bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMAGE, a randomized phase Ib/II study of elisidepsin (E) as a single agent in pretreated advanced gastroesophageal (GE) cancer.
Authors: Salazar Ramon , Metges Jean Philippe , Anthoney David Alan , Laus Gianluca , Alsina Maqueda Maria , Goncalves Anthony , Montagut Clara , Brown Jennifer , Gunzer Katharina , Szyldergemajn Sergio A. , Petty Russell D. 
Published: February 2017

92 Background: E is a new marine compound with broad in vitro/in vivo antitumor activity. Low μM concentrations lead to cell-death through membrane permeabilization. E has shown evidence of activity in pre-treated GE patients (pts) in phase I trials. Methods: The primary objective was to determine the tolerability and efficacy of E in pts with GE cancer after 1-2 prior chemotherapy (CT) lines. Initially, dose was optimized (Phase Ib) in two different schedules: a fixed flat dose (FD) of intravenous (i.v) E (8 and 10 mg), in 24h, biweekly (Arm A) and i.v E (3.0 and 3.75mg), in 3h, weekly (Arm B). After dose optimization patients were included and stratified by histology to each optimal dose (Phase II) to determine the rate of progression-free survival at week 16 ± 1 (PFS4) in an intention to treat analysis. If at least two out of 15 pts reached PFS4, recruitment would continue to a maximum of 40 pts per arm. Results: A total of 45 pts were recruited, 12 pts into Phase Ib (Arm A/B: 6/6 pts) and 33 pts into Phase II (Arm A/B: 15/18 pts). Median age was 60 years (35–81 years), 39 were males and ECOG PS was 1 in 75% of pts. Tumour sites were gastric (32% pts), esophageal (39% pts) and esophago-gastric junction (30% pts). Ninety percent of pts had metastatic disease, 31.8% of which had liver metastasis; 55% of pts had two prior lines of CT . No DLTs occurred during the first cycle in the Phase Ib. The optimal dose for Arm A was 10 mg FD, 24h, biweekly; the optimal dose for Arm B was 3.75mg FD, 3h, weekly. Two patients reached PFS4 in Phase Ib (Arm A). Only one patient reached PFS4 in Phase II (Arm A). No objective responses were observed. Therefore, protocol criteria for further recruitment were not met. The safety profile showed grade 1-2 toxicity pruritus (29.5%), nausea (15.9%), vomiting (6.8%) and fatigue (25%). Grade 3-4 toxicity consisted of asymptomatic reversible liver enzyme increases in 20.5% of patients. Conclusions: E is a very tolerable drug with a unique mechanism of action. In the current setting of non-stratified advanced GE patients, E has insufficient antitumor activity to warrant further investigation. Clinical trial information: 2010-020325-40.
SCOPE 1: A phase II/III trial of chemoradiotherapy in esophageal cancer plus or minus cetuximab.
Authors: Crosby Thomas , Hurt Chris , Falk Stephen , Gollins Simon , Mukherjee Somnath , Staffurth John , Ray Ruby , Bridgewater John A. , Geh Ian , Cunningham David , Maughan Tim , Griffiths Gareth 
Published: February 2017

LBA3 Background: SCOPE 1 is the largest multicentre trial of definitive chemo-radiotherapy (dCRT) in localised oesophageal cancer (LOC) in the UK and investigated adding cetuximab to standard cisplatin and fluoropyrimidine treatment. Methods: Patients in this phase II/III trial had LOC and been selected to receive dCRT and were randomised to receive cisplatin 60mg/m2 D1 and capecitabine 625mg/m2 daily D1-21 for 4 cycles, cycles 3 and 4 given concurrently with 50Gy in 25 fractions of RT with or without cetuximab 400mg/m2 D1 followed by 250mg/m2weekly. Recruitment continued from 02/2008 until analysis of the phase II endpoint (24 week failure free survival in the cetuximab arm, overall sample size 180: p1=0.60 and p2=0.75, α=0.05, β=0.9) in 01/2012. The phase II endpoint was not met and the IDMC recommended trial closure on the basis of futility. Results: 258 patients were recruited. Median age 67; morphology(%) SCC:ACA 73:27; tumour location(%) upper:middle:lower 11:45:44; stage(%) I:II:III 3:37:60; reason not for surgery(%) disease extent:patient choice:comorbidity 47:38:16. Patients who received cetuximab had: higher non-haematologic toxicity (78 vs 62.8%, p=0.004; primarily dermatological (22 vs 4%) and metabolic (24% vs 11%)); a lower rate of completion of standard therapy (capecitabine 69 vs 85%, p=0.002; cisplatin 77 vs 90%, p=0.005 and radiotherapy (75 vs 86%, p=0.027); reduced failure free survival at 24 weeks (66 vs 77%), median survival (22 vs 25 months, log rank p=0.043) and 2-yr survival (41 vs 56%). Conclusions: In SCOPE 1, disease control and survival in the standard dCRT arm is superior to any previous published multi-centre studies. The use of cetuximab was associated with greater toxicity, lower doses of dCRT and worse survival. Cetuximab cannot be recommended in combination with standard dCRT for unselected patients with oesophageal cancer. Strategies to build on these results should incorporate biomarker driven treatment and latest radiotherapy technologies to safely intensify treatment. This trial was sponsored by Velindre NHS Trust, conducted by Wales Cancer Trials Unit at Cardiff University and supported by CR-UK [grant number C20177/A7256]. Clinical trial information: 47718479.
COUGAR-02: A randomized phase III study of docetaxel versus active symptom control in advanced esophagogastric adenocarcinoma.
Authors: Ford Hugo , Marshall Andrea , Wadsley Jonathan , Coxon Fareeda Y. , Mansoor Wasat , Bridgewater John A. , Madhusudan Srinivasan , Falk Stephen , Middleton Gary William , Swinson Daniel , Chau Ian , Thompson Joyce , Blazeby Jane M. , Cunningham David , Kareclas Paula , Dunn Janet A. ,   National Cancer Research Institute, Upper GI Clinical Studies Group
Published: February 2017

LBA4 Background: Survival in patients who relapse after first-line chemotherapy for advanced esophagogastric adenocarcinoma (OGC) is poor though recently randomized trials have suggested a small survival benefit for second-line chemotherapy with taxanes or irinotecan. There is very little data on quality of life or survival, particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicenter open-label, randomized controlled phase III trial for patients with locally advanced or metastatic OGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine (PF) chemotherapy (CT). Patients were randomized (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC), which could include any treatment thought by the treating clinician to be appropriate for the management of symptoms including radiotherapy, steroids and supportive medications. The primary endpoint was overall survival. Secondary endpoints were response rate, toxicity, health related quality of life (HRQL) and healthcare resource use. Results: Between April 2008 and April 2012, 168 patients were recruited (84 patients in each arm). Median age was 65 years (range 28-84), 81% were male. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. Site of disease was stomach in 46%, esophagogastric junction in 34% and esophagus in 20%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. 19 (23%) patients completed 6 CT cycles (median 3 cycles per patient). The main reasons for not completing treatment were progression and toxicity. Docetaxel significantly improved overall survival over ASC alone (median 5.2 months (95% CI 4.1-5.9 months) for docetaxel; 3.6 months (95% CI 3.3-4.4 months) for ASC, HR=0.67 (95% CI 0.49-0.92); p=0.01). 7% had a partial response and 46% had stable disease after CT. 21% on docetaxel had grade 4 toxicity. Conclusions: The addition of docetaxel to ASC significantly improved overall survival. Docetaxel can be considered a standard of care in this setting. Clinical trial information: 13366390.
Effect of inhibition of the PI3K/Akt/mTOR pathway on AR splicing and downstream targets.
Authors: Liu XiaoMei , Gomez-Pinillos Alejandro , Shah Payal , Lavilla Carmencita , Ferrari Anna C. 
Published: February 2017

101 Background: Increased androgen receptor (AR) and PI3K/Akt/mTOR signaling drive androgen-independent (AI) prostate cancer (PC) progression. AR splice variants (SV) lacking the ligand-binding domain activate ligand-independent transcriptional programs that support castration resistant proliferation and survival. Treatment of the androgen-dependent PTEN null LNCaP (AD-cells), its AI derivative (AI-cells) and wt PTEN RV1 cells with the dual PI3K/mTOR inhibitor BEZ235 (E) combined with the histone deacetylase inhibitor Panobinostat (PAN) induced synergistic growth inhibition and cell death in vitro and in vivo. The effect of these treatments on AR splicing is unknown. Methods: LNCaP AD, AI and RV1 cells were treated with PAN 20nM, E 350nM, rapamycin (Rapa) 20nM and PI3Ki BKM120 (K) 1.5µM for 24h. Total (t) AR, SV’s and AR targets mRNA were measured by qtPCR and western. RV1 xenografts received 3 weeks E 35mg/kg/d or PAN 10mg/kg/QOD or PAN+E. Results: Baseline levels of tAR mRNA in AI were higher than AD and RV1 cells while SV1, SV7 and SV5-7 were higher in RV1 than AD and AI cells. Treatment with E, Rapa and K increased both tAR and SV’s mRNA’s and AR and PSA proteins. In contrast, treatment with PAN reduced tAR and SV’s levels in AD and AI with no effect on RV1. PAN reduced the induction of tAR by Rapa or K in AD, AI and RV1 but did not abrogate induction of SV’s. PAN inhibition was sufficient to abrogate the effect of E and decrease tAR and SV’s levels as well as AR protein and AR canonical and non-canonical targets (PSA, TMPRSS2 and UBE2C) and PSA protein below baseline levels in all cells treated with PAN+E. Similarly, RV1 tumors treated with E had a 50% increase in tAR and 20% in SV5-7 but no induction of CDK1 or UBE2C and a 35% reduction in PSA while RV1 tumors treated with PAN+E showed 40% reduction in both SV’s 1 and 7 and downstream targets CDK1 and UBE2C. Conclusions: Inhibition of PI3K/mTOR with E increases overall levels of AR transcription that is more pronounced on SV’s and uncouples AR’s transcriptional activity on canonical downstream targets in vivo. PAN can abrogate the stimulation of E by decreasing both SV’s expression and AR transcriptional activity on non-canonical targets. These effects may underlie their synergistic growth inhibition.
A phase II trial of temsirolimus in men with castration-resistant metastatic prostate cancer.
Authors: Armstrong Andrew J. , Shen Tong , Halabi Susan , Kemeny Gabor , Bitting Rhonda Lynn , Kartcheske Patricia , Embree Elizabeth , Morris Karla , Winters Carolyn , Jaffe Tracy , Fleming Mark T. , George Daniel J. 
Published: February 2017

105 Background: PTEN loss is common in advanced prostate cancer, leading to constitutive activation of the PI3 Kinase pathway. Temsirolimus blocks mTOR/TORC1, a key signaling node in this pathway; its activity in men with advanced castration-resistant metastatic prostate cancer is unknown. Methods: We conducted a single arm trial of weekly IV temsirolimus in men with chemorefractory metastatic CRPC who had >=5 circulating tumor cells (CTCs) at baseline (Cellsearch). The primary endpoint was change in CTCs at 8 weeks; secondary endpoints were composite progression-free survival (excluding PSA), PSA and radiographic response rates, safety, and survival. At PSA/CTC progression, an anti-androgen could be added while continuing temsirolimus. Results: Eleven patients were accrued out of a planned 20; the trial was stopped prematurely due to lack of efficacy/feasibility. Median age was 61, with 55% African-Americans and 36% Caucasians. Median baseline PSA was 390 ng/dl, median baseline CTC was 14 cells, 50% had significant pain, and 63% had >2 prior chemotherapy regimens. The median decline in CTC enumeration at week 8 was 48% and three patients experienced a decline in CTCs to <5. However, 73% of men had persistently unfavorable CTCs (>=5) over time and only 1 patient had a >=30% PSA decline. Median PFS was 1.9 months (95% CI 0.9-3.1) and median OS was 8.8 months (95% CI 3.1-15.6). Toxicities included grade 4 hypophosphatemia and grade 4 CNS hemorrhage, and frequent grade 3 fatigue, anemia, stomatitis, hypokalemia, weakness, and hyperglycemia. Persistently high N-cadherin expression on longitudinal CTC analysis was observed as a marker of epithelial plasticity and treatment resistance. Conclusions: Temsirolimus lacked sufficient clinical activity in men with metastatic CRPC, despite transient CTC improvements in some men. Future studies should focus on combination approaches or novel PI3K pathway inhibitors. Clinical trial information: NCT00887640.
Activity of gemcitabine-oxalipaltin (GemOx) plus prednisolone in patients with castration-resistant prostate cancer (CRPC) for whom docetaxel-based chemotherapy failed.
Authors: Lee Jae-Lyun , Kim Yesul , Ahn Jin-Hee , Choi MeeKyung , Hong Seung-Woo , Jeong In Gab , Song Cheryn , Hong Bum-Sik , Hong Jun Hyuk , Kim Choung-Soo , Ahn Hanjong 
Published: February 2017

108 Background: We assessed the cytotoxic effects of the gemcitabine in combination with oxaliplatin (GemOx) in prostate cancer cell lines and evaluated the efficacy and safety of GemOx in patients with metastatic castration-resistant prostate cancer (CRPC) who failed docetaxel based chemotherapy. Methods: Gemcitabine and oxaliplatin were preclinically tested for their cytotoxic activity in LNCaP, PC3 and DU145 cell lines. The combined drug effects were evaluated using the Chou and Taladay analysis. Clinically, patients with CRPC who failed prior docetaxel chemotherapy were treated with gemcitabine 1,000 mg/m2 at fixed-dose rate (10 mg/m2/min) and oxaliplatin 100 mg/m2 intravenously every 2 weeks and prednisolone 5 mg orally twice daily. Unless disease progression or intolerability develops, treatment could be continued until 12 cycles. Primary endpoint was PSA response rate (PCWG 1.0 criteria). Results: The IC50of gemcitabine and oxaliplatin were, respectively, 1.25 μM and 0.69 μM for LNCaP cells; 50.00+ μM and 12.81 μM for PC3 cells; and 11.23 μM and 11.04 μM for DU145 cells. The GemOx combination displayed synergistic effects in all 3 cell lines. In phase II study, 31 patients were accrued. At the time of this analysis 7 patients were still continuing treatment. The median age was 67 years (range 57 ~ 81) and the median dose of docetaxel exposure was 525 mg/m2. A total of 231 cycles administered with a median of 9 cycles per patient. PSA responses were observed in 52% (95% CI, 34~69) and partial responses were observed in 7 of 10 patients with measurable disease. Out of 23 patients, 10 patients achieved pain response (44%). With a median FU duration of 8.0 months, the median time to PSA progression was 6.4 months (95% CI, 3.5~9.2). Peripheral neuropathy developed in 78% of patients but remained of grade 1 ~2 intensities. Frequently observed grade 3 or 4 toxicities were neutropenia (10%), thrombocytopenia (10%), anemia (3%), and diarrhea (3%). Conclusions: GemOx is active and well tolerated in patients with CPRC after docetaxel failure and deserves further investigation in this setting (NCT 01487720). Clinical trial information: NCT01487720.
Study of the impact of Charlson comorbidity index and hypertension on survival in patients with metastatic castration-resistant prostate cancer.
Authors: Goyal Jatinder , Pond Gregory Russell , Galsky Matt D. , Hendricks Ryan , Small Alexander C. , Tsao Che-Kai , Sonpavde Guru 
Published: February 2017

111 Background: Clinical and laboratory factors, i.e. visceral metastasis, anemia, LDH, PSA, PSA-doubling time, bone scan progression, pain, performance status (PS), are recognized to be prognostic factors for overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC). We sought to determine if the Charlson comorbidity Index (CCI) and hypertension (HTN) provide prognostic information independent of these known factors. Methods: We retrospectively evaluated 221 patients with mCRPC treated with docetaxel plus prednisone (DP) combined with AT-101 (bcl-2 antagonist) or placebo on a randomized phase II trial. Both arms of the trial were combined since no differences in outcomes or toxicities were observed. Wilcoxon rank sum test and Fisher’s exact tests were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI ≥7 and HTN vs. no HTN). Cox regression analysis was done to identify whether CCI or HTN independently predicted OS after adjusting for trial stratification factors (pain, performance status), nomogram, risk-groups and PCWG-2 clinical sub-types. Results: CCI was 6 in 116 patients (52.7%) whereas it was 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in (1.8%) and 10 in 7 patients (3.2%) respectively. HTN was present in 107 (48.6%) patients. Patients with HTN had increased CCI (mean CCI 7.0 vs. 6.43, p < 0.001). Patients with CCI of ≥7 were older and exhibited worse ECOG-PS and anemia than patients with CCI of 6 (p<0.05). CCI was not found to be independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with CCI was borderline significantly associated with OS (p~0.08) on both univariable and multivariable analyses. Conclusions: CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further analysis of HTN in a larger dataset may be warranted given its borderline independent association with OS.
A multicenter population-based experience with abiraterone acetate (AA) in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Clayton Ravinder , Heng Daniel Yick Chin , Wu Jackson S.Y. , Zielinski Rob , North Scott A. , Emmenegger Urban , Hotte Sebastien J. , Al-Shamsi Humaid Obaid , Chen Leo , Eigl Bernhard J. 
Published: February 2017

113 Background: The COU-AA-301 trial showed that abiraterone (AA), an oral cytochrome p450 CYP17 inhibitor, improved survival for men with mCRPC progressing after docetaxel. AA is now a standard treatment in this setting. In order to better understand the non-clinical trial experience with AA, we undertook a multicenter retrospective analysis of patients (pts) treated with AA. Methods: Consecutive pts with mCRPC from 5 tertiary cancer centers in Canada who had received AA post-docetaxel were identified using centralized pharmacy records for each center. Pts who received AA for approved indications or within expanded access programs were included. Demographics, prognostic factors, treatment outcomes and toxicity profiles were collected. Results: One hundred and eighty seven pts, who initiated AA between Jan-2011 and Jun-2012, were included. Median age at diagnosis and AA start was 65 and 73 years. 73 (39%) pts had M1 disease at diagnosis. ECOG 0/1/2/3 was noted in 17/96/39/8 pts. Median PSA at AA start was 132 with a median PSAdt of 2.8 months. 54 (29%) pts received more than 1 prior course of chemotherapy. Median follow up was 20.5 months. Median survival from start of AA was 9.3 months (95% CI, 7.9-12.6). Regional results were: Alberta 14 months (95% CI, 13-18); BC 8.2 months (95% CI, 5.4-9.6); and Ontario 7.3 months (95% CI, 5.7-8.1). Median overall survival from date of mCRPC was 36 months (95% CI, 29-40); in Alberta this was 39 months (95% CI, 29-47); BC 26 months (95% CI, 18-41); and Ontario 33 months (95% CI, 25-41). AA was well tolerated with toxicities comparable to those seen in the trial population, with anemia and fatigue being the most common reported toxicity. Conclusions: This is one of the largest cohorts of men with mCRPC treated with AA in the non-clinical trial setting. Treatment outcomes corroborate with results reported in clinical trials, supporting the effectiveness of AA in an unselected population. A difference in survival outcomes between the different cancer regions can be attributed to differences in time to AA start. Future analyses to evaluate potential prognostic/predictive factors will be undertaken.
Epigenetic field effect markers as indicative of occult high-grade prostate cancer.
Authors: Gaston Sandra Marlene , Hayek Jihad E , Otto Gaetan , Yen James , Bigley Joseph , Van Neste Leander , Kearney Gary P 
Published: February 2017

116 Background: Epigenetic changes through DNA methylation can serve as biomarkers for the presence of prostate cancer (PCa). Gene methylation in histologically benign tissue adjacent to PCa can provide “field effect" biomarkers to detect cancer missed due to sampling errors. Such errors may also result in underestimates of PCa stage or grade, complicating decisions about Active Surveillance. We previously showed increased field effect methylation in GS 7 over GS 6 subjects in a small patient cohort. Here, established methylation markers of PCa (GSTP1, APC and RASSF1) were tested in a larger cohort to compare histologically benign biopsy cores from patients diagnosed with no cancer, low volume GS 6 cancer and GS 7 cancer. The objective was to confirm that epigenetic field effects may be useful for detecting occult high grade malignancies in diagnostic and prognostic settings. Methods: DNA was extracted from prostate biopsy tissue prints and used for multiplex methylation-specific PCR (MSP) assays of the 3 genes. All testing was done blinded. Each of 12 tissue cores was tested from a series of 76 biopsy patients: 34 diagnosed with GS 6 PCa, 22 with GS 7 PCa, and 20 no-cancer controls. Results: In 19 of the 22 GS 7 cases (86%), epigenetic markers were positive for field effects in one or more adjacent benign cores; 12 (54%) were positive for all 3 epigenetic markers. In contrast, only 9 of 34 cases (26%) GS 6 cases were positive for all 3 markers. We again observed that robust marker expression in histologically benign cores from cases diagnosed with low volume GS 6 PCa was associated with higher grade cancer at radical prostatectomy (upgrading). APC showed the best performance as a single marker “field effect” test for adjacent high grade PCa. Conclusions: GSTP1, APC and/or RASSF1 gene promoter methylation was observed to be more prevalent in histologically benign cores from biopsy patients diagnosed with GS 7 PCa, as compared with low volume GS 6. This study confirms previous findings in a larger cohort of subjects that these “field effect” biomarkers can be useful for detecting cancer adjacent to histologically negative biopsies and may be indicative of occult aggressive PCa.