bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase Ib study of mapatumumab in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC) and chronic viral hepatitis.
Authors: Sun W. , Nelson D. , Alberts S. R. , Poordad F. , Leong S. , Teitelbaum U. R. , Woods L. , Fox N. , O'Neil B. H. 
Published: February 2017

261 Background: Mapatumumab is a fully human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1). Sorafenib targets Mcl-1, a key TRAIL resistance protein, and accordingly could enhance mapatumumab's pro-apoptotic activity. Based on this and on preclinical data on mapatumumab in HCC cell lines, the current dose-escalation study is evaluating mapatumumab in combination with sorafenib in patients with advanced HCC. Methods: Eligible patients had advanced HCC, Child-Pugh A or Model for End-Stage Liver Disease score < 15, and were positive for hepatitis B surface antigen or hepatitis C antibody. Intravenous mapatumumab was administered at 3, 10 or 30 mg/kg every 21 days with sorafenib (400 mg twice daily) until disease progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) included events considered at least possibly related to mapatumumab and/or its interaction with sorafenib. Tumor measurements were performed every 2 cycles. Dose escalation required at least 3 patients in a cohort to receive >= 50% of full-dose sorafenib in the first 2 cycles. Results: To date, 19 patients have been enrolled in the 3 mg/kg (n=6), 10 mg/kg (n=9) and 30 mg/kg (n=4) cohorts and have received a median of 4 cycles (range 1 to 24 cycles); 4 patients have received >= 11 cycles. The maximum tolerated dose has not been reached. DLTs that prompted expansion of the 3 mg/kg and 10 mg/kg cohorts were elevations of amylase and/or lipase (1 at 3 mg/kg, 1 at 10 mg/kg). Other Grade 3-4 events considered at least possibly related to mapatumumab and/or its interaction with sorafenib included hepatic pain (1/17), thrombocytopenia (1/17), increased aspartate aminotransferase (1/17), increased lipase (1/17), and increased gamma-glutamyltransferase (1/17). Two patients have had a partial response and 4 patients have had stable disease lasting > 12 weeks, based on investigator assessment. Conclusions: Mapatumumab was well-tolerated at doses up to 30 mg/kg in combination with sorafenib in patients with HCC and viral hepatitis. A randomized phase II study of this combination in patients with advanced HCC is planned. [Table: see text]
Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for AMG 479 (A479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC).
Authors: Lu J. , Deng H. , Tang R. , Hsu C. , Kindler H. L. , Fuchs C. , Gansert J. , Bray S. , Loh E. , Zhu M. 
Published: February 2017

263 Background: A479 is an investigational, fully human monoclonal antibody against IGF1R. In a phase II study, 125 pts with mPC were randomized 1:1:1 to A479, placebo (P), or conatumumab in combination with G. Addition of A479 (12 mg/kg IV, Q2W) to G (1000 mg/m2) showed evidence of improved OS and PFS (Kindler, JCO 2010:28 abstr 4035). An E-R analysis was done to inform P3 dose selection for A479. Methods: A population PK model of A479 was constructed using data from multiple studies. An E-R analysis was performed with pts from the A479+G and P+G arms (∼40 pts/arm). The effect of estimated steady-state area under the curve (AUCss) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS- AUCss and PFS-AUCss associations were assessed by multivariate analysis. Exposure-safety data were analyzed with descriptive statistics and linear regression. P3 doses for A479 were explored with Monte Carlo simulations using population PK and parametric survival models. Results: There was a positive association between OS or PFS and higher AUCss in the A479+G arm (P<0.001, <0.001) that remained even when data from the A479+G and P+G arms were combined (P=0.033, 0.022). Pts with AUCss ≥ median (19.2 mg·h/μL) had longer median OS and PFS (16.0, 7.6 months) than pts with AUCss < median (4.7, 1.9 months). OS-AUCss and PFS-AUCss associations were significant after adjusting for potential confounding factors. Sensitivity E-R analyses were done to confirm the modeling results. The incidence of most adverse events was similar between the AUCss < and ≥ median groups, although the incidence of grade ≥3 hyperglycemia, neutropenia, and thrombocytopenia trended higher in pts with AUCss ≥ median. Population PK indicated 1.7-fold higher clearance of A479 in mPC than non-mPC pts. No G-A479 PK interactions were identified. PK simulations showed similar AUCss of A479 in mPC pts at 20 mg/kg and in non-mPC pts at 12 mg/kg. Simulations projected improved OS and PFS with 20 mg/kg vs 12 mg/kg A479. Conclusions: Increased exposure to A479 is associated with improved clinical outcomes in mPC. This supports the evaluation of 20 mg/kg A479 in P3. [Table: see text]
Phase II study of sorafenib with gemcitabine and erlotinib (GES) in first-line advanced pancreatic cancer.
Authors: Cohen D. J. , Leichman L. P. , Love E. , Ryan T. , Leichman C. G. , Newman E. , Levinson B. , Hochster H. S. 
Published: February 2017

266 Background: Addition of erlotinib (E) to gemcitabine (G) results in improved OS for patients (pts) with advanced pancreatic cancer. Many pancreatic tumors have constitutively activated ras/raf pathways and overexpress VEGF. Sorafenib (S), a multitargeted tyrosine kinase inhibitor, including VEGR 1-3, PDGFR-α and β and the RAF/MEK/ERK pathway, when combined with G and E may synergize, resulting in a more complete blockade of the signal transduction cascade in pancreatic cancer growth and progression, and improved outcome. Methods: Pts with previously untreated, histologically confirmed, unresectable pancreatic adenocarcinoma, PS 0-1, and adequate organ function were eligible and received G 1,000 mg/m2 over 30 min qw x 3 every 4w. E 150 mg PO daily and S 400 mg PO bid were given continuously. CT scans were performed every 2 cycles (8w). Primary endpoint included PFS at 4 mos and secondary endpoints included safety and tolerability of the novel combination, RR, and OS. Results: 45 pts enrolled, 44 evaluable for toxicity(1 not treated), and 30 evaluable for response. Median age was 64 (45-84), 32 males (71%), 43 (96%) had metastatic disease, PS was 0 in 26 (58%). Median number of cycles was 2 (0-10). Grade (gr) 3 toxicity included: thrombocytopenia 5; diarrhea 4; vomiting 4; HFS, hyperbilirubinemia, hyperglycemia and SOB each 3 pts; 1 bowel perforation and 1 epistaxis. Gr 4 toxicity included 1 each: bowel perforation, GI bleed, transaminitis, hyperglycemia and sepsis with hypotension. 2 patients only required dose reduction of S for HFS. There were 2 PR (7%), 13 SD (43%), overall RR of 7% and DCR of 50%. Median TTP 111 days (95% CI = 53-175) and median OS 195 days (144-290). PFS at 16 weeks was 49%, just reaching statistical significance. Conclusions: The combination of G and E plus S in the treatment of advanced pancreatic cancer is a well tolerated regimen without significant increased toxicity as compared to G alone, except for very manageable cutaneous reactions. While the primary endpoint met our pre-determined criteria (compared with NCIC PA.3), this study does not suggest a major benefit for addition of S to G-E when compared to published data. Supported in part by grants from Bayer Healthcare Pharmaceuticals/Onyx and OSI. No significant financial relationships to disclose.
Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: A retrospective analysis.
Authors: Weatherly J. , Eckmann K. , Patel D. , Landgraf A. N. , Slade J. H. , Wolff R. A. , Lin E. , Javle M. M. 
Published: February 2017

271 Background: Recent clinical trials for biliary cancers include a heterogenous group of patients with cholangiocarcinoma, gallbladder, and ampullary cancers. There are limited data regarding the relative effectiveness of known chemotherapeutic regimens specifically in intrahepatic or hilar cholangiocarcinoma. Methods: M. D. Anderson Cancer Center patients with unresectable intrahepatic and hilar cholangiocarcinoma who received first-line chemotherapy from January 1, 2005 to October 31, 2009 were reviewed. Eighty-five patients met inclusion criteria and were eligible for analysis. The primary objective of this project was to determine the overall tumor control rates with the chemotherapeutic regimens used for first-line treatment of unresectable intrahepatic and hilar cholangiocarcinoma. Secondary objectives included duration of response, overall survival, and prognostic factors. Results: The most commonly used regimen was gemcitabine/cisplatin (gem/cis; 53 patients, 62%), followed by oxaliplatin and capecitabine (14 patients, 16%). There was no significant difference between tumor control rates with gem/cis (72% PR/SD, 28% PD) and other regimens (69% PR/SD, 31% PD). There was also no significant difference between overall survival with the use of gem/cis (15.2 months) or alternative regimens (13.9 months). A decrease in overall survival was seen with elevated baseline CA 19-9 (p<0.0001), an initial diagnosis of unknown primary tumor (p=0.0001), and prior treatment with chemoradiation (p=0.0018). Conclusions: In this retrospective review, both gem/cis and alternative doublets (including capecitabine/oxaliplatin, gemcitabine/capecitabine, and gemcitabine/oxaliplatin) were effective regimens in maintaining disease control in the intrahepatic and hilar population. No significant financial relationships to disclose.
A phase Ib study of the MEK inhibitor GSK1120212 combined with gemcitabine in patients with solid tumors: Interim results.
Authors: Tolcher A. W. , Bendell J. C. , Patnaik A. , Papadopoulos K. , Bellew K. M. , Cox D. S. , Xu Y. , Burris H. A. , Le N. , Infante J. R. 
Published: February 2017

278 Background: GSK1120212 (212) is a reversible, allosteric inhibitor of MEK1/MEK2. The objectives of this open-label, single-arm study are to evaluate the safety, pharmacokinetics (PK), and anti-tumor activity of 212 + gemcitabine (gem), and to determine the recommended phase II regimen (RP2R) in patients (pts) with advanced solid tumors. Methods: 212 (1-2.5mg) is given continuously, orally, once daily. Gem (1,000mg/m2) is infused on days 1, 8, and 15 every 28 days. Doses are escalated to the maximum tolerated dose (MTD) and followed by an expansion cohort to confirm the RP2R tolerability. Results: 28 pts received ≥ 1 dose of 212 + gem, including 8 pancreatic, 6 breast, and 4 non-small cell lung (NSCLC) cancer pts. The MTD and RP2R is 2mg 212 + 1,000mg/m2 gem. Dose-limiting toxicities (DLTs) are G3/G4 febrile neutropenia (n=2), G3 AST elevation (n=2), and G2 uveitis (n=1). 16 serious adverse events (SAEs) were reported; 5 were considered to be related to study drugs (1 pneumonitis, 3 febrile neutropenia, 1 dyspnea). All DLTs and SAEs have resolved. The most common AEs at the RP2R (n=18) were rash (78%), fatigue (67%), thrombocytopenia (61%), neutropenia (50%), decreased appetite (50%), nausea (44%), diarrhea and constipation (39%); all ≤ G2 except thrombocytopenia (17% ≥ G3) and neutropenia (33% ≥ G3). Co-administration did not affect the PK profiles of 212 or gem. 25 pts had measurable disease at baseline. 1 pancreatic cancer pt with previous radiotherapy and 2 cycles of gem achieved a partial response and stayed on study for 6 months. 3 additional pancreatic cancer pts reported stable disease; 2 of which were on the study for 3.5-5 months and the third pt continues in the study. 1 triple-negative breast cancer pt, refractory to chemotherapy, and 1 parotid cancer pt experienced a complete response of their target lesions. Conclusions: 212 + gem is tolerable with an acceptable safety profile in this pt population, with evidence of clinical activity in pancreatic cancer. A randomized phase II study in previously untreated patients with metastatic pancreatic cancer is underway to investigate the clinical activity of this combination. [Table: see text]
Phase II study of segmental transcatheter arterial chemoembolization using ethiodized oil mixed with cisplatin powder for unresectable hepatocellular carcinoma.
Authors: Anai H. , Tanaka T. , Nishiofuku H. , Sueyoshi S. , Yamamoto K. , Morimoto K. , Inoue M. , Sakaguchi H. , Inaba Y. , Kichikawa K. ,   Nara 3
Published: February 2017

292 Background: Conventional transcatheter arterial chemoembolization (TACE) using with ethiodized oil mixed with epirubicin or doxorubicin hydrochloride mainly has been widely adapted for intermediate-stage hepatocellular carcinoma (HCC). However, cisplatin has stronger effect for HCC than epirubicin and in the recent years cisplatin powder was commercially available in Japan and then we can use cisplatin powder mixed with ethiodized oil for HCC. We conducted a phase II study to assess the safety and efficacy of segmental or subsegmental (Seg/Subseg) TACE using a suspension of cisplatin powder mixed with ethiodized oil for unresectable HCC. Methods: Twenty patients with single-nodule HCC that was not indicated for surgical treatment or local ablation therapy were enrolled in this study. Seg/Subseg-TACE was performed by using a 2-F tip microcatheter at a distal portion of the subsegmental artery supplying the tumor. Subsequently, the feeding artery was embolized with gelatin sponge particles. The suspension was prepared by mixing 100 mg of cisplatin powder with 10 ml of ethiodized oil. Primary endpoint of this phase II trial was 2-year local disease free survival (DFS); secondary endpoints evaluated were the safety, time to progression (TTP), and 2-year overall survival (OS) rate. Results: A total of 20 patients (male 15, female 5; mean age 72.4, range 62-83; Child Pugh's A 20) were treated single nodule HCC with Seg/subseg TACE. Median tumor size was 2.6cm (range1.2-5.0cm). The 2-year local DFS was 63.2 %. The following grade 3 or 4 toxicities were observed: platelets reduction 5%, aspartate transaminase elevation 55%, alanine transaminase elevation 40% and alkaline phosphatase elevation 5%. The median TTP was 17.6 months (95%CI, 5.25 to 29.9) and the 2-year OS rate was 94.7%. Conclusions: This phase II study demonstrates that segmental or subsegmental transcatheter arterial chemoembolization using a suspension of cisplatin powder mixed with ethiodized oil is well tolerable, and may achieve significant local tumor control and prolong survival. Further clinical trials are warranted. No significant financial relationships to disclose.
Phase I trial of temsirolimus (TEM) plus sorafenib (SOR) in advanced hepatocellular carcinoma (HCC).
Authors: Kelley R. K. , Nimeiri H. S. , Vergo M. T. , Chia K. , Mulcahy M. F. , Bergsland E. K. , Ko A. H. , Munster P. N. , Benson A. B. , Venook A. P. 
Published: February 2017

296 Background: SOR prolongs survival in patients (pts) with HCC. In preclinical studies, mammalian target of rapamycin (mTOR) inhibitors (I) impair HCC growth and angiogenesis. Adding mTOR-I to SOR augments antitumor effect. Phase I studies of mTOR-I plus SOR have shown tolerability but did not include cirrhotic pts. We developed a phase I trial of mTOR-I TEM plus SOR to determine safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) in pts with HCC. The study was approved and funded by the National Comprehensive Cancer Network (NCCN). Methods: Eligibility: Advanced HCC diagnosed histologically or clinically. No prior systemic therapy (Tx). Prior resection/local Tx permitted if ≥1 measurable site. ECOG score ≤2, Child-Pugh ≤7, bilirubin ≤2 mg/dL, platelets ≥75,000/mcL. Design: 3+3 escalation to MTD with dose-limiting toxicity (DLT) window 28 days; 6 pts at MTD for pharmacokinetics (PK). Endpoints: 1°: MTD, RP2D. 2°: Safety, toxicity, PK. Results: 9 pts enrolled to date: 7 at DL1, 2 at DL-1. Toxicity: DL1: 1 DLT of Gr3 thrombocytopenia. 1 pt removed for hypertensive urgency, adjudicated not Tx-related. 1 pt not evaluable due to abscess. 1 pt removed for Gr3 hypersensitivity to TEM in cycle 2. All remaining pts required reduction and/or delay for adverse events (AE). Tx-related AE at DL1 include: fatigue 57%, Gr3 11%; weight loss 22%, all Gr1; anorexia 57%, all Gr1/2; diarrhea 71%, all Gr1/2; rash/hand-foot syndrome 71%, Gr3 11%; thrombocytopenia 57%, Gr3 11%; hypophosphatemia 77%, Gr3 57%, refractory 11%. Study de-escalated to DL-1 due to non-DLT cumulative AE. DL-1: 2 pts enrolled have not had DLT nor dose reduction to date. Response: 4 of 7 pts in DL1 were evaluable. 3 of 4 had stable disease as best response. Conclusions: Tx-limiting, class-related AE occurred at DL1 of this double-biologic regimen. MTD in pts with Child-Pugh Class A cirrhosis appears lower than in pts without liver disease. Tolerability and dose delivery must be achieved to determine efficacy. A phase II study with correlative endpoints is planned at RP2D. Updated accrual and results will be presented. [Table: see text] [Table: see text]
Emotional well-being and quality of life in patients undergoing radiation therapy for pancreatic and hepatobiliary malignancies.
Authors: Samuelson B. T. , Fromme E. K. , Waller J. , Thomas C. R. 
Published: February 2017

297 Background: Therapy for GI malignancies has long been known to have a marked impact on quality of life, yet this relationship remains poorly understood. The specific aim of this analysis was to evaluate the impact of radiation therapy (RT) on emotional well-being and QOL in patients receiving RT for pancreatic and hepatobiliary malignancies. Methods: A retrospective, IRB-approved chart review was performed of 722 patients receiving RT for any cancer diagnosis between 1/1/2006 and 12/31/2008. Subjects completed the Functional Assessment of Cancer Therapy General (FACT-G) questionnaire before and after RT. Pre- and immediately post-RT course scores were compared using student t-tests with Bonferroni correction for multiple comparisons (7 comparisons, alpha =.007). Results: 722 of 1369 (52.7%) patients participated in the Patient Related Outcome database. Complete pre and post RT spirituality data were available for 73 (64.6%) patients with GI malignancies, including 24 (33%) with pancreatic or hepatobiliary disease. Average age was 61, 15 (63%) were male and 14 (58%) received definitive treatment. A decrease in both functional and physical well-being was demonstrated in post-RT scores as compared to pre-RT. Emotional well-being, however, increased (17.60 to 18.72, p=0.051), a trend not replicated in any of the other GI malignancies. Further analysis demonstrated this improvement was largely due to a decrease in positive response to the statements “I feel nervous” (1.21 to 0.67, p=0.009) and “I worry my condition will get worse” (1.58 to 1.25, p=0.043). A decrease in positive response to “I feel sad” and an increase in positive response to “I am satisfied with how I am coping with my illness” were also noted, but differences were not significant. Conclusions: Emotional well-being of those receiving RT for pancreatic and hepatobiliary malignancies appears to improve over the course of therapy, even while other measures of QOL decline. Additional investigations in larger populations are warranted to further elucidate this relationship. Documentation of PROs may have potential for impact on QOL for patients with these and other malignancies. No significant financial relationships to disclose.
In vitro and in vivo antitumor activities of a small and novel synthetic molecule: A potential therapy for hepatocellular carcinoma.
Authors: Batarseh K. I. 
Published: February 2017

300 Background: A small (molecular weight of 275) and novel pharmaceutically silver (I)-tartaric acid complex given the title name aliargentumycine was recently synthesized and the results on its in vitro cytotoxicity and mechanism of action on solid and hematopoietic malignancies were reported. Here the therapeutic potential of aliargentumycine on hepatocellular carcinoma was investigated. Methods: The in vitro and in vivo antitumor activities of aliargentumycine were studied on human HepG-2 xenograft model grown subcutaneously in female immunodeficient mice. Aliargentumycine was administered intratumorally, intravenously and orally twice a week at various concentrations. Results: The IC50 of aliargentumycine was found to be 1.49 ± 0.067 mg/ml, which is comparable to the value of 1.04 ± 0.07 mg/ml for doxorubicin, and almost half the value of 2.87 ± 1.02 mg/ml for sorafenib tosylate. The in vivo results demonstrated excellent statistically significant antitumor activities for the intratumoral, intravenous and oral routes of administration with Pi.t. < 0.00001, Pi.v. < 0.005 and Pp.o. < 0.003, respectively. Some animals showed complete tumor remission (tumor-free), and no tumor re-growth was observed even after treatment was stopped. Nonlinear regression on the data revealed that aliargentumycine results in significant tumor growth delay. All treated animals did not show any commonly observed signs of toxicity, including no body weight loss (p > 0.05). Mantel-Cox statistical tests revealed that there were significant tumor growth delays (p < 0.05) and survival advantages (p < 0.05). Conclusions: These promising findings might have great therapeutic potential on the future clinical treatment of hepatocellular carcinoma using aliargentumycine. No significant financial relationships to disclose.
Phase I/II study of arterial infusion with 5-fluorouracil combined with systemic gemcitabine for unresectable pancreatic cancer.
Authors: Tanaka T. , Nishiofuku H. , Sho M. , Anai H. , Sueyoshi S. , Yamamoto K. , Inaba Y. , Sakaguchi H. , Nakajima Y. , Kichikawa K. ,   Nara 2
Published: February 2017

307 Background: Unresectable pancreatic cancer is poorly responsive to conventional therapies. We conducted a phase I/II study to ascertain the recommended dose (RD) of 5-fluorouracil (5-FU) in arterial infusion chemotherapy combined with systemic gemcitabine in unresectable pancreatic cancer and to evaluate the safety and efficacy. Methods: 5-FU was administered through the pancreatic and hepatic arteries via the port system as a 5-hour infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. Gemcitabine was administered in 30-minute intravenous infusion at the same days. In phase I, escalating 5-FU doses for level 1 and 2 was set at 750mg and 1,000mg/m2, respectively. Dose of coadministered gemcitabine (1,000 mg/m2) was fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed, and RD was estimated in the first cycle. In phase II, more RD patients were added to assess tumor response, toxicity, overall survival and progression-free survival. Results: During the phase I, 7 patients were enrolled. DLT was not observed. One patient dropped out of this study because of insufficient drug distribution via the port system. Assuming RD at 1,000mg/m2 of 5-FU, the phase II enrolled a total of 16 patients (metastatic, 14; local advanced, 2). The tumor response rate was 68.8% (CR 0, PR 11, SD 2, PD 3). The grade 3 toxicities of neutropenia (6%) and thrombocytopenia (6%) were observed. Median overall and progression-survival times (all patients) were 9.8 and 6.2 months, respectively. Conclusions: Arterial infusion 5-FU 1,000mg/m2 combined with full-dose systemic gemcitabine was tolerable and can produce a high response rate with encouraging survival duration for unresectable pancreatic cancer. No significant financial relationships to disclose.