bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 2 study of galunisertib (TGF-Β R1 inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Kelley Robin Kate , Gane Edward , Assenat Eric , Siebler Jurgen , Galle Peter R. , Merle Philippe , Ollivier-Hourmand Isabelle , Cleverly Ann , Gueorguieva Ivelina , Lahn Michael M. F. , Faivre Sandrine J. , Benhadji Karim A. , Giannelli Gianluigi 
Published: September 2018

4097 Background: TGFβ signaling is associated with HCC progression. Inhibition of TGFβ R1 potentiates activity of sorafenib in in-vitro and in-vivo models. Here we report the clinical activity of galunisertib (G) plus sorafenib (S) in pts with incurable HCC and no prior systemic therapy. Methods: Eligibility criteria included incurable HCC with measurable disease per RECIST 1.1, no prior systemic therapy, Child Pugh A, ECOG PS ≤1.G was administered as 80 mg PO BID (lead-in Cohort 1) or 150 mg PO BID (lead-in Cohort 2 and expansion cohort), as intermittent dosing of 14 days on/off (28 days = 1 cycle). S was administered continuously as a 400 mg PO BID. Primary objective was to characterize time-to-progression (TTP) and biomarker changes in pts. Secondary objectives included evaluation of OS, PK, and toxicity (CTCAE v 4.0). Results: 47 pts were enrolled (Cohort 1 = 3, Cohort 2 and expansion cohort = 44). In the 150 mg BID cohort: Male = 88.6%; median age = 64 years; PS = 0/1, 81.8%/18.2%; etiology: hepatitis C = 34.1%, hepatitis B = 18.2%, alcohol = 20.5%, multiple = 13.6%; AFP≥200 µg/L = 50%; portal vein invasion = 34.1%. Incidence of AEs was similar between G dose levels. Overall in the 150mg BID cohort, treatment related AEs ( > 15%) were hand and foot syndrome (61.4%), diarrhea (40.9%), pruritus (22.7%), anemia and weight loss (20.5%), fatigue (29.5%), alopecia (18.2%), myalgia (22.7%), decrease in platelet count and nausea (15.9%). Two pts on 150 mg BID discontinued treatment due to study drug related AEs (anemia and weight loss). PK of G at 150 mg BID (n = 12) when co-administered with S, was similar to that observed in the G monotherapy study. G was rapidly absorbed and had an elimination half-life of approximately 8h. Median TTP (RECIST) was 4.1 (2.8, 5.5) months. OS, with a high censor rate of 55% was not mature at the time of this data cutoff. Median OS was 17.9 (14.8, NE) months. Conclusions: The combination of G plus S demonstrated acceptable safety and a meaningful OS of 17.9 months in an advanced HCC population. TTP was similar to S monotherapy in contemporary clinical trials though interpretation is limited by single arm design. Clinical trial information: NCT01246986.
Chemotherapy with or without definitive radiation therapy in locally advanced pancreatic cancer.
Authors: Zhong Jim , Switchenko Jeffrey M. , Behera Madhusmita , Kooby David A. , McDonald Mark William , El-Rayes Bassel F. , Landry Jerome Carl , Patel Pretesh R 
Published: September 2018

4103 Background: The recently reported LAP07 randomized trial calls into question the role of radiation therapy (RT) in the modern treatment of locally advanced pancreatic cancer (LAPC). However, advances in chemotherapy and RT limit application of the LAP07 results to current clinical practice. Here we utilize the National Cancer Database (NCDB) to evaluate the effects of RT in patients receiving chemotherapy for LAPC. Methods: Using the NCDB, patients with AJCC clinical stage T2-T4, N0-1, M0 adenocarcinoma of the pancreas from 2004-2014 were analyzed. Only those that received chemotherapy and did not undergo surgery were included. Patients were stratified into chemotherapy only (CT) and chemoradiation (CRT) cohorts. Patients undergoing definitive RT, defined as at least 20 fractions (fxs) or ≥ 5 Gy per fraction (i.e. SBRT) were included in the CRT cohort. Propensity-score matching (PSM) and landmark analysis were used to address selection bias and lead-time bias, respectively. The primary endpoint was overall survival (OS). Results: 13,004 patients met inclusion criteria, of which 7,034 (54%) received CT and 5,970 (46%) received CRT. After PSM, 5,215 patients remained in each cohort. Median follow-up was 22.6 months. The CRT group had younger median age (65 vs. 67) and less treatment at academic centers (44 vs. 51%); performance status was similar between groups. The median fractionated RT dose was 50.4 Gy in 28 fxs and SBRT dose was 24 Gy in 3 fxs. The CRT cohort demonstrated better OS compared with CT alone, with median and 1-yr OS of 12 vs. 10 months, and 50% and 41%, respectively (p < 0.001). On multivariable analysis, CRT was associated with superior OS with a hazard ratio (HR) of 0.79 (95% confidence interval (CI): 0.76-0.83, p < 0.001) compared with CT alone. The SBRT subgroup demonstrated the best survival (HR 0.71 [95% CI: 0.64-0.80], p < 0.001). OS was superior for CRT after PSM and for all patient subsets. Conclusions: In unresected LAPC, the addition of definitive radiotherapy to chemotherapy is associated with superior OS when compared with chemotherapy alone. Survival was greatest when SBRT was used. Definitive radiotherapy should remain a standard option for LAPC but optimal selection criteria remain unclear.
FOLFIRINOX (F-NOX) followed by individualized radiation for borderline-resectable pancreatic cancer (BRPC): Toxicity, R0 resection, and interim survival data from a prospective phase II study.
Authors: Murphy Janet E. , Wo Jennifer Yon-Li , Ryan David P. , Jiang Wenqing , Yeap Beow Y. , Drapek Lorraine C. , Blaszkowsky Lawrence Scott , Kwak Eunice Lee , Allen Jill N. , Clark Jeffrey W. , Faris Jason Edward , Zhu Andrew X. , Goyal Lipika , Mamon Harvey J. , Wolpin Brian M. , Lillemoe Keith D , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Ferrone Cristina , Hong Theodore S. 
Published: September 2018

4113 Background: F-NOX is increasingly utilized in BRPC as neoadjuvant therapy. However, prospective data remains limited; the largest series is a 22 patient (pt) cooperative group trial (Alliance A021101), in which 14 pts had R0 resection. In this study, we evaluate neoadjuvant F-NOX followed by individualized chemoradiation (CRT) for BRPC. Methods: Pts ECOG PS 0-1 with biopsy-proven BRPC defined by NCCN criteria were enrolled in a single institution, NCI-sponsored phase II study (NCT01591733). Pts received F-NOX for 8 cycles. If after chemotherapy the tumor was radiographically resectable, pts received short course CRT in 5 (protons 25 GyE) or 10 fractions (photons 30 Gy) with capecitabine 825 mg/m2 bid. If the tumor was still abutting vasculature, pts received CRT to 50.4 Gy with a vascular boost to 58.8 Gy. Primary endpoint was R0 resection rate. Results: 50 pts were enrolled from 8/2012 to 8/2016. Two pts were ineligible (lung metastasis, negative biopsy); 48 pts were evaluable. Median age was 62y (46-74). Median tumor size was 37 mm (21-56). Thirty-six pts (75%) had pancreatic head tumors. Median follow up was 18.2 months among 31 patients still alive. Of the evaluable pts, 40 (83%) completed therapy. Reasons for not completing therapy include pt withdrawal (3), physician decision (3), unacceptable toxicity (1) and progression (1). Grade 3 or greater toxicity occurred in 48% of pts, but no individual grade 3 toxicity exceeded 15%. Twenty-seven pts (56%) had short course CRT, while 13 pts (27%) had long course CRT. Twenty-nine pts were resected; R0 resection was achieved in 28/29 (96.5%). R0 resection rate among all evaluable pts was 58.3%. Median PFS among all evaluable pts was was 14.7 months; mOS was 37.7 months, with 1y OS 79.5% and 2y OS 59.3%. Among resected patients, mOS has not been reached. 1y PFS was 78.1% and 2y PFS 55.4%; 1y OS was 92.6% and 2y OS was 80.6%. Conclusions: Preoperative F-NOX followed by individualized chemoradiation in BRPC results in high R0 resection rates as well as prolonged mPFS and mOS in this large prospective cohort. Clinical trial information: NCT01591733.
Phase II study of autophagy inhibition with hydroxychloroquine (HCQ) and preoperative (preop) short course chemoradiation (SCRT) followed by early surgery for resectable ductal adenocarcinoma of the head of pancreas (PDAC).
Authors: Hong Theodore S. , Wo Jennifer Yon-Li , Jiang Wenqing , Yeap Beow Y. , Clark Jeffrey W. , Ryan David P. , Blaszkowsky Lawrence Scott , Drapek Lorraine C. , Mamon Harvey J. , Murphy Janet E. , Faris Jason Edward , Kwak Eunice Lee , Allen Jill N. , Zhu Andrew X. , Goyal Lipika , Lillemoe Keith D , Ferrone Cristina , DeLaney Thomas F. , Fernandez-del Castillo Carlos , Kimmelman Alec 
Published: September 2018

4118 Background: PDAC is highly dependent on autophagy, a metabolic process that renders cancer cells resistant to cytotoxic therapies. HCQ is an inhibitor of autophagy, and has preclinical activity in PDAC. We evaluate the efficacy of concurrent and adjuvant HCQ with preop SCRT and adjuvant chemotherapy in early, resectable PDAC. Methods: Pts with radiographically resectable, biopsy-proven PDAC of the head were enrolled from 12/2011-9/2016 on this IRB-approved, NCI-sponsored clinical trial (NCT01494155). Eligibility included no involvement of SMA or celiac artery on CT; adequate renal, hepatic and hematopoetic function; and ECOG PS 0/1. SCRT was 5 Gy x 5 with protons or 3 Gy x 10 with photons concurrent with Cape 825 mg/m2 BID wk 1 and 2 M-F. HCQ was started at 400 mg po BID 1 wk prior to radiation through SCRT until the day of surgery. Surgery was performed 1-3 wks after completion of SCRT. Pts were recommended to receive 6 mo of gemcitabine-based chemotherapy after surgery. Pts resumed HCQ after discharge from surgery and continued until progression. Follow-up was performed every 3 months with CT scanning every 6 mo. Sample size of 50 to evaluate an increase of 2-year PFS from 30% to 45%. Results: 50 pts were enrolled on study and all are evaluable for this analysis. Median age- 69 (range 54-86); pre-treatment CA19-9 median 69.5 U/mL ( < 1-10235), female- 24 pts (48%). Gr 3 toxicity was noted in 2 (4%) pts (nausea-1, hyperglycemia-1). All 50 pts completed SCRT. 46 pts underwent resection. Reasons for no resections: metastatic disease-2, toxicity-1, intercurrent illness- 1. 38 pts had R0 resection, 8 had R1 resection. 29 of 46 pts had positive nodes. 1 pt achieved pathologic complete response (CR), 2 pts had near CR . 11 pts remain on HCQ. Median follow up in 26 surviving pts is 18.3 months. mPFS is 11.7 mo, mOS 23.3 mo. OS-2 yr- 43.1%, PFS-2-yr 32.0%. Conclusions: HCQ with preop SCRT and adjuvant gemcitabine-based chemotherapy is well tolerated but did not meaningfully impact DFS. Further pathologic/correlative studies, particularly in outstanding pathologic responders and long term survivors are ongoing. Clinical trial information: NCT01494155.
A phase I/II trial of TG01/GM-CSF and gemcitabine as adjuvant therapy for treating patients with resected RAS-mutant adenocarcinoma of the pancreas.
Authors: Palmer Daniel H. , Dueland Svein , Valle Juan W. , Aksnes Anne-Kirsti 
Published: September 2018

4119 Background: TG01 (a mixture of 7 RAS peptides) is an injectable antigen-specific cancer immunotherapy targeted to treat patients (Pts) with KRAS mutations, found in more than 85% of pancreatic adenocarcinomas. There is scope for improvement in adjuvant treatment of resected pancreatic cancer; with 1- and 2-year published overall survival (OS) rates ranging from 56-80% and 30-54% respectively. TG01 induces RAS mutant-specific T-cell responses which are enhanced by co-administration of GM-CSF. This study evaluates safety, immunological response and OS of TG01-immunotherapy with adjuvant gemcitabine chemotherapy. Methods: Pts were eligible after an R0 or R1 pancreatic adenocarcinoma resection. As soon as possible after surgery, TG01 (0.7 mg intradermal injection (id)) together with GM-CSF (0.03 mg id) was given on days 1, 3, 5, 8, 15, 22 and 2-weekly thereafter until the end of gemcitabine (starting within 12 weeks of surgery and given for 6 cycles). Thereafter TG01/GM-CFS were given 4-weekly up to 1 yr and 12-weekly up to 2 yrs. Immune response was assessed using antigen-specific (TG01) Delayed-Type Hypersensitivity (DTH) and T-cell proliferation. OS was assessed from surgery; ~8 weeks before first TG01 injection. Results: To date, 19 pts (68% R1) from 3 sites (Norway and UK) and have been followed for 2 yrs.Eight SARs in 5 pts have occurred; 4 related to gemcitabine (anemia, pulmonary infection and 2 fever); 3 related to TG01/GM-CSF (2 anaphylaxes and 1 hypersensitivity); and 1 possibly related to all products (dyspnea). The allergic reactions only occurred after several cycles of gemcitabine and resolved within 1-2 hrs. There was no treatment related deaths.16/19 (84%) pts had a positive DTH by week 11. Proliferation of mutant RAS specific T-cells is being analyzed. OS rate at 1 and 2 yrs were 89.5% (95% CI 75.7, 100.0) and 68.4 (95% CI 47.5, 89.3), respectively. Median OS was 33.1 months (95% CI 16.8, 40.1). Conclusions: TG01/GM-CSF generated early immune responses in 84% of patients with R0/R1 resected pancreatic cancer. The regimen was generally well tolerated although some late, manageable allergic reactions were seen. OS was encouraging in view of published reports. Clinical trial information: NCT02261714.
Characteristics and outcomes of resected pancreatic cystadenocarcinoma: 1,205 cases from the National Cancer Data Base.
Authors: Wang Jiping , Wang Xuefei , Heuthorst Lianne , Clancy Thomas E. , Pezzi Christopher 
Published: September 2018

4129 Background: Cystadenocarcinoma (CAC) of the pancreas is a rare pancreatic and therefore there is limited data on the characteristics, treatment and prognosis of this disease. Methods: Patients who underwent resection for CAC (n = 1,205) between 2003 and 2012 were identified from National Cancer Data Base. The clinicopathological characteristics and treatment outcomes were compared to patients with resected ductal adenocarcinoma (DAC) (n = 15,696). Cox-proportional hazard model was used to adjust for potential prognostic factors. A nomogram was constructed and validated to predict the outcomes of patients with CAC by using multiple variable Cox-proportional model and receiver operating characteristics curve methods. Results: Compared with resected DAC, patients with resected CAC are diagnosed at a younger age (58.7 vs. 61.2, p < 0.0001); female predominant (63.7% vs. 48.8%, p < 0.0001); more often Black (15.0% vs. 9.3%, p < 0.0001);had larger tumor (0-2, 2-4 and > 4cm:17.5%, 24.3%, 53.5% vs. 16.8%, 48.3% , 32.1%, respectively, p < 0.0001); have less total number of examined lymph nodes (10.6 vs. 14.5, p < 0.0001) and fewer positive lymph nodes(0.6 vs. 2.3, respectively). CAC patients were less likely to receive chemotherapy (28.8% vs. 62.5%, p < 0.0001) and radiation therapy (16.4% vs. 36.9%, p < 0.0001). CAC patients had significantly better overall survival than those with DAC (5 year survival: 55.6% vs. 17.3%, p < 0.0001). The survival advantage was primarily seen in patients with early stage disease (5 year survival: 70.9% vs. 36.9% in stage I patients, p < 0.0001, and 32.7% vs. 14.5% in stage II patients, p < 0.0001 respectively) and persisted after adjusting the known prognostic factors including age, AJCC staging, Charlson-Deyo score, type of surgery, chemotherapy, tumor size, and lymph node ratio (adjusted hazard ratio: 0.43, 95% confidence interval: 0.39-0.48, p < 0.0001). Conclusions: Patients with CAC had significantly better survival than those with pancreatic DAC even after controlling for known prognostic factors. The proposed nomogram could accurately predict patients’ outcome and may be used as a tool for clinical decision making.
Phase II study of individualized sunitinib (SUN) as first-line therapy for metastatic renal cell cancer.
Authors: Bjarnason Georg A. , Knox Jennifer J. , Kollmannsberger Christian K. , Soulieres Denis , Ernst D. Scott , Zalewski Pawel , Canil Christina M. , Winquist Eric , Hotte Sebastien J. , North Scott A. , Heng Daniel Yick Chin , Macfarlane Robyn Jane , Venner Peter M. , Kapoor Anil , Hansen Aaron Richard , Eigl Bernhard J. , Czaykowski Piotr , Boyd Ben , Wang Lisa , Basappa Naveen S. 
Published: September 2018

4514 Background: Higher SUN exposure is associated with better outcomes. Patients (pts) with minimum toxicity on the standard schedule do worse than pts needing dosing changes for toxicity. Methods: It was hypothesized that toxicity-driven dose/schedule individualization would improve the primary endpoint (PFS) from 8.5 (EFFECT trial) to 14 months (mo), with 99 pts required to detect this with 90% power and 2-sided alpha = 0.05. In a prospective phase II study (eligibility as EFFECT) pts start on 50 mg/day (d) for 28 d with treatment (Rx) breaks reduced to 7 d. If grade-2 toxicity develops before d 28, pts stay on a 50 mg on the next cycle with the number of d on Rx individualized aiming for ≤ grade-2 toxicity. Dose is reduced to 37.5 mg and then 25 mg if pts do not tolerate a 50 mg or 37.5 mg dose respectively for at least 7 d. Pts with minimum toxicity on d 28 are escalated to 62.5 mg and then 75 mg. Results: 117 pts were enrolled in 12 centers. Nine non-evaluable pts came off early due to toxicity (5), non-compliance (2) and global deterioration (2). Of 108 pts evaluable for response (IMDC favorable 31.5%, intermediate 58.3%, poor 10.2%. Bone mets 19%, Nephrect 83%), 10 are still on Rx. Dose was escalated in 20 pts (18.5%) to 62.5 mg (12 pts) and then to 75 mg (8 pts). In 49 pts (45.4%) eligible for dose reduction by standard criteria, a 50 mg dose was maintained but for 7 - 24 d, while 7 pts (6.5%) stayed on a 28 d schedule. Dose was reduced to 37.5 mg in 22 pts (20.4% vs. 36 - 63% in 4 large SUN trials) and to 25 mg in 10 pts (9.3% vs. 27 - 43% in 4 trials). Rx was stopped due to toxicity in 10/117 pts (9.3% vs. 15 - 19% in 4 trials). See table for response (ORR, 108 pts) and survival (117 pts) data vs. EFFECT (146 pts). The median followup is 15.5 mo (0.6 -37.9) for PFS and 24.5 mo (4.4 - 47.7) for OS. Conclusions: The null hypothesis of the PFS being 8.5 mo can be rejected with a p < 0.001. Individualized dosing is safe and feasible in a multicenter setting and associated with improved dose intensity and one of the best ORR, PFS and OS reported for a TKI. Clinical trial information: NCT01499121. [Table: see text]
Infusional gemcitabine + docetaxel/melphalan/carboplatin (GemDMC) ± bevacizumab (BEV) as an effective high-dose chemotherapy (HDC) regimen for refractory of poor-risk relapsed germ-cell tumors (GCT).
Authors: Nieto Yago , Tu Shi-Ming , Campbell Matthew T. , Bassett Roland , Tannir Nizar M. , Ward John Francis , Hofstetter Wayne Lewis , Jones Roy B. , Andersson Borje , Gulbis Alison M , Ledesma Celina , Timmons Melissa , Trapp Michelle , Champlin Richard E. , Pagliaro Lance C. 
Published: September 2018

4519 Background: Tandem HDC with carbo/etoposide (CE) is curative for a portion of relapsed GCT pts. However, outcomes of refractory or high-risk relapsed pts remain poor. We tested a new HDC regimen of GemDMC, based on DNA damage repair inhibition. We combined BEV with HDC given their potential synergy and the high vascularity of GCT metastases. Methods: Eligibility: Intermediate (int)/high-risk (Beyer Model), creatinine ≤1.8 mg/dL and adequate organ function. HDC included BEV (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 pts, we amended the trial omitting BEV. The trial was powered to distinguish a target 50% 2-yr RFS from an expected 25% in this population. Results: We enrolled 69 male pts in cohorts 1 (BEV, N=42) and 2 (no BEV, N=27) (Table). Pts were heavily pretreated and most had refractory tumors. Main AE: mucositis and renal (4 HDC-related deaths in cohort 1, 1 in cohort 2). Tumor markers normalized in 90% pts with active tumors at HDC. After HDC, 19 pts were in CR and 28 in PRm- (of these, 22 had residual lesions resected with no viable tumor found in 20/22, 2 xRT, 4 monitored). Median f/u = 39 (2-105) mo. The 2-yr RFS rates in cohorts 1 and 2 = 52% and 78%, respectively. Their respective 2-yr OS rates = 55% and 81%. Conclusions: Sequential HDC with GemDMC–ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the anticipated results. Addition of BEV increases toxicity but not tumor control. Clinical trial information: NCT00936936. [Table: see text]
Integrated biomarker analysis for 412 renal cell cancer (RCC) patients (pts) treated on the phase 3 COMPARZ trial: Correlating common mutation events in PBRM1 and BAP1 with angiogenesis expression signatures and outcomes on tyrosine kinase inhibitor (TKI) therapy.
Authors: Voss Martin Henner , Kuo Fengshen , Chen David , Marker Mahtab , Patel Parul , Redzematovic Almedina , Riaz Nadeem , Chan Timothy A. , Choueiri Toni K. , Hsieh James , Motzer Robert J. , Hakimi A. Ari 
Published: September 2018

4523 Background: In RCC biology mutations in PBRM1 and BAP1are largely non-overlapping and collectively affect >50% of pts. How and through which mechanism they influence disease kinetics is poorly understood. Sunitinib and pazopanib inhibit angiogenesis, a key driver in RCC. We analyzed mutation status and gene expression signatures in a large cohort of pts receiving first-line sunitinib or pazopanib on the COMPARZ trial. Methods: RNA and DNA were extracted from archival tissue. PBRM1 and BAP1mutation status was determined via a custom exon-targeted platform. Transcriptome analysis was done using Affymetrix GeneChip HTA 2.0. We computed a 43 gene angiogenesis expression score with previously reported dynamic response to VEGF-directed therapy in xenograft models (Masiero, Cancer Cell 2013). DNA and RNA findings were correlated with clinical outcomes using parametric and non-parametric tests. Results: 412 pts contributed tumor RNA, 377 pts DNA; 362 pts both. PBRM1 and BAP1 were mutated (MT) in 44% and 15% of pts, respectively. Presence of PBRM1mutations correlated with superior PFS (p=0.008) and OS (p=0.004) on log-rank test, and PBRM1 mutation rate was higher in pts with objective response than those with progression (Fisher’s Exact, p=0.012). In contrast, pts with MT BAP1 had inferior OS compared to those whose were wild type (WT) (log-rank, p=0.012). Across all 412 pts angiogenesis score associated favorably with outcome on uni and multivariate analyses (Cox proportional hazard regression, OS p<0.001 and PFS p<0.005); scores were higher in 123 pts with objective response than 81 pts with progression as best response (Mann-Whitney, p=0.009). Angiogenesis scores were higher in PBRM1 MT vs WT patients (Mann-Whitney, p<0.001), but lower in BAP1 MT vs WT patients (p<0.001). Conclusions: PBRM1 and BAP1 mutations appear to have opposite effects in advanced RCC. Loss of PBRM1 enhances the pro-angiogenic microenvironment of RCC with favorable effects on response to TKI; BAP1 loss associates with decreased angiogenic signaling and adverse outcome to TKI. Clinical trial information: NCT00720941.