bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A multi-disease phase I study.
Authors: Chau Ian , Bendell Johanna C. , Calvo Emiliano , Santana-Davila Rafael , Arkenau Hendrik-Tobias , Mi Gu , Jin Jin , Rege Jessicca , Ferry David , Herbst Roy S. , Fuchs Charles S. 
Published: September 2018

4046 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: Ongoing, multi-cohort, phase 1a/b trial enrolled pts with G/GEJ adenocarcinoma, measurable disease, ECOG PS 0-1, previously treated (Cohorts A and B) or untreated (Cohort A2) for advanced disease. PD-L1 was positive (tumor proportion score [TPS] ≥1%) or negative (TPS < 1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. R was administered at 8 mg/kg on Days 1&8 (Cohorts A and A2) or 10 mg/kg on Day 1 (Cohort B) with P 200 mg on Day 1 q3W. Primary objective- assess safety and tolerability of R+P; preliminary efficacy will be examined. Results: As of 21-Nov-2016, 41 previously treated G/GEJ pts were enrolled. Median age was 58 y, 76% male, 66% had ECOG PS of 1, 46% were PD-L1+, and 59% received study treatment as third or subsequent line. Median duration on therapy was 2.8 mo and 4.1 mo for A and B, respectively. Overall, 33 (80%) pts experienced a treatment-related AE (TRAE) and similar between cohorts A and B. Ten (24%) pts experienced grade 3-4 TRAEs, most commonly colitis (7%) and hypertension (7%). One treatment-related death occurred (pneumonitis and pulmonary sepsis). Responses occurred in 3 (7%) pts with 46% disease control rate (DCR). Progression-free and overall survival rates at 6 mo were 22.4 % (95% CI, 9.8-38.0) and 51.2% (95% CI, 33.9-66.1) respectively. Nine (22%) pts remain on treatment. Eighteen of 25 planned treatment naïve G/GEJ pts were enrolled. Median age was 70 yr, 83% male, 56% had ECOG PS of 0, and PD-L1 status is pending. Median duration on therapy was 2.1 mo. Twelve (67%) pts experienced a TRAE. Grade 3 TRAEs occurred in 5 (28%) pts (hypertension [n = 3], diarrhea, and acute kidney injury). No grade 4-5 events occurred. Preliminary efficacy data showed 3 (17%) pts responded with 50% DCR. Median PFS is immature and 89% of pts remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated encouraging antitumor activity in treatment naïve and previously treatedadvanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.
Meaningful changes in quality of life (QoL) in patients with gastric cancer: Exploratory analyses from RAINBOW and REGARD.
Authors: Chau Ian , Fuchs Charles S. , Ohtsu Atsushi , Liepa Astra M. , Cui Zhanglin Lin , Hsu Yanzhi , Al-Batran Salah-Eddin 
Published: September 2018

4047 Background: EORTC QLQ-C30 is a well-established QoL instrument for cancer patients (pts), but there is limited information for gastric cancer. To identify priority domains and describe meaningful changes, we explored data from 2 randomized ramucirumab phase 3 trials in pts with previously treated gastric or gastroesophageal junction cancer. Methods: Pts completed QLQ-C30 v3.0 at baseline and Q6W while on study. Data from all treatment arms were pooled (N=1020). Changes from baseline in QoL domains were compared by best overall response (BOR) and ECOG performance status (PS) using analysis of covariance. Odds ratios (ORs) for BOR and PS outcome groups per QoL unit (point) change were estimated by cumulative logit regression modeling, with OR≤0.85 considered meaningful. Results: Changes from baseline in QoL domains were significantly associated with BOR and PS outcomes (Table). ORs for BOR and PS outcomes for these domains were statistically significant (p<0.05) and suggested changes of 10-15 points predict clinical outcomes. Conclusions: QLQ-C30 is sensitive to clinical outcomes in advanced gastric cancer patients, particularly in global QoL, functional status and disease symptoms of fatigue, pain, and appetite loss. These analyses can inform trial designs and interpretation of results. [Table: see text]
Circulating tumor DNA analysis for outcome prediction in localized esophageal cancer.
Authors: Azad Tej D. , Chaudhuri Aadel , Newman Aaron M. , Stehr Henning , Schroers-Martin Joseph , Chabon Jacob J. , Fang Penny , Qiao Yawei , Liao Zhongxing X. , Komaki Ritsuko , Alizadeh Ash A. , Lin Steven H. , Diehn Maximilian 
Published: September 2018

4055 Background: Blood-based biomarkers are not used in routine clinical practice in patients with esophageal carcinomas (ECs). Circulating tumor DNA (ctDNA) is an attractive biomarker that could be applied to ECs. We performed a study to explore pre- and post-treatment ctDNA analysis using the next generation sequencing-based CAPP-Seq method as a prognostic biomarker for localized EC. Methods: We prospectively enrolled 29 patients with localized EC treated with chemoradiotherapy (CRT) between June 2011 and October 2015. 12 (43%) patients were treated with CRT alone and 17 (57%) were treated with CRT followed by esophagectomy. Our cohort included patients with stage IB (1; 3.4%), II (7; 24.1%), and III (21; 72.4%) disease. Eight (27.6%) harbored squamous cell carcinoma (SCC) and 21 (72.4%) adenocarcinoma (AC). All patients received pre-treatment evaluation by thoracic CT, PET/CT, and esophagoduodenoscopy. ctDNA levels were quantitated in pre-treatment and post-treatment plasma samples using CAPP-Seq. Results: Median follow-up time was 21 months. We detected ctDNA pre-treatment in 72.4% of cases (N = 21) with a median concentration of 2.69 haploid genome equivalents per mL (hGE/mL; range 0.34-107.3). Pre-treatment ctDNA concentrations were strongly correlated with metabolic tumor volumes (MTV; R2= 0.74; p = 1.7e-07) and were significantly higher in SCC than AC patients (28.2 vs. 2.1 mean hGE/mL; p = 0.002). Overall survival (OS) at 2 years for pretreatment ctDNA+ vs. ctDNA- patients was 47% vs. 86% (HR = 6.0; 95% CI = 0.74-49.2; p < 0.05) and trended toward significance when accounting for stage, histology, and age (p = 0.09). A single post-treatment plasma sample was collected within 3 months of treatment and was available for 19 patients. Post-treatment ctDNA was detected in 3 (15.7%) patients with a median concentration of 11.5 hGE/mL (range 2.2–11.9). Post-treatment ctDNA detection was strongly predictive of poor event-free survival (p < 0.0001) and time to distant metastasis (p < 0.0001). Conclusions: Our data suggest that pre- and post-treatment ctDNA levels may be prognostic for patients with localized EC and could potentially guide risk-adapted adjuvant therapy approaches.
Phase II study of BKM120 in patients with advanced esophageal squamous cell carcinoma (EPOC1303).
Authors: Kato Ken , Doi Toshihiko , Kojima Takashi , Hara Hiroki , Takahashi Shunji , Muro Kei , Nishina Tomohiro , Wakabayashi Masashi , Nomura Shogo , Sato Akihiro , Ohtsu Atsushi 
Published: September 2018

4069 Background: BKM120 is an oral pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, which showed promising activity in breast cancer and squamous cell carcinoma of head and neck. We prospectively investigated clinical activity, safety and biomarkers of BKM120 in advanced esophagus squamous cell carcinoma (ESCC). Methods: We conducted a multicenter phase II study of BKM120 monotherapy in patients with pretreated advanced ESCC. All the patients had a treatment history of fluoropyrimidine and platinum. BKM120 of 100 mg/day was orally administered in a 28-day cycle. A primary end-point was a disease control rate (DCR). Using Simon’s minimax two-stage design, total of 41 patients were required for primary analysis (promising DCR of 60%, non-promising one of 40%, one-sided alpha level of 10% and power of 90%). The response rate (RR), progression-free survival (PFS), overall survival (OS), and safety were also evaluated as secondary endpoints. Tumor samples for all the patients were required for gene alternation analysis in comprehensive genomic profiling assay (FoundationOne). Results: A total of 42 patients (median age, 62.5 years; performance status 0/1 = 28/14) were enrolled. One ineligible patient was excluded from primary analysis. Nineteen and two patients had SD and unconfirmed PR. DCR was 51.2% (95% CI, 35.1% to 67.1%), which met the primary endpoint of the study. Median PFS and OS was 2.0 months (95% CI, 1.8 to 3.2 months) and 9.0 months (95% CI, 6.4 to 11.7 months), respectively. Common grade 3 or 4 adverse events were anorexia, rash, hyponatremia, lipase increased, and abnormal hepatic function (including increased transaminase levels), which were profiles similar to previous studies of BKM120 monotherapy. No treatment-related deaths occurred. Further analyses of the gene alternation are ongoing. Conclusions: BKM120 monotherapy showed promising efficacy and mild toxicity profile in patients with pretreated advanced ESCC. BKM120 is worth evaluating in a further confirmatory study. Result of subgroup analyses with respect to gene alternation status will be presented. Clinical trial information: UMIN000011217.
A phase I study of DKN-01 (D), an anti-DKK1 monoclonal antibody, in combination with gemcitabine (G) and cisplatin (C) in patients (pts) for first-line therapy with advanced biliary tract cancer (BTC).
Authors: Eads Jennifer Rachel , Stein Stacey , El-Khoueiry Anthony B. , Manji Gulam Abbas , Abrams Thomas Adam , Khorana Alok A. , Miksad Rebecca A. , Mahalingam Devalingam , Sirard Cynthia A. , Zhu Andrew X. , Goyal Lipika 
Published: September 2018

4075 Background: DKK1 is a secreted modulator of Wnt signaling often expressed in tumors, including BTC. DKK1 expression in BTC is associated with advanced stage and shorter survival. Depletion of DKK1 has efficacy in BTC xenograft models, inhibits cell invasion, and decreases MMP9 and VEGF-C expression, known promoters of metastasis and angiogenesis. D is a humanized monoclonal antibody against DKK1. This study evaluated the safety and efficacy of D in combination with GC in pts with advanced BTC. Methods: In Part A, pts received D at either 150 or 300 mg (and 300 mg D in Part B expansion) with 1000 mg/m2 G and 25 mg/m2 C on days 1 and 8 of each 21-day cycle. Response assessed every 2 cycles using RECISTv1.1. Results: 27 pts were enrolled; 4 dosed at 150 mg and 23 dosed at 300 mg. Median age: 65; Female: 74%; White: 85%. Gallbladder cancer 37%, intrahepatic cholangiocarcinoma 59%. 3 pts had prior G: 2 pts with adjuvant G; 1 pt with 2 prior regimens. Median number of cycles with D: 8 (range 1, 17). Median duration on study 6.8 mos; 8 pts still on therapy. No dose limiting toxicities or D-related serious adverse events have been observed. 24 pts (89%) had grade 3/4 treatment emergent adverse events (TEAEs); events in ≥ 3 pts include: neutropenia (n = 19), leukopenia (n = 9), thrombocytopenia (n = 9), hyperbilirubinemia (n = 6), anemia (n = 5), AST/ALT elevation (n = 4), and ALP elevation, bacteremia, hypertension, and hyponatremia (n = 3 each). The MTD of D + GC was 300 mg. At the MTD; 7 pts had a confirmed partial response (PR), 14 pts had stable disease > 6 weeks, and 1 pt had progressive disease. Both overall and MTD median PFS were 9.4 mos (95% CI 4.6, NE); median overall survival and duration of response were not reached. Conclusions: The addition of D (300 mg) to GC demonstrated a preliminary PFS of 9.4 mos and disease control rate of 96% with a 32% PR rate in pts with BTC. D + GC is well tolerated with no new emerging safety trends. Clinical trial information: NCT02375880.
Final progression-free survival (PFS) analyses for lanreotide autogel/depot 120 mg in metastatic enteropancreatic neuroendocrine tumors (NETs): The CLARINET extension study.
Authors: Wolin Edward M. , Pavel Marianne , Cwikla Jaroslaw B , Phan Alexandria T. , Raderer Markus , Sedlackova Eva , Cadiot Guillaume , Capdevila Jaume , Wall Lucy , Rindi Guido , Lombard-Bohas Catherine , Liyanage Nilani , Thanh Xuan Mai Truong , Ruszniewski Philippe , Caplin Martyn E. ,   CLARINET Investigators
Published: September 2018

4089 Background: In the CLARINET core study, lanreotide Autogel (LAN) 120 mg deep sc monthly significantly improved PFS vs PBO in metastatic grade-1/2 enteropancreatic NETs. An interim analysis of patients with stable disease (SD) in the core study continuing LAN in the open-label extension (OLE, of which safety was primary objective) showed continued antitumor effects. Here, we report final LAN PFS analyses for subgroups according to tumor origin and prior therapy. Methods: In the core study, patients with metastatic well/moderately differentiated non-functioning (N-F) enteropancreatic NETs, Ki-67 <10%, no prior somatostatin-analog treatment and no other prior medical therapies in the previous 6 months were randomized to LAN 120 mg (n=101) or PBO (n=103) for 96 weeks or until death/progressive disease (PD; RECIST 1.0). Patients with SD receiving LAN and any patient receiving PBO could enter a single-arm (LAN) OLE (NCT00842348). Main efficacy endpoint: PFS (time from core-study randomization to death/PD) for core-study intent-to-treat population from Kaplan–Meier survival analysis. Here, PFS was analyzed in subgroups of LAN–LAN patients. Results: OLE final population comprised 89 patients (LAN–LAN 42 [41 with SD]; PBO–LAN 47 [15 with SD]); 38% had pancreatic and 38% midgut NETs. During the OLE, 40% continuing LAN vs 47% switched to LAN had treatment-related adverse events. No new safety concerns were identified. Overall LAN median PFS from the LAN–LAN group was 38.5 months, and varied with tumor origin and prior therapy (Table). Conclusions: CLARINET OLE suggests sustained antitumor effects with LAN 120 mg in enteropancreatic NETs irrespective of tumor origin, and suggests benefits with LAN as early treatment. Clinical trial information: NCT00842348. [Table: see text]
Efficacy of gemcitabine with erlotinib in rash-positive patients selected according to eligibility for FOLFIRINOX.
Authors: Haas Michael , Boeck Stefan Hubert , Siveke Jens T. , Schenk Michael , Lerch Markus , Caca Karel , Freiberg-Richter Jens , Fischer von Weikersthal Ludwig , Kullmann Frank , Reinacher-Schick Anke C. , Fuchs Martin , Ettrich Thomas Jens , Kanzler Stephan , Kunzmann Volker , Kruger Stephan , Westphalen Benedikt , Held Swantje , Heinemann Volker 
Published: September 2018

4108 Background: The efficacy and safety of gemcitabine + erlotinib has not yet been defined prospectively in patients (pts) with metastatic pancreatic cancer (mPC) selected according to the inclusion criteria defined by Conroy et al. for FOLFIRINOX (e. g. ECOG 0-1, age < 75, bilirubin < 1.5xULN). Methods: In this German phase II trial, 150 pts with histologically confirmed mPC were recruited between July 2012 and July 2015 in 20 centers. If pts showed skin rash of any grade within 4 weeks after start of treatment with gemcitabine (1000 mg/m2 weekly) and erlotinib (100 mg daily), this regimen was continued; rash-negative pts were switched to FOLFIRINOX. The primary study endpoint was the 1-year survival rate in rash-positive pts (hypothesis: ≥40%). Results: Ninety pts who were under treatment with gemcitabine + erlotinib for 4 weeks developed skin rash of any grade: the 1-year survival rate in those pts positive for skin rash was 40.0% (95%CI 29.8-50.9); median overall survival (OS) counted from day of first treatment was 10.1 months (mo) (95%CI 9.0-12.5), progression-free survival (PFS) 3.9 mo (95%CI 3.5-4.9), objective response rate (ORR) and disease control rate (DCR) were 21% and 64%, respectively. Median treatment duration with gemcitabine+erlotinib was 3.7 mo (Range 0.7-17.5). In rash-negative pts who were switched to FOLFIRINOX after 4 weeks of gemcitabine + erlotinib (n = 28) the 1-year survival rate was 46.4% (95%CI 27.5-66.1), median OS 10.6 mo (95%CI 6.6-13.6), median PFS 5.2 mo (95%CI 2.3-7.9) and the corresponding ORR and DCR rates were 29 and 54%, respectively. The rate of salvage therapy was 53% after gemcitabine+erlotinib, mostly consisting of 5-FU-based schemas (42 % 5-FU/folinic acid + irinotecan or oxaliplatin, 38% FOLFIRINOX) and 43% after FOLFIRINOX (all pts received gemcitabine, 67% in combination with nab-paclitaxel). In the Intention To Treat (ITT) population (n = 145) OS was 9.7 mon (95%CI 7.8-10.9). Conclusions: In rash-positive pts deemed fit for FOLFIRINOX first-line treatment with gemcitabine + erlotinib appears effective achieving a one-year-survival rate of 40%. Early switch to FOLFIRINOX was an effective strategy in rash-negative patients. Clinical trial information: NCT01729481.
Nomogram for predicting overall survival (OS) in patients (pts) treated with nab-paclitaxel (nab-P) plus gemcitabine (Gem) or Gem alone for metastatic pancreatic cancer (MPC).
Authors: Goldstein David , Von Hoff Daniel D. , Chiorean E. Gabriela , Reni Michele , Tabernero Josep , Ramanathan Ramesh K. , Aly Abdalla , Botteman Marc , Wilkersen Julia , Margunato-Debay Sandra , Lu Brian , Louis Chrystal Ursula , Renschler Markus Frederic , McGovern Desmond Micahel Thomas , Lee Chee Khoon 
Published: September 2018

4109 Background: Prognostic nomograms have been developed in various cancers, including ovarian, breast, and gastrointestinal; however, there is limited information on nomograms in MPC. The large, phase 3 MPACT study of nab-P + Gem vs Gem alone for the treatment of MPC provides a robust database for the development of a nomogram to predict OS using baseline patient variables. Methods: A multivariable Cox model was created from MPACT data using factors that were significantly predictive of OS in univariable analysis or considered clinically important (stepwise selection to remain in model). From the Cox model, a nomogram was derived that assigned points equal to the weighted sum of relative significance of each variable. The nomogram was internally validated using bootstrapping, a concordance index (c-index), and calibration plots. Results: Data from all 861 pts were used. Seven of the 34 considered variables were retained in the multivariable analysis (Table; all factors significant at the P < 0.01 level, except for analgesic use [ P = 0.07]). The resulting nomogram was able to distinguish low (n = 216), medium (n = 430), and high (n = 215) risk groups (c-index: 0.69; CI: 0.67-0.71) with median OS values of 12.9, 8.2, and 3.7 months, respectively. Calibration curves showed that the nomogram’s predicted probabilities were mostly consistent with observed probabilities for 6-, 9-, and 12-month OS. Conclusions: Treatment arm, Karnofsky performance status (KPS), neutrophil-to-lymphocyte ratio (NLR), albumin level, sum of longest tumor diameters (SLD), and presence of liver metastasis were the key predictors of OS. This nomogram, which will be presented in visual format in the final presentation, may help physicians and pts make informed treatment decisions. Clinical trial information: NCT00844649. [Table: see text]
Single agent HuMab-5B1 (MVT-5873), a monoclonal antibody targeting sLea, in patients with pancreatic cancer and other CA19-9 positive malignancies.
Authors: O'Reilly Eileen Mary , Wang Judy Sing-Zan , Yu Kenneth H. , Lowery Maeve Aine , Varghese Anna M. , Bendell Johanna C. , Borazanci Erkut Hasan , Estrella Hayley , Fowler Kimberly , Hoskin Mariella , Jun H. Toni , Melink Teresa J. , Maffuid Paul , Klein Pamela , Gutheil John , Bauer Todd Michael 
Published: September 2018

4110 Background: MVT-5873, a fully human IgG1 monoclonal antibody (mAb), targets sialyl Lewis A (sLea), an epitope on CA19-9. CA19-9 is expressed in pancreatic (PDAC) and other GI cancers, plays a role in tumor adhesion and metastasis, and is a marker of an aggressive tumor phenotype. MVT-5873 is active as a single agent and with chemotherapy in murine xenografts. Methods: MVT-5873 was given IV every other week (Group 1) or weekly (Group 2). Eligible patients had progressive, locally-advanced or metastatic PDAC or other CA19-9+ malignancy and ECOG PS ≤1. Dose escalation followed a 3+3 design with a 10 patient expansion at MTD. Endpoints include safety, MTD, pharmacokinetics (PK) and efficacy. Exploratory endpoints include changes in serum CA19-9 levels. Results: As of 2-Feb 2017, data are available from N = 25 in Groups 1 (N = 9) and 2 (N = 16) at doses ranging from 1 to 3 mg/kg. Dose limiting toxicities of transient grade 3 elevations in AST, ALT, and total bilirubin were encountered at 3 mg/kg in both groups. Liver function laboratory abnormalities typically emerged and resolved within a week of dosing without significant clinical sequelae. Of toxicities deemed possibly related, most were low grade and included GI toxicity (abdominal pain/cramps/diarrhea/nausea) and infusion reactions. Infusion reactions were mitigated by using pre-medications and decreasing the infusion rate. Initial PK data demonstrate initial (20 hours) and terminal (211 hours) half-lives, comparable to other mAbs. Stable disease of > 4 months was observed in 24% of patients. CA19-9 levels were measured pre- and post-dose with each treatment. Immediate reductions showed dose-dependent reductions of up to 97% from baseline at 3 mg/kg. Downward trends of CA19-9 with successive doses were seen, with 48% and 22% of patients exhibiting ≥50% and ≥90% reductions in CA19-9 levels, respectively. Conclusions: Single agent MVT-5873 appears safe and tolerable at biologically active doses. DLTs included reversible serologic liver toxicity. The safety profile, efficacy, and reductions in serum CA19-9 levels over time support further development of MVT-5873 in this indication both as a single agent and in combination. Clinical trial information: NCT02672917.