bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436).
Authors: Infante J. R. , Falchook G. S. , Lawrence D. P. , Weber J. S. , Kefford R. F. , Bendell J. C. , Kurzrock R. , Shapiro G. , Kudchadkar R. R. , Long G. V. , Burris H. A. , Kim K. B. , Clements A. , Peng S. , Yi B. , Allred A. J. , Ouellet D. , Patel K. , Lebowitz P. F. , Flaherty K. T. 
Published: February 2017

CRA8503 Background: In preclinical models, the BRAF/MEK inhibitor (i) combination GSK436/GSK212 has demonstrated enhanced activity against BRAF-mutant cancer cells compared to either drug alone, delayed emergence of GSK436 resistance, and prevented proliferative skin lesions attributable to BRAFi exposure. Methods: Eligible patients (pts) had BRAF V600 mutation positive solid tumors. Part 1: pharmacokinetic (PK) drug-drug interaction (DDI) study. Part 2: Dose escalation of continuous daily dosing of the combination followed by expansion cohorts; Part 3: Randomized phase II trial in untreated stage IV melanoma. Results: 45 pts have received ≥ 1 dose of GSK212 + GSK436, including 43 melanoma (all BRAFi naïve), 1 NSCLC and 1 salivary duct carcinoma. PK results of 7 pts in Part 1 showed no effect of GSK212 on single dose of GSK436. There was no clinically meaningful DDI between GSK436 and GSK212 after repeat dosing of the combination (Part 2). GSK436 was dosed 75-150 mg BID in combination with GSK212 1.0, 1.5, 2.0 mg QD. The recommended dose was 2 mg QD GSK212 in combination with 150 mg BID GSK436. At 1.5 mg GSK212, there was one DLT, a recurrent grade (G) 2 neutrophilic panniculitis. The only G4 adverse event (AE) was a sepsis-like syndrome with fever/hypotension. G3 AEs included generalized rash (n=2, 4%) and neutropenia (n=2, 4%). Skin toxicity ≥ G2 occurred in 9 (20%) pts; of these, G2 rash (n=4, 8%) and G2 macular rash (n=1, 2%). No cutaneous squamous cell carcinoma (SCC) or hyperproliferative skin lesions have occurred at any dose level. Other common G2 toxicities were pyrexia (n=5, 11%), vomiting (n=2, 4%) and fatigue (n=2, 4%). Of 16 evaluable pts in Part 2, 13 pts had PR and 3 SD for an ORR of 81% (95% CI 54.4%-96.0%) and all but 2 pts remain on study. In 10 evaluable pts who received 150 mg BID GSK436 + ≥1 mg QD GSK212, 9 pts had PR and 1 SD. Conclusions: GSK212 at 2 mg QD combines safely with GSK436 150 mg BID, no SCC thus far and decreased frequency of rash compared to previous trials of single agent GSK436 and GSK212, respectively. The preliminary anti-tumor activity warrants further investigation; the randomized phase II trial (Part 3) is accruing.
Ampullary cancer ESPAC-3 (v2) trial: A multicenter, international, open-label, randomized controlled phase III trial of adjuvant chemotherapy versus observation in patients with adenocarcinoma of the ampulla of vater.
Authors: Neoptolemos J. P. , Moore M. J. , Cox T. F. , Valle J. W. , Palmer D. H. , Mcdonald A. , Carter R. , Tebbutt N. C. , Dervenis C. , Smith D. , Glimelius B. , Coxon F. Y. , Lacaine F. , Middleton M. R. , Ghaneh P. , Bassi C. , Halloran C. , Olah A. , Rawcliffe C. L. , Büchler M. W. ,   European Study Group for Pancreatic Cancer
Published: February 2017

LBA4006 Background: The effect of adjuvant treatment on overall survival (OS) of resected ampullary adenocarcinoma is not known. The aim was to compare the survival effect of adjuvant chemotherapy compared to observation (OBS) after resection and within the chemotherapy group to compare 5-fluorouracil/folinic acid (5-FU/FA) against gemcitabine (GEM). Methods: Patients were stratified by R0/R1 margins, randomised into three arms: (1) 5-FU/FA (FA, 20 mg/m2 iv bolus then 5-FU, 425 mg/m2, iv bolus, 1-5d every 28 days); (2) GEM (100mg/m2 iv infusion 1d, 8d and 15d every 4 weeks); (3) observation. The primary outcome measure was OS of chemotherapy versus no chemotherapy. 300 patients (200 chemotherapy and 100 observation) would provide 80% power to detect a 15% 5y survival difference, p<0.05. Results: 304 patients were randomised (July 2000 to April 2008), 199 to chemotherapy (101 5FU, 98 GEM) and 105 to observation. Median (range) age was 62 (35 – 81) years; 187 (61.5%) were men. Median (IQR) maximum tumour diameter was 20.0 (15.0 – 28.0) mm, 186 (63%) were moderately differentiated tumours, 174 (57%) had involved lymph nodes and 276 (91%) were R0 resections. Independent prognostic factors were tumour diameter and grade, lymph node status and R0/R1 status. Median (95% CI) OS for chemotherapy [57.1 (41.7 – 73.8) months] versus no chemotherapy [43.0 (27.6 - ) months] gave an HR (95% CI) of 0.85 (0.61 – 1.18), p=0.323. For R0 patients median (95% CI) OS for chemotherapy [58.4 (45.4 – 84.0) months] versus no chemotherapy [45.1 (26.7 - ) months] gave an HR (95% CI) of 0.78 (0.55 – 1.11), p=0.173. Cox proportional hazards modelling for all 304 patients p=0.161 and for 276 R0 patients p=0.057. Conclusions: This is the only large adjuvant trial ever conducted for ampullary adenocarcinoma. The results suggest a benefit for adjuvant monochemotherapy in patients with clear resection margins.
Result of interim analysis of overall survival in the GCIG ICON7 phase III randomized trial of bevacizumab in women with newly diagnosed ovarian cancer.
Authors: Kristensen G. , Perren T. , Qian W. , Pfisterer J. , Ledermann J. A. , Joly F. , Carey M. S. , Beale P. J. , Cervantes A. , Oza A. M. ,   GCIG
Published: February 2017

LBA5006 Background: ICON7 was designed to investigate safety and efficacy of adding bevacizumab to standard chemotherapy in women with newly diagnosed ovarian cancer. Analyses of mature progression-free survival (PFS) data suggest a PFS benefit from bevacizumab (p=0.0041, a 15% improvement at 12 months and 1.5 months overall), and a trend for overall survival (OS) improvement, hazard ratio (HR)=0.81, 95%CI=0.63 to 1.04, p =0.098. The final analysis of OS will be performed when 715 deaths have occurred. An interim analysis with at least 365 deaths was requested by regulatory authorities considering licensing. This was approved by the independent data monitoring and steering committees. A subgroup analysis for poor prognosis patients (FIGO III debulked to >1.0cm or FIGO IV with debulking) was performed in an exploratory manner. Methods: Eligible women with high-risk early (FIGO stage I or IIa (grade 3 or clear cell), capped ≤10%) or advanced (stage IIb-IV) epithelial ovarian, primary peritoneal or fallopian tube cancer were randomised (1:1) to 6 cycles of 3 weekly chemotherapy (carboplatin AUC 5 or 6 and paclitaxel 175mg/m2) alone, or the same chemotherapy given concurrently with bevacizumab (7.5mg/kg) for 5 or 6 cycles followed by continued 3-weekly single-agent bevacizumab for 12 additional cycles or until progression whichever was the earlier. Results: From December 2006 to February 2009, 1,528 women were randomised from 263 centres in 7 GCIG groups. Baseline characteristics were balanced between arms: median age (57 years); ECOG PS 0-1 (47%); high-risk early-stage disease (9%); poor prognosis patients (30%); histology (69% serous, 8% endometrioid, 8% clear cell). Overall OS analysis: median follow-up 28 months, 377 deaths (200 standard, 177 bevacizumab), HR=0.84, 95%CI=0.69 to 1.03, p=0.099. Exploratory subgroup analysis of poor prognosis patients: 188 deaths (109 standard, 79 bevacizumab), HR=0.64, 95%CI=0.48 to 0.85, p=0.0022 with p=0.015 for test for interaction (treatment/risk group). Conclusions: The overall trend for improvement in OS from bevacizumab continues with a numerically larger benefit in poor prognosis patients.
OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).
Authors: Aghajanian C. , Finkler N. J. , Rutherford T. , Smith D. A. , Yi J. , Parmar H. , Nycum L. R. , Sovak M. A. 
Published: February 2017

LBA5007 Background: BEV, a humanized anti-VEGF monoclonal antibody, has shown a progression-free survival (PFS) benefit in 2 frontline phase III trials in patients with EOC, PPC and FTC. The therapeutic impact of BEV in combination with carboplatin (C) and gemcitabine (G) followed by single agent BEV to disease progression (PD) was evaluated in this phase III trial in the platinum-sensitive recurrent setting. Methods: Patients had recurrent, platinum-sensitive EOC, PPC or FTC, 1 prior regimen, no prior BEV, ECOG performance status 0-1, measurable disease. Subjects were randomized to: Arm A: [IV C (AUC 4, Day (D) 1) + G (1,000 mg/m2 D1 and 8) + placebo (PL) D1] q21D x 6 cycles (c) → PL q21D until PD or unacceptable toxicity (tox) Arm B: [CG + BEV (15 mg/kg) D1] q21D x 6 c → BEV q21D until PD or tox primary endpoint was investigator assessed PFS (RECIST). Secondary endpoints included objective response (OR), overall survival (OS), duration of response and safety. The design provided 80% power to detect a 27% reduction in the hazard of progression or death in Arm B vs A, limiting the overall type I error of 5%. Results: OCEANS enrolled 484 patients (242 per arm) from 4/07 - 1/10, median follow up of 24 months. BEV plus CG followed by single agent BEV to PD significantly increased PFS compared to CG alone (HR=0.484, p<0.0001). OR increased by 21% (p<0.0001). OS data is immature with only 29% of patients having had an event. The safety profile was consistent with other BEV trials. Conclusions: Results show a statistically significant and clinically relevant benefit when bevacizumab is added to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC. This is the first phase III trial of an antiangiogenic to demonstrate a clinical benefit to these patients. [Table: see text]
Bevacizumab (BEV) plus second-line taxane (TAX) or other chemotherapy (CT) for triple-negative breast cancer (TNBC): Subgroup analysis of RIBBON-2.
Authors: Brufsky A. , Valero V. , Tiangco B. , Dakhil S. R. , Brize A. , Duenne A. A. , Bousfoul N. , Rugo H. S. , Yardley D. A. 
Published: February 2017

290 Background: In three randomized trials in the first-line metastatic breast cancer (MBC) setting, combining BEV with CT significantly improved progression-free survival (PFS; primary endpoint) and objective response rate (ORR) vs. CT alone. BEV also showed a significant PFS benefit in the second-line MBC setting (RIBBON-2) when combined with TAX or other CT. We analyzed data from the subgroup of patients (pts) with TNBC in RIBBON-2. Methods: Eligible pts had MBC that had progressed on first-line CT without BEV. Second-line CT (TAX, gemcitabine, capecitabine, or vinorelbine) was chosen before 2:1 randomization to CT with either BEV (10 mg/kg q2w or 15 mg/kg q3w) or placebo (PLA). All pts could receive BEV at progression. The primary endpoint was PFS. Results: RIBBON-2 included 684 pts; 159 (23%) had TNBC and of these, 67 (42%) received TAX with BEV/PLA. Baseline characteristics were broadly similar in the two treatment arms. In an exploratory analysis of pts with TNBC, BEV + CT led to significantly improved PFS and ORR vs. CT alone, and a trend toward improved overall survival (OS). The magnitude of the effect was particularly pronounced in pts receiving TAX CT. Conclusions: Pts with TNBC derive significant ORR and PFS benefit from BEV combined with second-line CT. Despite the small sample size, there was a trend (HR 0.624; p = 0.0534) toward OS benefit in pts treated with BEV, especially with TAX CT. [Table: see text]
A phase I/II study of S-1 plus cisplatin alternating with S-1 plus docetaxel in patients with advanced gastric cancer (AGC).
Authors: Hosokawa A. , Ogawa K. , Kajiura S. , Tsukioka Y. , Kobayashi T. , Horikawa N. , Kobayashi Y. , Yoshioka A. , Sumi S. , Sugiyama T. 
Published: February 2017

101 Background: S-1 plus cisplatin has been regarded as standard first-line chemotherapy for patients with AGC in Japan, and S- 1 plus docetaxel showed promising results for AGC in clinical trials. To investigate the usefulness of S-1 plus cisplatin alternating with S-1 plus docetaxel as first-line treatment in patients with AGC, we conducted a phase I/II study to determine the maximum tolerated dose (MTD), the recommended dose (RD), preliminary efficacy and toxicity. Methods: Eligibility criteria included pathologically confirmed AGC; no prior chemotherapy; Age 20 to 74, ECOG performance status (PS) of 0 to 2; adequate organ function; and written informed consent. Cisplatin was administered on day1 and the dose was escalated by 10 mg/m2 from starting dose of 40 mg/m2 in phase I part. S-1 was given orally at 80 mg/m2 on day1-14. Docetaxel was administered at 40 mg/m2 on day 22 in combination with S-1 80 mg/m2 on days 22-35. The treatment was repeated every 6 weeks. The RD was studied in every 3-6 patients cohort and determined according to the pre-defined DLTs. Primary endpoint of phase II was the response rate (RR). Results: Between Aug 2006 and Jul 2010, 33 pts were enrolled. Nine patients entered the phase I part and 24 enrolled in phase II part. In the phase I part, the MTD of cisplatin was presumed to be 50 mg/m2, because 50% of patients (3/6) developed DLTs. Therefore, the RD of cisplatin was estimated as 40 mg/m2, and the 27 patients received the treatment at RD level. Patients characteristics were as follows: median age=65 years (range 48-74), Male: female=21:6, PS 0:1:2=11:16:0, diffuse: intestinal=19:8, initially unresectable: recurrent=24:3. The RR was 59.2% (95% CI, 40.7-77.7). Median follow-up period was 14.6 months, median PFS was 7.9 months, and median survival time was 17.2 months, although survival data remain to be confirmed. Major grade 3/4 toxicities were neutropenia (63%), leucopenia (41%), and anemia (33%). These toxicities were tolerable and manageable. No treatment-related death was observed. The updated analysis will be presented at the meeting. Conclusions: This alternating treatment seems to be effective and well tolerated in the first-line treatments in patients with AGC. No significant financial relationships to disclose.
Induction cisplatin, paclitaxel, and 5FU (PTF) before definitive local therapy for locally advanced esophageal squamous cell carcinoma (SCC).
Authors: Fernandez R. , Lopez de Argumedo G. , Fuente N. , Ferreiro J. , Martinez M. , Azkona E. , Gutierrez E. , Iza E. , Casas R. , Mane J. 
Published: February 2017

115 Background: Induction chemotherapy for locally advanced oesophageal SCC is controversial. Triple combination is under study with promising results. We analyse induction therapy with PTF before local definitive therapy in terms of response, resectability, toxicity and survival. Methods: Pts diagnosed of locally advanced oesophageal SCC have been included. Treatment schedule: paclitaxel 175 mg/m2 and CDDP 75 mg/m2 on day 1 and 5FU 800 mg/m2/day days 1-4, every 28 days. After 2-3 cycles surgery is considered. If unresectable, radical radiotherapy (64 Gy) and concomitant carboplatin (60 mg/m2, d 1–5 during 1st, 4th and, if feasible, 7th week of RT) are administered. Results: From May-02 to Feb-10 48 pts have been treated (44M, 4F). Age: 56,7 (32–70). PS 0-1: 8-40. Location: Upper: 14, Middle: 25, Distal: 8, Whole: 1. T2/3/4:1/26/21, N0/1: 12/36. M1a: 6. Weight loss over 10 kg: 11 pts. Cycles delivered: 140; median 3. Toxicity (episodes): Anemia 3: 1. Emesis 3: 2. Mucositis 3: 2. Asthenia 2-3: 8. Two pts died in remission (one of them with a pCR at necropsy) due to gastrostomy complications and oesophagus-tracheal fistula, treatment related. Two pts developed oesophagus-tracheal fistula as a late event after response to therapy. Response rates: CR 7 (14.6%), PR 16 (33.3%), SD 18 (37.5%), PD 7 (14.6%). Treatment after PTF: Surgery 14 pts (1 upper, 9 middle, 4 distal). One (distal) unresectable at surgery, one (middle) not resected because of liver cirrhosis, two not resected because of liver metastases, unexpected findings at surgery. pCR: 2. pPR 8 (R0: 7, R1: 1). Chemoradiation: 25, improving 2 SD to PR, 4 PR to CR and 3 SD to CR. One PR and 4 SD progressed immediately after chemoradiation. Progression: 33 (local 14, systemic 11, both 8); died: 34. Median progression free survival: 35.7 weeks (95% CI 30.2-41.2). Median overall survival: 50.7 weeks (95% CI 35.2-66.1). Conclusions: Induction PTF has a good toxicity profile with a high response rate and disease control during therapy. Surgical rescue is possible in middle and distal tumours. Local definitive therapy with chemoradiation is the best approach for unresectable or upper third tumours. No significant financial relationships to disclose.
Multicenter feasibility study of 5-FU, leucovorin, plus paclitaxel (FLTAX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake.
Authors: Takiuchi H. , Yasui H. , Nishina T. , Takahari D. , Nakayama N. , Taira K. , Kusaba H. , Fuse N. , Hironaka S. , Nakajima T. E. 
Published: February 2017

119 Background: Oral fluoropyrimidine plus cisplatin is widely used as a standard treatment for advanced gastric cancer, but patients (pts) with severe peritoneal metastasis often cannot tolerate this regimen. The aim of this study was to assess the feasibility of fluorouracil (5-FU), leucovorin (LV), plus paclitaxel (PTX) for peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake. Methods: Peritoneal disseminated gastric cancer with massive ascites or inadequate oral intake were enrolled in Part I (Level 1 (n=6): 5-FU bolus/l- LV div 2hr/PTX div 1hr = 500/250/60, Level 2 (n=6): 600/250/80 mg/m2 (day1, 8, 15, q4w) to determine dose-limiting toxicity (DLT) and recommended dose (RD). In Part II (n=19), primary endpoint was completion rate of 2 cycles to evaluate the feasibility of this regimen at RD level. Results: One of Level 1 pts had DLT with grade 4 gastrointestinal perforation. Two of Level 2 pts had DLT (grade 3 febrile neutropenia and grade 3 infection with normal neutrophils) and treatment-related death (TRD) was observed in one patient due to pneumonia with grade 4 neutropenia. The RD was determined to be Level 1. Twenty-five patients were enrolled at RD level: first-line/second-line=18/7, performance status 0/1/2=1/19/5. The completion rate of 2 cycles was 92% and objective response rate of ascites was 45%. Grade 3 or 4 neutropenia was observed in 12% (febrile neutropenia in 8%). Five patients out of 7 second-line patients died within 30 days after last administration of FLTAX (TRD: 1 and disease progression: 4). Conclusions: RD of FLTAX regimen was 5-FU/l-LV/PTX=500/250/60 mg/m2. This regimen was feasible as the first-line treatment against peritoneal disseminated gastric cancer patients with massive ascites or inadequate oral intake. [Table: see text]
Trimodality treatment for advanced esophageal cancer: Impact of minimally invasive esophagectomy.
Authors: Williams D. G. , Carpenter S. , Ross H. J. , Paripati H. , Ashman J. B. , Callister M. D. , Harold K. L. , Jaroszewski D. E. 
Published: February 2017

125 Background: Esophageal cancer is best managed by multimodality therapy, frequently with chemotherapy (C) or chemo- radiotherapy (CRT) preceding resection. Minimally invasive esophagectomy (MIE) is increasingly accepted, but studies of MIE in advanced esophageal and gastroesophageal junction cancer after induction CRT are lacking. This report presents the data on MIE as part of tri-modality therapy for esophageal cancer at Mayo Clinic in Arizona (MCA). Methods: Patients (pts) who underwent CRT before or after MIE for cancer at MCA between November 2006 and May of 2010 were reviewed retrospectively. Results: 46 pts (40 males, and 6 females) met study criteria and were reviewed. Median age was 62 years (41-88 years). 45 pts (98%) had adenocarcinoma and one pt had squamous carcinoma. Initial clinical stage was IIA in 10 pts (22%), IIB in 3 pts (7%), III in 26 pts (55%), and IVA in 7 pts (15%) with positive celiac nodes. 43 pts (93%) underwent preoperative CRT with additional intra-operative radiotherapy in 4 pts. Median operating time was 354 min (range 211-567 min), median blood loss was 225 ml (range 50-1,400 ml), and median hospital stay was 8 days (range 5-48 days). 19 pts (41%), including the 3 who did not undergo preoperative CRT, received postoperative C or CRT due to either residual disease at resection or to local recurrence. 30 of 43 pts undergoing MIE after CRT were down staged (11 CR [25.6%], 10 near CR [23.3%]) demonstrating a major response to neoadjuvant therapy in 48.9% of pts. One pt died in hospital (from ARDS and sepsis subsequent to aspiration pneumonia) and two pts died within 30 days of surgery (one from pulmonary embolism, and the other from unknown causes) for a 30 day surgical mortality of 6.5%. 29 pts (63%) had a complication of surgery including 11 (24%) minor and 18 (39%) major complications. After a median follow-up of 13 months (range 0.9-43 months) 16 pts were diagnosed with recurrent disease and 10 of these pts have died of their disease. Conclusions: CRT with MIE is associated with an acceptable morbidity and mortality level for pts with locally advanced esophageal cancer. These results compare favorably with morbidity, mortality, and recurrence rates in open esophagectomy pts. No significant financial relationships to disclose.
The clinical values of methylation status of P16 and APC genes in bile in diagnosis of malignant obstructive jaundice.
Authors: Yin X. , Yan G. , Peng J. , Liang L. 
Published: February 2017

171 Background: Preoperative definitive diagnosis of malignant obstructive jaundice caused by biliary and pancreatic carcinomas still remains a major challenge. Hypermethylation of tumor suppressor genes have been implied in carcinogenesis of biliary and pancreatic malignancies. The diagnostic values of methylation status of tumor suppressor genes in bile in malignant obstructive jaundice have not been well-documented. Methods: Bile was prospectively collected from 70 patients with obstructive jaundice treated at our hospital between November 2008 and Sepetember 2009. Forty-eight of them were proved to be malignant obstructive jaundice (biliary carcinoma in 36, pancreatic carcinoma in 8 and duodenal carcinoma in 4) by pathological examination, and 22 were benign obstructive jaundice caused by cholelithiasis. DNA was extracted from bile and modified by sodium bisulfite. Methylation-specific PCR was run to detect methylation status of P16 and APC gene promoters. Their diagnostic values in malignant obstructive jaundice were assessed. Results: Hypermethylation of P16 promoter was presented in 72.9% (35/48) malignant obstructive jaundice, and 9% (2/22) bengin obstructive jaundice (p<0.05). Hypermethylation of APC promoter was presented in 56.2% (27/48) malignant obstructive jaundice, and 9% (2/22) bengin obstructive jaundice (p<0.05). With respect to their diagnostic values in malignant obstructive jaundice, sensitivity, specificity, positive predictivity and negative predictivity were 72.9%, 90.9%, 94.6% and 60.6%, respectively, for P16 gene; 56.2%, 90.9%, 93.1%, 48.8%, respectively, for APC gene. Conclusions: Methylation status of P16 and APC gene promoters in bile was valuable in diagnosis of malignant obstructive jaundice, with an excellent specificity. P16 gene had a higher sensitivity than APC gene. No significant financial relationships to disclose.