS (HR, 0.69; CI, 0.52-0.90; p=.006), bone involvement (HR, 1.52; CI, 1.06-2.18; p=.02), and lung as primary site (HR, 1.55; CI, 1.01-2.36; p=.04). Adjusted for covariates, a 38% reduction in risk of progression was observed for E+O (HR, 0.62; 95% CI, 0.51-0.87; p=.003). Conclusions: In the phase III RADIANT-2 trial, baseline CgA levels, WHO PS, lung as primary site, and bone involvement were important prognostic factors. Exploratory analysis adjusted for these prognostic factors indicated significant benefit of everolimus therapy.
Phase I/II study of preoperative (pre-op) short course chemoradiation (CRT) with proton beam therapy (PBT) and capecitabine (cape) followed by early surgery for resectable pancreatic ductal adenocarcinoma (PDAC) of the head.
Authors: Hong Theodore S. , Ryan David P. , Borger Darrell R. , Blaszkowsky Lawrence Scott , Yeap Beow Yong , Deshpande Vikram , Wo Jennifer Yon-Li , Wadlow Raymond Couric , Kwak Eunice Lee , Allen Jill N. , Clark Jeffrey W. , Zhu Andrew X. , Ferrone Cristina , Mamon Harvey J. , Adams Judith A. , Winrich Barbara , Grillo Tarin , DeLaney Thomas F. , Fernandez-del Castillo Carlos 
Published: March 2020

4021 Background: Standard adjuvant 6 week CRT may delay and reduce tolerability of adjuvant gemcitabine-based chemotherapy. We explore the safety and efficacy of a one-week course of pre-op CRT with PBT and cape followed by early pancreaticoduodenectomy (PD). Methods: Patients with radiographically resectable, biopsy-proven PDAC of the head were enrolled from May 2007-December 2010 on this prospective, NCI-sponsored clinical trial. Eligibility included no CT involvement of SMA or celiac artery; No metastatic disease. Dose level 1 consisted of PBT delivered 3 Gy x 10. Pts in subsequent dose levels received 5 Gy x 5 in progressively shortened schedules: level 2 (wk 1 M W F, wk 2 T Th), level 3 (wk 1 M T Th F, wk 2 M), level 4 (wk 1 M-F). PBT was targeted at pancreatic mass with elective nodal coverage. Pts received Cape 825 mg/m2 BID wk 1 and 2 M-F. Surgery was performed 1-6 wks after completion of cape. Patients were recommended to receive 6 mo of gemcitabine after surgery. Genotyping of 15 genes (including KRAS, PIK3CA, BRAF, NRAS, TP53, IDH1) was performed. Results: 50 pts were enrolled on study. 48 patients are eligible for this analysis. 3 pts were treated at each of dose levels 1-3. 6 pts were at dose level 4, which was selected as MTD. No DLTs were observed. 35 patients were treated in the phase II portion at the MTD. Gr 3 toxicity was noted in 2 pts (chest wall pain-1, colitis-1). 38 pts underwent PD. Reasons for no PD were: metastatic disease-9, unresectable tumor-1. Mean post-op length of stay was 7 days (range 5-47). 6/38 (16%) resected pts had positive margins. 28/38 (74%) had positive nodes. Median follow up is 21 months among the 19 patients still alive. 4/48 (8%) local failures in ALL patients. mOS and mPFS are 18 and 10 months respectively for ALL patients and 27 and 14 months for RESECTED patients. Of 28 patients with genotype data available, 22 (79%) had KRAS mutations. 10/22 KRAS mt and 4/6 KRAS wt pts are alive. Conclusions: Pre-op CRT with 1 wk of PBT and capecitabine followed by early surgery is well tolerated and associated with favorable local control. Complete genotype and DPC4 data will be presented at the meeting.
Ethnic gene profile of genes involved in angiogenesis to predict regional bevacizumab efficacy difference in gastric cancer.
Authors: Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Loupakis Fotios , Azuma Mizutomo , Gerger Armin , Graziano Francesco , Ning Yan , Labonte Melissa Janae , El-Khoueiry Rita , Bohanes Pierre Oliver , Benhaim Leonor , Páez David , Watanabe Masahiko , Koizumi Wasaburo , Lenz Heinz-Josef 
Published: March 2020

4026 Background: AVAGAST showed regional bevacizumab (Bev) efficacy difference (RBED), namely, Asian (Asi) patients (pts) with gastric cancer (GC) had no benefit whereas European and Pan-American patients had more benefit from Bev. Recently, germline gene polymorphisms in angiogenesis have been recognized as predictive marker for Bev efficacy. Allele frequency (AF) in gene polymorphisms may vary depending on ethnicity. We tested the hypothesis whether angiogenic pathway gene polymorphisms may have different AF among Asi, Caucasian (Cau), and Hispanic (Hisp) in GC and this disparity may explain RBED. Methods: Three-hundred pts [Japanese (Jap), Cau, and Hisp, 100 from each race] with histopathologically confirmed GC were collected from Japan, USA, Austria, and Italy between 1991 and 2011. These pts were divided into 2 groups as training set (n=50) and validation set (n=50) in each race. Seven functional gene polymorphisms previously reported as predictive marker were selected. All samples were analyzed using PCR-based direct DNA- sequencing. Fisher's exact test was used to compare the distribution of AF among races. Results: Significant disparate distributions in favorable AF for Bev were shown among races in Table. Jap GC pts had significant lower AF of 5 predictive gene polymorphisms in training set, and among these 5, three predictive gene polymorphisms were also validated. Conclusions: Our preliminary results showed significant disparate AF distributions in predictive gene polymorphisms for Bev, and these disparities may explain RBED in AVAGAST. Further investigation is warranted to elucidate RBED. [Table: see text]
Efficacy and safety of bevacizumab combined with chemotherapy in the treatment of patients with metastatic well-differentiated duodeno-pancreatic endocrine tumors (BETTER study).
Authors: Ducreux Michel , Seitz Jean-François , Smith Denis , O'Toole Dermot , Lepère Céline , Bitoun Laurence , Mitry Emmanuel 
Published: March 2020

4036 Background: Gastrointestinal neuroendocrine tumors (NET) overexpress vascular endothelial growth factor (VEGF), thus we hypothesized that Bevacizumab (Bv), a monoclonal antibody targeting VEGF in combination with chemotherapy may show an activity in duodeno-pancreatic NET. Methods: This multicenter, open-label, non-randomized, two- group phase II trial assessed in one group the efficacy and safety of Bv (7.5 mg/kg IV on day 1, every 3 weeks), combined with 5-FU/streptozotocin (stz): 5-FU 400 mg/m²/d; Stz 500 mg/m²/d IV, d1-5/ every 42 days, during a minimum of 6 months in patients (pts) with progressive, metastatic, well-differentiated duodeno-pancreatic NET (WHO 2000), not previously treated with chemotherapy, ECOG PS ≤2 and Ki 67 index < 15%. Primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), response rate, safety and quality of life. Study duration was 24 months. Results: In the ITT population, 34 pts were enrolled, 22 (64.7%) were men, median age 55.3 years (37.0-77.6), 33 (97.1%) pts had ECOG-PS 0/1. Most metastases were in the liver 33 (97.1%) pts or lymph nodes 14 (41.2%) pts. Ki-67 proliferative index was 0-2% in 8 (25%) pts, 3-4% in 5 (15.6%), 5-9% in 6 (18.8%), 10-14% in 12 (37.5%) and 15% in 1(3.1%) pt. Median treatment duration was 14.0 months; median number of cycles was 10. At 24 months, median PFS was 23.7 months [95%CI: 14.5; not reached] based on 18 events. PFS rate at 18 months was 62%. Tumor control rate was 100% (n= 34) including partial response in 19 (55.9%) pts and stable disease in 15 (44.1%) pts. Survival rate at 24 months was 88%. Median OS was not reached, 5 patients died. CTC grade 3/4 Adverse Events (AEs) occurred in 23 (67.6%) of pts, mainly digestive 5 (14.7%) pts. G3/4 Bv targeted AEs were hypertension in 7 (20.6%) pts and thromboembolism in 4 (11.8%). Conclusions: Efficacy data in this phase II trial assessing a novel approach with Bv and 5-FU/stz in duodeno-pancreatic NET is encouraging and the toxicity profile is acceptable. Results suggest that Bv may have a place in the treatment of pancreatic NET and warrant further investigation in a phase III trial.
Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric cancer (AGC) enrolled in the phase III GRANITE-1 study.
Authors: Yeh Kun-Huei , Van Cutsem Eric , Ohtsu Atsushi , Shen Lin , Ajani Jaffer A. , Rizvi Syed , Sedova Michaela , Costantini Chiara , Smith Heind , Sahmoud Tarek , Bang Yung-Jue 
Published: March 2020

4081 Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol 2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the oral mammalian target of rapamycin inhibitor EVE showed that incidences of stomatitis, rash, infections, and pneumonitis were greater in Asian pts; however, the number of Asian pts enrolled was small. GRANITE-1 provides an opportunity to evaluate EVE safety in a broader Asian population. Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts aged ≥18 y with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d + best supportive care (BSC) or placebo + BSC. Randomization was stratified by region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was continued until disease progression or unacceptable toxicity. Adverse events (AEs) were collected throughout the study and for 28 d after final dose of study drug and assessed according to the Common Terminology Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival. Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363 (55%) were enrolled in Asia and received EVE (n=243) or placebo (n=120). EVE did not significantly reduce the risk of death in the overall (HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs 35%). Among EVE-treated pts, rates of any-grade rash, infections, and pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs 2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and 0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt (from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The safety profile of EVE in Asian pts with AGC was similar to that observed in ROW pts with AGC and with EVE in other cancers. No new safety signals were identified. Pneumonitis was relatively uncommon in Asian and ROW pts.
Relief of bowel-related symptoms with telotristat etiprate in octreotide refractory carcinoid syndrome: Preliminary results of a double-blind, placebo-controlled multicenter study.
Authors: O'Dorisio Thomas M. , Phan Alexandria T. , Langdon Robert M. , Marek Billie J. , Ikhlaque Nadeem , Bergsland Emily K. , Freiman Joel , Law Linda , Banks Phillip Lee , Frazier Kenneth , Jackson Jessica , Zambrowicz Brian , Kulke Matthew 
Published: March 2020

4085 Background: Diarrhea associated with carcinoid syndrome has been attributed to tumor production of serotonin. Telotristat etiprate, (LX1032, LX1606), is an oral inhibitor of peripheral serotonin synthesis. This study explored the safety, tolerability, and efficacy of telotristat etiprate in carcinoid patients with octreotide-refractory diarrhea. Methods: Carcinoid patients with ≥4 bowel movements (BMs)/day on octreotide were randomized 3:1 to receive telotristat etiprate or placebo as double-blind treatment. Patients enrolled in sequential, escalating dose cohorts of 150, 250, 350, or 500 mg tid, followed by a 500 mg tid expansion cohort. Patients were followed for toxicity, 24-hr urinary 5-HIAA (u5-HIAA), BM frequency, and self-reported bowel-related symptoms. Subjects were asked “In the past 7 days, have you had adequate relief of your carcinoid syndrome bowel complaints such as diarrhea, urgent need to have a bowel movement, abdominal pain or discomfort?” Responses (yes or no) were analyzed as categorical variables. Results: 16 patients enrolled in the 4 escalating dose cohorts and 7 in the expansion cohort; 18 on telotristat etiprate and 5 on placebo. Median age: 62 yrs; mean 6.3 BMs/day (range, 4-10). AEs included primarily mild-moderate diarrhea, nausea, and abdominal discomfort. In treated subjects, adequate relief was reported as: Week 1 - 6/18 (33.3%), Week 2 - 5/16 (31.3%), Week 3 - 5/15 (33.3%), and Week 4 - 6/13 (46.0%). No placebo subjects reported improvement at any timepoint. Biochemical response (≥50%reduction in u5-HIAA) and BM response (≥30% reduction in daily BMs for 2 weeks) were associated with reporting of adequate relief. For evaluable telotristat etiprate-treated patients, 9/16 (56%) experienced a biochemical response and 5/18 (28%) experienced a clinical (BM) response; no placebo subjects achieved either biochemical or clinical response. Conclusions: Treatment with telotristat etiprate was associated with decreases in u5-HIAA and BM frequency, and with self-reported relief of bowel related symptoms. Treatment in an extension phase with open-label telotristat etiprate is ongoing.
A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC).
Authors: Chi Kim N. , Hotte Sebastien J. , Ellard Susan , Gingerich Joel Roger , Joshua Anthony Michael , Yu Evan Y. , Gleave Martin Edwin 
Published: March 2020

4514 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at 12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31% treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts with CRPC. Funded by a grant from the Terry Fox Research Institute.
18F-16β-fluoro-5α-dihydrotestosterone (FDHT) PET as a prognostic biomarker for survival in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Fox Josef J. , Jia Xiaoyu , Heller Glenn , Schöder Heiko , Humm John , Haupt Eric C. , Schneider Coursen , Scher Howard I. , Larson Steven M. , Morris Michael J. 
Published: March 2020

4517 Background: At present there is no imaging biomarker for patients with mCRPC as the disease primarily metastasizes to bone, which is difficult to visualize and quantify using standard techniques. We have conducted clinical trials in which patients with progressive mCRPC are scanned using FDG-PET to examine glucose metabolism, and FDHT-PET. FDHT is a novel tracer and structural analog of dihydrotestosterone that binds to the androgen receptor (AR) to demonstrate AR overexpression, a key biologic feature of mCRPC. We previously reported an association between baseline FDG-PET and overall survival in mCRPC. We now present the prognostic utility of baseline FDHT-PET. Methods: We prospectively scanned mCRPC patients with FDG and FDHT-PET prior to a change in therapy as part of imaging clinical trials. PET results were represented as the hottest lesion (SUVmax), or average of the five hottest lesions (SUVmaxavg). Five lesions per patient were recorded. If less than 5 lesions were captured, a value of 1 was imputed for the remaining lesions. Clinical and lab parameters were collected. Univariate analysis was performed on PET, clinical and lab variables for association with overall survival (OS). Multivariate models of prognostic factors were constructed. Results: 170 mCRPC patients were imaged with FDG and 116 also had FDHT-PET at baseline. Median survival was 21.2 months (95%CI: 19.1-24.0). On univariate analysis, FDHTmax, FDHTmaxavg, FDGmaxavg, PSA, hemoglobin, alkaline phosphatase, and LDH were associated with OS. FDHTmax and FDHTmaxavg were significantly correlated with one another. In a multivariate model, FDHTmaxavg and LDH were prognostic of survival. In a separate model assessing FDG, FDGmaxavg and LDH were also prognostic. Conclusions: FDHT not only allows for a visual assessment of the AR axis in prostate cancer, but appears to associate with overall survival in mCRPC. Increased AR activity as measured by FDHT SUVmaxavg held greater prognostic value than PSA or Gleason score. FDHT is also being evaluated as a clinical response indicator and pharmacodynamic measure with AR directed therapies.
Defining the genetic basis of everolimus sensitivity in metastatic bladder cancer (MBC) by whole-genome sequencing (WGS).
Authors: Iyer Gopa , Milowsky Matthew I. , Al-Ahmadie Hikmat , Hanrahan Aphrothiti , Janakiraman Manickam , Heguy Adriana , Viale Agnes , Socci Nicholas D , Sander Chris , Bochner Bernard , Bajorin Dean F. , Berger Michael F , Taylor Barry S. , Solit David B. 
Published: March 2020

4527 Background: MBC is rarely cured with standard chemotherapy and novel agents are clearly needed. A phase II trial of everolimus in MBC resulted in 1 near-complete response (CR), 1 partial response, and 3 minor responses. We used WGS and a Next Generation exon capture assay to identify the genetic aberrations underlying treatment response. Methods: In the near-CR case, tumor and peripheral blood DNA was subjected to WGS (Illumina) using 2x100 bp paired-end libraries for 40X haploid coverage. Raw sequence data was aligned to hg19 and somatic point mutation detection was performed. Tumor DNA from 13 additional patients on the trial was analyzed using an exon capture sequencing assay. Results: 184 exonic somatic mutations were identified in the everolimus complete responder by WGS, including a 2 bp frameshift truncation in TSC1 and a nonsense mutation in NF2. Sanger sequencing of an additional 96 high-grade bladder tumors found 5 (6.2%) tumors containing TSC1 alterations and no NF2 mutations. Of the 13 patients on the trial who underwent targeted exon sequencing, 3 (23%) possessed nonsense TSC1 mutations and 2 had minor treatment responses (17% and 24% tumor regression). 1 patient with a 7% tumor regression had a somatic missense TSC1 variant. 8 (89%) of 9 patients with tumor progression as best response were TSC1 wild-type. Patients with TSC1-mutant tumors remained on drug for longer duration (7.7 vs. 2 months, p=0.004, Wilcoxon rank sum test). Conclusions: Everolimus is an active agent in MBC in patients with TSC1 mutant tumors. The pattern of co-mutation in patients with TSC1 mutant tumors is complex and combination therapies will likely be required to achieve durable responses in most patients. Our results also highlight the potential utility of WGS in identifying novel predictors of response to targeted inhibitors.