bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maintenance sunitinib (MS) or observation (O) in metastatic pancreatic adenocarcinoma (MPA): Clinical and translational results of a phase II randomized trial (NCT00967603).
Authors: Reni Michele , Cereda Stefano , Milella Michele , Novarino Anna , Passardi Alessandro , Mambrini Andrea , Di Lucca Giuseppe , Ferrari Laura , Belli Carmen , Danova Marco , Bergamo Francesca , Franceschi Enrico , Rovati Bianca , Fugazza Clara , Ceraulo Domenica , Villa Eugenio 
Published: March 2020

4017 Background: Combination chemotherapy (CT) prolonged progression-free survival at 6 months (PFS6) of patients (pts) with MPA from <20% with gemcitabine (GEM) to >50%. To prolong CT over 6 months has unproven benefit and is hampered by cumulative toxicity. This open-label, randomised, multi-centre phase II trial explored the role of MS in pts with MPA without progressive disease (PD) after CT, using an O group as calibration arm. The role of circulating endothelial cells (CEC) as biomarker of MS activity was explored. Methods: Adult pts with pathologic diagnosis of MPA, performance status (PS) >50%, without radiological PD or CA19.9 raise >20% after 6 months of CT were stratified based on PS and previous CT and randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum of 6 months (arm B). Primary endpoint was PFS6. Sample size (H0 10%; H1 30%; a .10; b .10) was 26 pts per arm and MS had to be considered of interest with >5 pts PFS6. CEC were evaluated by flow cytofluorometry on a baseline peripheral blood sample. Results: 56 pts (29 arm A; 27 arm B) were enrolled. One arm B pt had kidney cancer and was excluded. Pts characteristics were (A/B): median age 64/61 years; median PS 90/100; median CA19.9 45/32; previous CT: GEM 3/3; combination CT 26/22. Main grade 3-4 toxicity in arm B was 15% neutropenia; 12% thrombocytopenia and hand-foot syndrome, 8% diarrhea. Second line CT was given to 76% of pts in both arms. One arm A (3%) and 6 arm B pts (23%; p=.01) were PFS6; 2y overall survival (OS) was 4% and 25% (p=.09). Blood sample for CEC analysis was available for 46 of 55 pts (84%). In arm A, median PFS was longer for pts with CEC number <30 (lower terzile group) when compared to >30 (2.9 versus 1.9 months; p.08). MS significantly increased PFS in CEC >30 group (3.4 months; p=.01). No PFS difference between arms was observed in <30 group (2.3 months). Conclusions: This is the first randomized trial on maintenance therapy in MPA. In arm B, the primary endpoint was fulfilled and 2y OS was remarkably high, suggesting that MS may have a role in pts with MPA. The number of CEC may be useful to predict benefit from MS.
FOLFIRI.3 (CPT-11 plus folinic acid plus 5-FU) alternating with gemcitabine or gemcitabine (G) alone in patients (pts) with previously untreated metastatic pancreatic adenocarcinoma (MPA): Results of the randomized multicenter AGEO phase II trial FIRGEM.
Authors: Trouilloud Isabelle , Dupont-Gossard Anne Claire , Artru Pascal , Lecomte Thierry , Gauthier Mélanie , Aparicio Thomas , Thirot-Bidault Anne , Malka David , Lobry Celine , Asnacios Amani , Lacombe Sophie , Fein Francine , Fanica Daniela , Dubreuil Olivier , Marthey Lysiane , Zaanan Aziz , Bonnetain Franck , Taïeb Julien 
Published: March 2020

4018 Background: CPT-11 showed modest activity and tolerability in MPA. We developed a new strategy to improve efficacy and tolerability of CPT-11 based regimen in MPA pts. Methods: Chemotherapy-naive pts with histologically proven MPA, bilirubin levels < 1.5 ULN and performance status (PS) 0-1 were randomized in a phase II trial to receive either FOLFIRI.3 (CPT-11 90 mg/m2 as a 60-min infusion on day (D) 1, leucovorin 400 mg/m2 as a 2-hr infusion on day 1, followed by 5-FU 2000 mg/m2 as a 46-hr infusion and CPT-11 90 mg/m2, repeated on D3, at the end of the 5-FU infusion, every 2 weeks) for 2 months alternarting with G (1000 mg/m² at a fixed dose rate of 10 mg/m²/min on D1, D8, D15, D29, D36 and D43) for 2 months (arm A) or G alone (arm B). Using Fleming design the primary end point was rate of progression free survival (PFS) at 6 months from (H0) 25% over (H1) 45% needing to include 49 pts/arm. Results: Between 2007 and 2011, 98 pts were enrolled (males: 59, median age: 62 years, PS 0: 32%). Median follow-up was 23 months. Grade 3-4 toxicities per pts (%) in arm A/B were diarrhea 13/0, nausea-vomiting 11/4, neutropenia 51/25 and febrile neutropenia 4/0. No toxic death occurred. Response rate were 40 and 11% as disease control rate (CR+PR+SD) were 73 and 52% in arm A and B, respectively. The primary endpoint of the trial was met with rate of PFS at 6 months of 48% (95% CI: 33-63) in arm A while in arm B PFS was 30% (95% CI: 17 - 44). One year PFS was 23% (95%CI: 11.5-36) and 11% (95%CI: 4-21), respectively. Conclusions: FIRGEM strategy is feasible and efficient with a manageable toxicity profile in good condition pts with MPA. A phase III trial comparing this strategy with the FOLFIRINOX triplet therapy focusing on quality of life should now be performed.
Baseline albumin (b-alb) as a potential predictive biomarker for the efficacy of bevacizumab (B) therapy (tx) in patients (pts) with advanced pancreas cancer (APCA): A comparative analysis.
Authors: Martin Ludmila Katherine , Geyer Susan Michelle , Bingman Anissa , Zalupski Mark M. , Bekaii-Saab Tanios S. 
Published: March 2020

4039 Background: Phase III studies of B in unselected pts with APCA have demonstrated no improvement in outcome. Recent data suggest certain subsets of APCA patients may benefit from B. Lower b- alb results in a 15-20% increased rate of B clearance that may decrease exposure to B. The resulting clinical implications are not well understood. We evaluated the potential predictive and prognostic role of b-alb in pts with APCA receiving gemcitabine (G)-based tx with or without B. Methods: Relevant data were collected from 3 prospective phase II studies of G-based tx. Pts were grouped according to exposure to B (Gr 1) or no B (Gr 2) and by b-alb < 3.4 g/dL (< LLN) or > 3.4 g/dL (>LLN). Univariate and multivariate analyses of clinical outcome (OS, TTP) were conducted for each group and all pts. Results: 100 pts (46M, 54F) with median age 63 (range 28-82) were included. 94% had stage IV. Median b-alb was similar in both groups. Clinical outcomes by alb are outlined in the table. In Gr 1 but not Gr 2, b-alb > 3.4 g/dL was significantly associated with improved OS and TTP. For pts with b-alb >3.4 g/dL, maintenance of alb >3.4 g/dL throughout tx was significantly associated with improved survival in Gr 1 but not Gr 2. Multivariate analysis revealed significant association between alb > 3.4 and OS regardless of B status (p=0.004) although this was strongly influenced by the survival differential in Gr 1. Conclusions: APCA pts with b-alb > 3.4 g/dL appear to derive significant benefit from B and this benefit is most pronounced in pts who maintain alb > 3.4 g/dL throughout B tx. This finding was not observed in pts treated without B. b-alb > 3.4 g/dL including maintenance of alb > 3.4 g/dL during B tx may predict for improved efficacy of B in APCA. These findings require further investigation in larger prospective trials. [Table: see text]
Development of the SP120 rabbit monoclonal antibody for determining hENT1 status and predicting response to gemcitabine in pancreatic ductal adenocarcinoma.
Authors: Boeck Stefan Hubert , Raponi Mitch , Richardson William , Towne Penny , Isaacson Jeffrey D. , Ranger-Moore Jim , Powell Eric , Clements June , Feng Janine D. , McElhinny Abigail , Ormanns Steffen , Kirchner Thomas , Regine William , Winter Kathryn A. , Ansari Daniel , Rolfe Lindsey , Allen Andrew R. , Andersson Roland , Heinemann Volker , Dicker Adam P. 
Published: March 2020

4041 Background: Human equilibrative nucleoside transporter 1 (hENT1) is the primary membrane channel through which gemcitabine (Gem) enters pancreatic tumor cells. Patients whose tumors have low expression of hENT1 may derive little benefit from Gem therapy. Methods: We have developed and analytically validated a rabbit monoclonal antibody, SP120, immunohistochemistry (IHC) in vitro diagnostic (IVD) assay, used on the VENTANA BenchMark ULTRA automated slide staining platform, for assessing hENT1 expression in pancreatic adenocarcinoma. Results: SP120 was shown to be sensitive and specific for membrane expression of hENT1 with variable expression demonstrated across a panel of primary pancreatic adenocarcinoma samples. Using retrospectively collected primary tumor samples (n = 201) from a randomized controlled clinical adjuvant trial (RTOG 97-04), we developed and verified a hENT1 scoring algorithm and cut-off for identifying patients least likely to benefit from Gem (hENT1-low). We confirmed the predictive value of the hENT1 assay by showing there was no association with clinical outcome in the 5FU-treated control group. The distribution of hENT1 expression was similar between these samples and an independent set of 130 pancreatic adenocarcinoma specimens from the AIO-PK0104 study (77 were confirmed metastatic biopsies). Importantly, 100% concordance in hENT1 status (high vs. low) was demonstrated between 16 primary tumors and paired, contemporaneous metastatic lesions. Overall, using this cut-off, approximately two thirds of pancreatic tumors displayed low-hENT1 expression across the different data sets (n = 363). Conclusions: The hENT1 IHC IVD has been developed and is being used in a pivotal trial of a novel lipid-conjugated Gem (CO-101, which enters tumor cells independently of hENT1), vs. Gem in hENT1-low pancreatic cancer patients (NCT01124786). This study is the first prospective test of the hypothesis that gemcitabine is not active in tumors with low hENT1 expression.
Phase I/II study of 90Y-clivatuzumab tetraxetan (90Y-hPAM4) combined with gemcitabine (Gem) in advanced pancreatic cancer (APC): Final results.
Authors: Ocean Allyson J. , Guarino Michael J. , Pennington Kenneth L. , Springett Gregory M. , Gulec Seza A , Bekaii-Saab Tanios S. , Montero Alberto J. , Mitchell Edith P. , Kauh John S. , Sung Max W. , Gold David V. , Horne Heather , Wegener William A. , Goldenberg David M. 
Published: March 2020

4043 Background: A Phase I/II trial evaluated single and repeated cycles of fractionated radioimmunotherapy (RAIT) with 90Y-labeled humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC. Methods: Cycles of Gem once-weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4 were repeated until progression, withdrawal or unacceptable toxicity. In Part I, 90Y doses were escalated with Gem fixed at 200 mg/m2. In Part II, Gem was increased up to 1000 mg/m2, with 90Y fixed at 12 mCi/m2 for cycle 1 and lowered for retreatment. Results: Of 100 pts entered, 10 withdrew early, while 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 6.5, 9, 12, or 15 mCi/m2, with the same cycle repeated 1-3 times in 13 pts. By CT-RECIST criteria, 6 pts (16%) had PRs and 16 (42%) had stabilization as best response (58% disease control). After cycle 1, 52% (13/25) with PET-avid images had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median OS was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived ≥1 yr.], and with improved efficacy at higher 90Y doses. NCI-CTCv3 Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). In Part II, 52 pts received increased Gem without evidence of improved efficacy, while 13 pts were retreated with more acceptable toxicity at lower 90Y doses of 6.5 or 9 mCi/m2. Treatment was well tolerated with no infusion reactions. Infections requiring IV antibiotics occurred at a low rate and responded to appropriate coverage (bacteremia/sepsis, 7%; febrile neutropenia, 4%; ascending cholangitis, 3%; pneumonia, 2%; others 1%). One case of bleeding occurred, due to rectal tumor invasion. Anecdotal reports of good performance and decreased pain medication requirements require further validation. Conclusions: Fractionated RAIT with 90Y-hPAM4 combined with low-dose 200 mg/m2 GEM appears promising as a treatment regimen for APC. Hematologic toxicity was dose limiting. A 90Y-hPAM4 dose of 12 mCi/m2 for cycle 1 and 6.5 mCi/m2 for cycle 2 have been selected as suitable for further clinical development in the first-line setting.
A phase IB study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: An Academic GI Cancer Consortium (AGICC) study.
Authors: Leichman Lawrence P. , O'Neil Bert H. , Berlin Jordan , Weekes Colin D. , Ames Patricia , McKinley Marti , Davies Angela M. , Cohen Steven J. ,   Academic Gastrointestinal Cancer Consortium (AGICC)
Published: March 2020

4052 Background: The combination of gemcitabine (gem) and nab-paclitaxel (nab) has demonstrated promising activity in advanced pancreatic cancer. Erlotinib (erl) adds modest benefit to gemcitabine. We initiated this phase IB study to evaluate the safety of the three drug combination and obtain preliminary evidence of efficacy. Methods: Patients (pts) with previously untreated locally advanced (la) or metastatic (met) pancreatic cancer with ECOG PS 0-1 were treated with gem and nab IV days 1,8,15 and once daily erl days 1-28 Q28 days. Standard 3+3 design was used with dose levels (DL) (gem,nab,erl): 1(1,000, 125, 100), -1 (1,000, 100, 100), -2 (1,000, 75, 100), -3 (1,000,75,75). CT scans were obtained Q 2 cycles. DLT was defined as ≥grade (gr) 3 non-hematologic, febrile neutropenia, ≥gr 3 thrombocytopenia, or missing ≥2 doses gem, nab or >5 doses erl within first cycle (C). Results: Nineteen pts were enrolled and completed a total of 62 cycles (range 0-11). Pt characteristics: M/F (9/10), White/Hispanic/AA (15/2/2), median age 63 (range 54-78), ECOG PS 1=11, met/la (12/7). In DL1, 1/3 pts had gr3 dehydration in C 2 and 1/3 had gr 4 neutropenia/sepsis in C 4. Although not formally DLT, 3 more pts were enrolled. Of the next 3 pts, 1 DLT of gr 3 diarrhea/gr 4 neutropenia in C 1 was noted and 1 other pt DC’d therapy for neutropenia after 2 cycles. Of 3 pts in DL -1, 2 DLTs (gr 3 optic neuropathy, too many missed doses) were observed. Of 3 pts in DL -2, 2/3 had DLT (gr 3 esophagitis/fatigue and gr 3 transaminitis). Of 6 evaluable pts in DL -3, no DLTs were observed. Most common gr 3/4 toxicities were neutropenia (9), dehydration, thrombocytopenia (3 each), and hypotension (2). Of 13 pts evaluable for response, 6 had partial response (46%), 5 stable disease (38%), and 2 progressive disease (15%) as best response. Median PFS and OS of entire cohort were 5.3 and 9.3 months respectively. Conclusions: The combination of erlotinib with gemcitabine and nab-paclitaxel is not tolerable at standard single agent dosing of all drugs. However, significant clinical activity was noted, even at DL -3. Further study of the combination will need to incorporate reduced dosing.
M402, a heparan sulfate mimetic and novel candidate for the treatment of pancreatic cancer.
Authors: Schultes Birgit Corinna , Lolkema Martijn P.J.K. , Chu Chia Lin , Zhou He , Long Alison , Lockley Michelle , Avery William , Kurtagic Elma , Galcheva-Gargova Zoya , Miller Paul , Duffner Jay , Maschek Birgit J , Jarlenski Donna , Tuveson David A. , Roach Jim , Venkataraman Ganesh , Kishimoto Takashi K , Flaherty Keith T. 
Published: March 2020

4056 Background: Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors (such as HGF, HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. We have rationally designed a heparan sulfate mimetic, M402, which has been previously shown to affect tumor progression and metastasis through disruption of multiple pathways. We hypothesized that M402 could modulate tumor-stroma interactions and enhance the efficacy of gemcitabine, and evaluated its efficacy in two preclinical models. Methods: A genetically engineered mouse model (GEMM; KrasLSLG12D p53LSLR172H) featuring spontaneous pancreatic tumor formation and metastasis assessed M402’s effect on tumorigenesis and metastasis. The orthotopic Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, a fibrotic response that hinders effective delivery of chemotherapeutics, via inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate cells. In both models, M402 was studied as monotherapy and with gemcitabine. Results: In the GEMM, M402 significantly prolonged survival in combination with gemcitabine while each monotherapy showed modest efficacy. M402, alone and in combination, also reduced metastases and local invasion and inhibited epithelial-to-mesenchymal transition. In the Capan-2 model, gemcitabine was increasingly less effective as desmoplasia progressed over time. The addition of M402 to gemcitabine increased its efficacy with respect to primary tumor burden. Metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy with dose-dependency, which correlated with reduced SHH signaling. Conclusions: M402 can modulate tumor-stroma interactions involved in the metastatic and desmoplastic pathways in two pancreatic cancer models supporting the translation of these findings into a clinical study. A first-in-human study is planned that will evaluate the safety, pharmacokinetics, efficacy, and biomarker profiles of escalating M402 doses in combination with gemcitabine in patients with metastatic pancreatic cancer.
Activity of front-line FOLFIRINOX (FFX) in stage III/IV pancreatic adenocarcinoma (PC) at Memorial Sloan-Kettering Cancer Center (MSKCC).
Authors: Lowery Maeve A , Yu Kenneth H. , Adel Nelly G. , Apollo Arlyn J. , Boyar Michelle S. , Caron Philip , Ilson David , Segal Neil Howard , Janjigian Yelena Yuriy , Reidy Diane Lauren , Abou-Alfa Ghassan K. , O'Reilly Eileen Mary 
Published: March 2020

4057 Background: The PRODIGE/ACCORD trial recently established FFX as a treatment option for good performance status (PS) pts with stage IV PC (Conroy et al, NEJM 2011). We evaluated the activity and toxicity associated with FFX therapy in pts with advanced PC treated at MSKCC outside of a clinical trial. Methods: 80patients (pts) treated withFFX as 1st-line therapyat MSKCC between 07/1/10 and 12/30/11, were identified from an institutional database (prior IRB approval). Records were reviewed for demographic, treatment, toxcity, and response data. Results: 61 and 19 pts received FFX for stage IV and III PAC respectively. Demographics and outcomes are summarized in the table. Median starting dose of FFX was 80% of that used in the PRODIGE/ACCORD trial. Median overall survival (OS) was 12.5 months (mo) (95% CI 9.5–15.5) in pts treated with 1st line FFX for stage IV PAC and 13.7 mo (95% CI 11.3–15.8) in pts with stage III PAC. 68% of pts with stage IV PAC who discontinued FFX for disease progression (PD) or toxicity received 2nd-line gemcitabine-based therapy. Conclusions: We observed activity and acceptable toxicity in carefully selected patients treated with FFX at 80% dose intensity and routine use of growth factor support. Treatment with FFX resulted in median OS of > 1 year in pts with stage IV PAC and is an active front-line regimen. [Table: see text]
Benefits of platinum-based chemotherapy (Pt-chemo) in pancreatic adenocarcinoma (PC) associated with BRCA mutations: A translational case series.
Authors: Faluyi Olusola Olusesan , Tran Ben , Kanji Zaheer , Moore Sara , Zogopoulos George , Borgida Ayelet , Holter Spring , Gallinger Steven , Moore Malcolm J. 
Published: March 2020

4058 Background: The prognosis of PC is poor with limited response to standard chemotherapy. Prior randomized studies of cisplatin and gemcitabine in PC demonstrated no additional benefit over gemcitabine alone. Preclinical data and case reports suggest that BRCA mutant PC may have increased sensitivity to Pt-chemo. Our case series characterizes the benefits of Pt-chemo in germline BRCA mutant PC. Methods: Patients with PC and germline BRCA mutations were identified using the Ontario Pancreatic Cancer Study and Pharmacy databases. Review of clinical records provided demographic, treatment and survival data. Radiology review assessed responses to chemotherapy. RNA was extracted from tumor samples for gene expression studies using a panel of DNA repair genes and Nanostring technology. BRCA loss of heterozygosity (LOH) was also investigated. Results: We identified 14 PC patients with BRCA mutations (8 BRCA2, 6 BRCA1). 11 of these had metastatic disease of which 5 received Pt-chemo. Of the 5 treated with Pt-chemo, there were 3 partial responses (PR) and 2 complete responses (CR) using Recist criteria. For the remaining 6 not treated with Pt-chemo, there was 1 PR with gemcitabine. Additionally, two patients with locally advanced disease at diagnosis became resectable following Pt-chemo. Overall survival was superior for patients receiving Pt-chemo (33.0±25.6 vs 7.3±4.5 months; p=0.04). Gene expression and LOH results will be presented. Conclusions: Responses and survival associated with Pt-chemo observed in our case series of BRCA mutant PC adds to existing data supporting the use of Pt-chemo in this subgroup. Despite the low (2 to 5%) prevalence of BRCA mutations in PC, the benefits gained from personalizing treatment using Pt-chemo supports BRCA testing in selected patients.
Choice of chemotherapy in the treatment of metastatic squamous cell carcinoma of the anal canal.
Authors: Eng Cathy , Rogers Jane , Chang George J. , You Y. Nancy , Das Prajnan , Rodriguez-Bigas Miguel A. , Ohinata Aki , Phillips Jonathan , Abbruzzese James L. , Wolff Robert A. 
Published: March 2020

4060 Background: Metastatic squamous cell carcinoma (SCCA) of the anal canal is an uncommon malignancy with no standard approach. The reported median overall survival (OS) is 9-12 months (M) following 5-FU + cisplatin (FC)-based therapy. The aim of this study is to evaluate first-line chemotherapy approaches in this patient (pt) population. Methods: A retrospective analysis was conducted of 428 pts with metastatic SCCA of the anal canal identified from the MDACC tumor registry between 1/1/2000 - 5/31/2011. Electronic medical records were reviewed for histology, date of diagnosis and/or recurrence, site of metastasis, type of therapy provided, response rate (RR), progression-free survival (PFS), OS, and lines of salvage therapy. All eligible pts were required to be treatment-naïve for metastatic disease and have radiographic imaging at MDACC. Waiver of informed consent was obtained. Results: 99 pts fulfilled all criteria; 10 were lost to follow-up; 12 did not initiate chemotherapy. 77 pts were evaluable; M: F = 20:57; median age = 55 years (range: 37 - 82); HIV(+) = 5% (4/77); prior chemoXRT with curative intent: 70% (54/77), complete response (CR): 87% (47/54), median time to development of metastatic disease =17M. 29% (22/77) presented with metastatic disease. Sites of disease included distant lymph nodes (41%); liver (45 %); lung (25%); bone (15%); and brain (8%). The median follow up was 37M. 73% (56/77) of patients were treated with platinum-based therapy; 51% (n=39) received FC and 22% (n= 17) received carboplatin + paclitaxel (CP). The median PFS was 6M; FC trended better than CP for PFS (7M vs. 5M, p<0.067). The overall median OS = 29M. 40% (31/77) of pts received neoadjuvant first-line therapy followed by metastasectomy (68%), XRT (26%), or both (6%); resulting in a median OS = 35M. Conclusions: Metastatic SCCA of the anal canal is a malignancy in which 5-FU+cisplatin is a commonly used regimen. Our analysis suggests FC results in improved PFS over CP but is underpowered supporting further analysis. The short median PFS with front-line chemotherapy, and yet longer OS reflects the challenges in treating this patient population and the importance of multidisciplinary management in select cases.