bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II/III randomized trial of exclusive chemoradiotherapy with or without dose escalation in locally advanced esophageal carcinoma: The CONCORDE study (PRODIGE 26).
Authors: Crehange Gilles , Bonnetain Franck , Peiffert Didier , Le Prise Elisabeth , Etienne Pierre-Luc , Rio Emmanuel , Pereira Renata , Noel Georges , Benezery Karen , Seitz Jean Francois 
Published: February 2017

TPS190 Background: INT 0123 failed to demonstrate an overall survival benefit with chemoradiotherapy dose escalation in locally advanced esophageal cancer. Nearly 45% of the patients had local persistent or recurrent disease. Several drawbacks surround the interpretation of the results of INT 0123. Improvements in target definitions with planning CT and 18F FDG PET/CT in keeping with improvements in radiation dose delivery that better protect healthy tissues with 3D conformal radiation therapy and/or IMRT should lead to the retesting of dose escalation in the modern era of new technologies. Methods: Patients are randomized into two groups: Experimental group: 40Gy ENI followed by a 26-Gy boost to the primary tumor and involved nodes (i.e. 33 daily fractions of 2Gy) with concomitant and adjuvant FOLFOX-4 weeks 1, 3, 5, 7, 9 and 11. Control group: 40Gy ENI followed by a 10-Gy boost to the primary tumor and involved nodes (in 25 daily fractions of 2Gy) with concomitant and adjuvant FOLFOX-4 weeks 1, 3, 5, 7, 9 and 11. Randomization using minimization to ensure balanced allocation across: Center / Adeno vs Squamous cell carcinoma / stage III vs I-II / weight loss / 3D-CRT vs IMRT. The principal hypothesis is that the rate of survival without locoregional relapse at 2 years will reach 50% in the reference arm and 65% in the experimental arm (Hazard ratio = 0.62). With a risk α = 0.05 (bilateral test) and β = 0.15 (power 85%). If we use a rate of 5% for lost to follow-up, it will be necessary to recruit 266 patients. The main inclusion criteria are: age < 75 years, WHO Status 0, 1 and 2, Enteral or parenteral feeding planned before the start of treatment if oral calorie intake < 1500 kcal, Histologically proven carcinoma of the esophagus, adenocarcinoma or squamous cell, T3, N0-N3, M0 (UICC 7thedition), T1-T2, N0-N3, M0 with a contra-indication for surgery, Absence of tracheo-esophageal fistula, Absence of thoracic or upper abdominal irradiation for another tumor, Written informed consent. 141 of the 160 patients required in phase II of the trial were included by September 22nd 2015. (ClinicalTrials.gov Identifier: NCT01348217). Clinical trial information: NCT01348217.
A phase I trial with cohort expansion of BYL719 in combination with gemcitabine and nab-paclitaxel in locally advanced and metastatic pancreatic cancer.
Authors: Soares Heloisa P. , Nguyen Danny , Springett Gregory M. , Kim Richard D. , Williams-Elson Irene , Miller Kara , Kothari Nishi , Mahipal Amit 
Published: February 2017

TPS467 Background: The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway which is aberrantly stimulated in many tumors has emerged as a potential target for anticancer therapy. Although several class I PI3K inhibitors are under development, there is considerable evidence suggesting that targeting a single isoform of PI3K (p110α) would have sufficient antitumor activity and improved therapeutic window. The PI3K pathway is frequently activated and plays an important role in pancreatic cancer. Further, PI3KCA mutations, the gene encoding isoform p110α, are observed in this disease. BYL719 is an oral class I α-specific PI3K inhibitor that showed anti-tumor activity in different preclinical models. Recently, the first in human phase 1 trial of BYL719 defined the maximum tolerated dose (MTD) at 400 mg once daily. Methods: This is a single institution, open label, single group, phase I study with cohort expansion that utilizes the standard 3+3 design for dose. The primary objective is to determine the MTD of BYL719 in combination with gemcitabine and nab-paclitaxel as frontline therapy in patients with locally advanced, recurrent or metastatic pancreatic adenocarcinoma. Up to 24 patients will be enrolled in 4 dose escalation levels. The MTD is defined as the highest dose level at which 1 or less of 6 patients experience a dose limiting toxicity (DLT). Once the MTD is reached and/or the recommended dose for expansion is determined, an additional dose expansion cohort of 15 patients will be included. Secondary endpoints include characterizing the safety profile at the MTD and DLTs associated with it as well as obtaining pharmacokinetic data. Peripheral blood and pre-treatment tumor samples will be collected for evaluation of biomarkers that could predict treatment response, including levels of pAKT, p4EBP1 and pS6. BYL719 will be administered daily. Standard doses of gemcitabine and nab-paclitaxel will be given on days 1, 8 and 15 of the 28 days cycle. Patients will get restaging scans every 2 cycles. As per September 2015, twelve patients have been included in this study which is currently enrolling patients on cohort 3. Clinical trial information: NCT02155088 Clinical trial information: NCT02155088.
Perioperative stromal depletion by PEGPH20 in pancreatic ductal adenocarcinoma.
Authors: Ko Andrew H. , Cinar Pelin , Tempero Margaret A. , Nakakura Eric K. , Yeh Benjamin M , Chondros Dimitrios 
Published: February 2017

TPS476 Background: Treatment with PEGylated recombinant human hyaluronidase (PEGPH20) depletes stromal HA in pancreatic tumors, resulting in increased intratumoral perfusion and improved drug delivery. This Phase 2 study evaluates the clinical, biologic, and radiographic effects of neoadjuvant PEGPH20, gemcitabine (GEM) and nab-paclitaxel (NAB) in patients (pts) with borderline resectable pancreatic ductal adenocarcinoma (PDAC). Methods: Therapy-naïve patients aged ≥ 18 years with histologically confirmed PDAC defined as borderline resectable by consensus national guidelines will be eligible. Pts must have ECOG PS of 0-1 and adequate renal, marrow and hepatic function. Co-primary endpoints include incidence of postoperative pancreatic fistula and pathologic complete response rate. The trial uses a 2-stage design. In Part 1 (n = 15), pretreatment endoscopic ultrasound-guided core biopsies and functional MRI (fMRI) will be obtained. After a 1-week run-in with PEGPH20 (3μg/kg on Days [D]1 and 4), pts will undergo repeat biopsy and fMRI. Pts will then receive PEGPH20 (3μg/kg), NAB (125 mg/m2) and GEM (1000mg/m2) on D1, 8 and 15 of a 28-day cycle. Enoxaparin (1mg/kg daily) and dexamethasone (8mg pre- and post- PEGPH20) will be administered prophylactically. CA 19-9 levels will be checked monthly. Restaging CT will be obtained at the end of Cycles 2 and 4, with repeat fMRI performed after Cycle 4. Pts who are judged to be appropriate operative candidates upon multidisciplinary tumor board review will go to surgery at that point. Tissue analyses will be performed on the serially collected tumor samples, including the resected pancreatic specimen, with a focus on HA expression and immune cell infiltrates. Upon recovery, pts will receive 2 adjuvant cycles of GEM and NAB. If the predefined safety threshold is met in Part 1, an additional 21 pts will be enrolled in Part 2, without the one-week PEGPH20 run-in or pre- and post-run-in biopsies. Assuming 25 of the 36 pts are evaluable (i.e., able to go to surgery), a post-operative fistula rate of 11% would be able to be estimated with 95% CI of 3.4%-23.1%. Study initiation has begun as of September 2015. Clinical Trial Information: NCT02487277 Clinical trial information: NCT02487277.
LAPACT: An open-label, multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) in patients (pts) with locally advanced pancreatic cancer (LAPC).
Authors: Philip Philip Agop , Lacy Jill , Dowden Scot D. , Sastre Javier , Bathini Venu Gopal , Cardin Dana Backlund , Ma Wen Wee , Sobrero Alberto F. , Koski Sheryl L. , Borg Christophe , Tonini Giuseppe , Rivera Fernando , Hwang Jimmy J. , Knoble Jeanna L. , Al Baghdadi Tareq , Saif Wasif M. , Meiri Eyal , Kayitalire Louis , Li Jack , Hammel Pascal 
Published: February 2017

TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.
Phase I study of veliparib with gemcitabine and radiation therapy in patients with borderline resectable and locally advanced unresectable pancreatic cancer.
Authors: Tuli Richard , Nissen Nicholas N. , Annamalai Alagappan , Hoffman David M. J. , Bryant Miranda , Tighiouart Mourad , Rogatko Andre , Rokhsar Sepehr , Scher Kevin S. , Jamil Laith , Lo Simon , Hendifar Andrew Eugene 
Published: February 2017

TPS487 Background: Targeted inhibition of PARP1/2 is one way to further exploit the well-known synergy between gemcitabine (G) and radiotherapy (RT) in locally advanced pancreatic cancer (LAPC). PARP1/2 inhibitors, such as veliparib (V), have shown excellent anti-tumor activity when used with other cytotoxic therapies. This synergy may be further exploited in pancreatic cancer by targeting tumors with pre-existing defects in double- strand DNA repair. Extrapolating from our own laboratory findings (Tuli et al, Transl Oncol, 2014) and based on our hypothesis that PARP1/2 inhibition with G and RT will result in enhanced tumor control, we are conducting an IRB- approved phase I study in patients with borderline resectable and LAPC. Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of V, which is defined as the dose level resulting in a probability (θ = 0.4) that a dose limiting toxicity (DLT) will occur within six weeks. Treatment cycle is 3 weeks followed by weekly evaluation for an additional 3 weeks. G (1000 mg/m2) is administered on days 1, 8, 15. RT (36 Gy) is given in 15 fractions (2.4 Gy/day). V is administered BID in 20 mg increments beginning at a dose of 20 mg. Inclusion criteria: histolopathological diagnosis of borderline resectable or LAPC, age > 18 years, KPS > 70%, life expectancy > 6 months, normal organ and marrow function, and negative pregnancy test. Dose escalation follows a Bayesian escalation without control (EWOC) design, where time to DLT is modeled using a proportional hazards model with constant baseline hazard rate. Secondary objectives: 1) measure clinical activity using RECIST 1.1 for PFS, OS; 2) evaluate pre-treatment tumor biopsy specimen and longitudinal blood samples for baseline levels of DNA repair proteins (ERCC1, XRCC1, PAR, etc.) as potential prognostic, predictive and correlative biomarkers; and 3) assess BRCA1/2, PALB2, PTEN germline and somatic mutations using validated gene sequencing, immunohistochemical and quantitative PCR methods. Since December 2013, 26 patients have consented with 22 enrolled. Clinical trial information: NCT01908478.
HER2 amplification as a ‘molecular bait’ for trastuzumab-emtansine (T-DM1) precision chemotherapy to overcome anti-HER2 resistance in HER2 positive metastatic colorectal cancer: The HERACLES-RESCUE trial.
Authors: Siena Salvatore , Bardelli Alberto , Sartore-Bianchi Andrea , Martino Cosimo , Siravegna Giulia , Magri' Alessandro , Leone Francesco , Zagonel Vittorina , Lonardi Sara , Amatu Alessio , Tosi Federica , Racca Patrizia , Ponzetti Agostino , Ciardiello Fortunato , Marsoni Silvia 
Published: February 2017

TPS774 Background: We previously documented HER2 amplification in 5% of KRAS wild-type metastatic colorectal cancer (mCRC; Valtorta E. et al, Modern Pathology, 2015). Despite refractoriness to standard chemotherapy and to cetuximab, patients with HER2 amplified mCRC achieve 30% response rate (RR) and long lasting objective responses (median duration 8.5 mos.) when treated with lapatinib (L) and trastuzumab (T) [HERACLES trial - EudraCT 2012-002128-33; Siena et al. J Clin Oncol 33, 2015 (suppl; abs 3508)]. We sampled responding HERACLES patients at progression, and found persistent high levels of HER2 tested by IHC and FISH on tissue re-biopsies, or by droplet digital liquid biopsy in plasma ctDNA (LB). We reasoned that HER2 in these tumors could still be exploited as “molecular bait” for T-DM1, an antibody-drug conjugate of trastuzumab linked to the cytotoxic agent emtansine. We thus conducted a preclinical trial in a patient-derived xenograft (PDX) model generated from the viable biopsy of a acquired-resistant HERACLES patient. In a 2-arm trial against control (6 PDXs per arm), we compared T-DM1 to pertuzumab, and found that only T-DM1 treated animals achieved tumor responses. We therefore designed a proof-of-concept trial of T-DM1 in HER2 amplified mCRC patients progressing or relapsing after T+L treatment. Methods: HERACLES-RESCUE is an independent phase II trial assessing the efficacy of T-DM1 in HER2 amplified mCRC progressing after anti-HER2 (L+T) therapy within the HERACLES trial. Response rate is the primary endpoint. Using the A’Hern approach to retrofit the sample size from the constrained sample size of patients treated in HERACLES, and assuming α = 0.15, β = 0.85 and H0 = 5%, if 2 responses will be observed in 13 patients we would be able to define a clinically relevant true response rate of 25% (H1). Eligibility: progression/relapse within HERACLES L+T treatment, lack of KRAS mutations by LB, measurable disease (RECIST v1.1), ECOG PS ≤ 1, and adequate organ function. Treatment: T-DM1: 3,6 mg/kg q21d. A first patient was treated on August 2015. EudraCT number: 2015-003275-30; Funded by AIRC Grant # 9970. Clinical trial information: 2015-003275-30.
Neoadjuvant chemotherapy alone with mFOLFOXIRI in locally advanced rectal cancer: A single-arm phase II study.
Authors: Deng Yanhong , Zhang Jianwei , Cai Yue , Hu Huabin , Ling Jiayu , Xiao Jian , Huang Meijin , Kang Liang , Wang Lei , Lan Ping , Wang Jianping 
Published: February 2017

TPS783 Background: Pre-operative 5-Fu based chemoradiation is still the standard of treatment for locally advanced rectal cancer (LARC). Although local recurrence rate had been controlled, about 30% of patients will develop distant metastases, which is the main obstacle for improving survival of LARC. Besides, preoperative radiation causes lots of concerns about anal and sexual functions. Whether systemic chemotherapy alone is effective enough in treating rectal cancer is not yet known. In our previous study of neoadjuvant mFOLFOX6 with or without radiotherapy in LARC, about 30% of patients in the arm with chemotherapy alone showed good response. And FOLFOXIRI had showed higher response rate in metastatic colorectal cancer. This phase II study is to explore whether pre-operative FOLFOXIRI could further improve the ratio of tumor downstaging (ypT0-2N0) in LARC. Methods: The primary endpoint is the ratio of tumor downstaging to ypT0-2N0M0 (pCR and stage I).The secondary endpoint included pathologic complete response rate, 3-year disease free survival rate, 3-year local recurrence rate, and safety. We hypothesized that FOLFOXIRI could improve the downstaging rate from 30% to 50% with 5% type I error and 80% power. 84 patients met inclusion criteria will be enrolled in the trial. All patients will receive the study regimen every 2 weeks for 4-6 cycles. MRI of the pelvic will be performed every 2 cycles of the therapy to assess clinical response. If the tumor response over 20% after 4 cycles of treatment, the patient will go to surgery (TME) directly or 2 more cycles of treatment before surgery under the decision of MDT. On the contrary, if the tumor show poor response (< 20%), short-term radiotherapy will be performed before operation. After surgery, 6-8 cycles of mFOLFOX6 will be given as adjuvant chemotherapy. Clinical trial information: NCT02217020 Clinical trial information: NCT02217020.
Phase III double-blinded, placebo-controlled study of MABp1 for improving survival in metastatic colorectal cancer.
Authors: Goel Sanjay , Wyrwicz Lucjan , Choi Minsig , Coveler Andrew L. , Ucar Antonio , Brown Alexander Ward , Sarosiek Tomasz , Wong Lucas , Stecher Michael , Fisher George A. , Hendifar Andrew Eugene 
Published: February 2017

TPS784 Background: Interleukin 1 alpha (IL-1a) is a pro-inflammatory cytokine that initiates and propagates sterile inflammatory responses. IL-1a is present on the surface of tumors, and released from necrotic cells within the microenvironment, where it upregulates MMPs, VEGF, chemotactic cytokines, and IL-6 contributing to tumor growth and infiltration of the microenvironment by T-regulatory cells and tumor associated macrophages. IL-1a is also found on the surface of platelets and activates vascular endothelium allowing for circulating tumor cells to establish new areas of metastasis. Specific blockade of IL-1a with the true human IgG1k antibody MABp1, is expected to deprive the tumor of its ability to grow, spread, and evade immune surveillance. A phase I/II study showed radiographic evidence of tumor response in mCRC patients, as well as clinically meaningful improvement in cancer associated symptoms, with no significant toxicity. In the context of this therapy, the improvement in key cancer symptoms, including reversal of lean body mass loss, fatigue, and anorexia, is the direct result of an anti-neoplastic effect and is expected to correlate with an overall survival benefit. Methods: This “Phase III Study of MABp1 in Patients With Advanced Colorectal Cancer (XCITE)” is a global study of 600 patients, ECOG-PS 0-2, metastatic CRC refractory to oxaliplatin, irinotecan, fluoropyrimidine, and EGFR-inhibitors if KRAS wildtype. Patients are randomized 2:1 to receive MABp1 7.5 mg/kg iv every two weeks plus best supportive care (BSC) versus placebo (iv Q2 week) plus BSC. BSC does not include any other therapy with proven anti-cancer activity. The primary endpoint is OS, with secondary endpoints of PFS, ORR, change in lean body mass, and QoL. Patients continue on trial until clinical or radiographic progression as defined by the immune related response criteria (irRC). The study is powered to show a clinically meaningful improvement in OS, evaluated by log-rank test with a one-sided alpha of 0.025. As of September 2015, enrollment is currently underway in the United States and Europe, and results of the first interim analysis are expected in 2016. [NCT01767857]. Clinical trial information: NCT01767857.
Measuring value in bundled payments for head and neck cancer.
Authors: Lee Seohyun , Spinks Tracy E. , Guzman Alexis B. , Weber Randal S. , Hanna Ehab Y. , Hessel Amy Clark , Beadle Beth Michelle , Hutcheson Kate A. , Incalcaterra James , Wood Nancy M. , Jones Delrose , Feeley Thomas W. 
Published: February 2017

11 Background: Value, defined as outcomes relative to costs, cannot be improved without rigorous long-term measurement. To assess value within a bundled payment pilot for head and neck cancer, we aim to generate timely, patient-centered outcomes and robust, near-real time financial tracking (Porter and Teisberg, Redefining health care. Creating value-based competition on results; Harvard Business School Press, 2006). Methods: Clinical and quality experts created an outcome measure set for head and neck cancer, using a three-tiered outcomes hierarchy from Michael Porter of Harvard Business School as a framework. Process measures were identified to evaluate compliance with standards of care. Data sources were verified and patient-reported outcomes were collected via a patient portal. A REDCap database was created to aggregate all longitudinal outcomes. The project managers and financial leaders identified key financial metrics to be tracked for enrolled patients. Outcomes and financial data were built into a dashboard to deliver timely, actionable information on value. Patients will be tracked for 2 years post-treatment completion. Results: 22 outcome measures and 6 process measures are being collected for all enrolled patients. Financial indicators, such as cumulative costs and fee-for-service payment vs. bundled payment, are being tracked for each patient. Currently, most outcomes and financial data are extracted manually. Implementation of a new electronic health record (EHR) should alleviate much of this administrative burden (Table). Conclusions: The project demonstrates the feasibility of value measurement for bundled payment. With provider and patient input, the outcome measures direct attention to what is important to patients and is actionable by clinicians. Additionally, near real-time financial tracking offers insights into the financial implications of this alternative payment model for cancer care. With automation via the EHR, this value measurement methodology can be scaled for other disease sites and additional payers. [Table: see text]