bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter phase Ib/II study of DNA-PK inhibitor peposertib (M3814) in combination with capecitabine and radiotherapy in patients with locally advanced rectal cancer.
Authors: Romesser Paul Bernard , Holliday Emma B. , Philip Tony , Garcia-Carbonero Rocio , Capdevila Jaume , Tuli Richard , Sarholz Barbara , Kuipers Mirjam , Rodriguez Almudena , Diaz-Padilla Ivan , Miller Eric David 
Published: January 2021

TPS144 Background: Perioperative radiotherapy and chemotherapy, followed by total mesorectal excision, is the standard of care for patients with locally advanced rectal cancer (LARC). However, 1/3 of these patients still develop distant metastases, indicating the need for more effective therapies. In addition, strategies that increase pathological complete response rates are needed to enable non-surgical management of LARC. DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage repair pathway for double-strand break repair. Peposertib (M3814), a potent, selective, orally administered DNA-PK inhibitor, has been shown to potentiate the effect of ionizing radiation in a human colon cancer xenograft model and several colon cancer cell lines. Peposertib is being investigated in several different trials across multiple indications. This Phase Ib/II study (NCT03770689) aims to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of the neoadjuvant treatment combination of peposertib, capecitabine, and radiotherapy (RT) in patients with LARC. Methods: Patients aged ≥18 years with histologically confirmed and resectable Stage II/III rectal adenocarcinoma are eligible. Induction chemotherapy is permitted, but residual disease must first be documented by MRI, digital rectal examination and endoscopy. Patients who received other anticancer therapies or those with prior pelvic RT are excluded. At open-label Phase Ib (open), 18–30 patients (n = 3 per cohort) will receive peposertib + capecitabine (orally, 825 mg/m2 twice daily [BID]) + RT (45–50.4 Gy), 5 days/week. Peposertib 50 mg once daily (QD) was the starting dose. Additional dose levels will range between 100─800 mg QD. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. At Phase II (planned), 150 patients will be randomized (1:1) to receive oral capecitabine (825 mg/m2 BID) + RT (45–50 Gy), with either oral peposertib (recommended phase II dose [RP2D] or placebo, QD for 5 days/week. Primary objectives are to define a maximum tolerated dose and RP2D (Phase Ib), and to evaluate the efficacy of peposertib + capecitabine + RT in terms of pathological/clinical complete response (Phase II). Secondary objectives include assessment of antitumor activity (Phase Ib), quality of life outcomes (Phase II), and PK of peposertib, and the safety and tolerability of the combination therapy (both phases). To date, one patient has received peposertib 50 mg QD, six patients peposertib 100 mg QD, three patients peposertib 150 mg QD, and three patients peposertib 250 mg QD. Clinical trial information: NCT03770689.
Olaparib ± bevacizumab versus bevacizumab + fluorouracil in patients with unresectable or metastatic colorectal cancer not progressing on first-line FOLFOX + bevacizumab: Phase III LYNK-003 study.
Authors: Mayo Carlos Alberto , Gurary Ellen B. , Marinello Patricia 
Published: January 2021

TPS156 Background: Patients with metastatic colorectal cancer (CRC) often receive intensive platinum-based regimens, such as FOLFOX (fluorouracil [5-FU], leucovorin, oxaliplatin), as first-line (1L) therapy. For patients who do not progress during 1L platinum-based induction therapy, maintenance with a less intensive regimen can enhance clinical benefit and reduce toxicity. The CAIRO3 study showed a progression-free survival (PFS) benefit and a trend toward overall survival (OS) benefit in patients who received maintenance treatment with a fluoropyrimidine and bevacizumab versus observation following induction treatment of six cycles of platinum-based therapy. Olaparib is an oral PARP inhibitor that has efficacy in platinum-sensitive cancers. The randomized, open-label, phase 3 LYNK-003 trial will investigate the efficacy and safety of olaparib, alone or with bevacizumab, compared with bevacizumab plus 5-FU in advanced CRC that has not progressed during 1L induction treatment with FOLFOX plus bevacizumab. Methods: Patients aged ≥18 years with histologically confirmed metastatic or unresectable CRC that has not progressed after 1L induction of ≥6 cycles of FOLFOX plus bevacizumab and who can no longer tolerate oxaliplatin are eligible. Patients must have an ECOG performance status of 0-1, adequate organ function, and provide tumor tissue for biomarker analysis. Patients will be randomly assigned 1:1:1 to olaparib 300 mg twice-daily (BID), olaparib 300 mg BID plus bevacizumab 5 mg/kg every 2 weeks (Q2W), or bevacizumab 5 mg/kg Q2W plus 5-FU 2400 mg/m2 over 46-48 hours Q2W. Randomization will be stratified by response to prior FOLFOX plus bevacizumab (stable disease vs partial response/complete response), mutation status ( BRAFmut and/or Rasmut vs BRAFwt plus Raswt), and number of prior FOLFOX plus bevacizumab cycles (6-8 vs > 8 cycles). Response will be assessed by computed tomography or contrast-enhanced magnetic resonance imaging per RECIST 1.1 by blinded independent central review (BICR) every 8 weeks for the first 12 months and every 12 weeks thereafter. Treatment will continue until documented disease progression, unacceptable toxicity, investigator’s decision to discontinue, or patient withdrawal. The primary endpoint is PFS per RECIST 1.1 by BICR. Secondary endpoints are OS, objective response rate, duration of response, and safety. Approximately 525 patients will be enrolled. Currently, patients are being enrolled at 18 locations in 4 countries. Clinical trial information: NCT04456699.
A phase Ib multicenter study of trifluridine/tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients with advanced recurrent or unresectable gastric and gastroesophageal adenocarcinoma (aGEC) after at least one line of treatment with a fluoropyrimidine and platinum containing regimen.
Authors: Dayyani Farshid , Tam Kit , Kim Edward , Keshtmand Parvin , Ejadi Samuel , Lee Fa Chyi , Cho May Thet 
Published: January 2021

TPS251 Background: In 2L+ aGEC, taxanes +/- ramucirumab or IRI are recommended treatment options. IRI has been tested in multiple single arm and randomized trials in second line (2L)+ aGEC, with reported objective response rates (ORR) in the 15-29% range and median progression-free survival (PFS) of <3 months (mo). Outcomes for aGEC remain poor with a median overall survival (OS) of 9.6 mo and PFS at 6 mo (PFS6) of only 36%. The TAGS trial in third line (3L)+ aGEC showed a significant improvement in OS from 3.6 mo to 5.7 mo with FTD/TPI over placebo. A 2L treatment with taxanes after 1L platinum containing regimens is currently associated with worsening peripheral neuropathy, which often leads to dose reductions, treatment delays, and a reduced quality of life for patients. The feasibility of FTD/TPI combined with IRI (+/- bevacizumab) in a modified 14-day schedule has been published for advanced colon cancer (PMID: 31924737) with no new safety signals while also encouraging activity in a cohort of heavily pretreated patients. Methods: Hypothesis:The combination of FTD/TPI with IRI in 2L+ aGEC is feasible, clinically active, and provides a treatment option which is not associated with development of peripheral neuropathy. Trial Design: 2-center, prospective, open label, non-randomized phase 1b trial. Eligibility: Diagnosis of aGEC, 1+ line of treatment including a fluoropyrimidine/platinum, ECOG 0-2, adequate organ function. Treatment:FTD/TPI 25mg/m2 on days 1-5 and IRI 180mg/m2 on day 1 every 14 days. G-CSF in allowed as needed. Primary objective: Feasibility of the regimen and estimate of efficacy. Primary endpoint: PFS6. Secondary objectives: OS, ORR, adverse events. Total number of pts to be enrolled N=20. Current enrollment (September 2020) N=14. Clinical trial information: NCT04074343.
A phase IIb, open-label, single-arm study of zanidatamab (ZW25) monotherapy in subjects with advanced or metastatic HER2-amplified biliary tract cancers.
Authors: Pant Shubham , Ducreux Michel , Harding James J. , Javle Milind M. , Oh Do-Youn , Wasan Harpreet Singh , Fortenberry Allison , Josephson Neil C. , Mwatha Anthony , Wang Kui , Fan Jia 
Published: January 2021

TPS352 Background: Advanced biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CC), have a poor prognosis. Zanidatamab (ZW25) is a novel bispecific antibody that targets HER2 domains ECD2 and ECD4, resulting in increased antibody binding density and improved receptor internalization and downregulation relative to trastuzumab. In an ongoing phase I trial (ZWI-ZW25-101; NCT02892123), single-agent zanidatamab was well tolerated and showed promising anti-tumor activity across HER2-expressing solid tumors, including BTCs. These results formed the basis for a phase IIb study of zanidatamab in patients with BTC. Methods: Study ZWI-ZW25-203 (NCT04466891) is a global, multicenter, open-label, single-arm, phase IIb trial designed to evaluate the anti-tumor activity of zanidatamab monotherapy in patients with HER2-amplified, inoperable and advanced or metastatic BTCs, including GBC and CC. Patients must have received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced disease and have experienced disease progression after (or developed intolerance to) their most recent prior therapy. New or archival tumor tissue is required from all patients for HER2 amplification and protein expression testing at a central lab using in situ hybridization (ISH) and immunohistochemistry (IHC) assays. Approximately 100 patients with HER2 amplification by ISH will be enrolled. Zanidatamab 20 mg/kg will be administered intravenously every 2 weeks until one of the treatment discontinuation criteria is met. The primary endpoint of the study is the confirmed objective response rate (ORR) by independent central review per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Secondary endpoints include duration of response (DOR), proportion of patients with DOR ≥ 16 weeks, disease control rate, progression-free survival, overall survival, safety, quality of life, and disease-related pain. The safety and tolerability of zanidatamab will be assessed by recording the frequency and severity of adverse events, serious adverse events, and laboratory abnormalities, as well as the frequency of zanidatamab dose modifications. The study is currently open for enrollment. Clinical trial information: NCT04466891.
Perioperative chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone in gallbladder carcinoma or in front of radical resection in BTC: The phase III GAIN trial.
Authors: Goetze Thorsten Oliver , Lorenzen Sylvie , Bankstahl Ulli Simone , Lang Sven A. , Wittel Uwe A , Heeg Steffen , Bechstein Wolf Otto , Schnitzbauer Andreas , Pession Ursula , Reim Daniel , Keck Tobias , Königsrainer Alfred , Piso Pompiliu , Vogel Arndt , Wirth Thomas , Rahbari Nuh N. , Reissfelder Christoph , Belle Sebastian , Pauligk Claudia , Al-Batran Salah-Eddin 
Published: January 2021

TPS353 Background: Radical surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) and Gallbladder Carcinoma (GBC). Nevertheless, 5-year OS is only 20–40% after curatively intended resection. GBC is the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. The majority of gallbladder carcinoma cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication, so called incidental gallbladder carcinomas. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. Encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase management of GBC and intrahepatic as well extrahepatic cholangiocarcinoma, especially because data regarding pure adjuvant chemotherapy in BTC`s are currently conflicting. Methods: GAIN is a multicenter, randomized, controlled, open-label phase III trial, including pts with GBCs in front of radical liver resection and pts with resectable/borderline resectable intra- and extrahepatic cholangiocarcinomas (ICC/ECC). Pts. are randomized to either neoadjuvant systemic chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) followed by radical surgery or to direct surgery without neoadjuvant treatment. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has just started; first patient in was on December 6th, 2019. Clinical trial information: NCT03673072.
A phase II study of infigratinib in previously treated advanced/metastatic cholangiocarcinoma with FGFR gene fusions/alterations.
Authors: Javle Milind M. , Kelley Robin Kate , Springfeld Christoph , Abou-Alfa Ghassan K. , Macarulla Teresa , Tanasanvimon Suebpong , Goyal Lipika , Borbath Ivan , Bitzer Michael , Yong Wei-Peng , Philip Philip Agop , Alvarez-Gallego Rafael , Pande Amit , Shepherd Stacie Peacock , Fontaine Jacki , Roychowdhury Sameek 
Published: January 2021

TPS356 Background: The FGFR family plays an important role in cholangiocarcinoma, with FGFR2 gene fusions detected in about 15% of patients with cholangiocarcinoma. Infigratinib is an FGFR1–3-selective oral tyrosine kinase inhibitor under evaluation in multiple indications including front-line and pre-treated cholangiocarcinoma. CBGJ398X2204 is an ongoing phase II study evaluating the efficacy of single-agent infigratinib in patients with advanced or metastatic cholangiocarcinoma with FGFR genetic alterations who have received prior gemcitabine. Methods: Study CBGJ398X2204 consists of 3 cohorts and patients in all cohorts receive oral infigratinib once daily for 21 days of a 28-day treatment cycle. Treatment will continue until progressive disease, intolerance, withdrawal of consent, or death. Cohort 1 includes patients with FGFR2 gene fusions or translocations. Cohort 2 includes patients with FGFR genetic alterations other than FGFR2 gene fusions (patients in both Cohorts 1 and 2 must not have received any prior FGFR inhibitors). Cohort 3 includes patients with FGFR2 gene fusions who have received prior treatment with a selective FGFR inhibitor other than infigratinib. The primary endpoint is objective response rate (ORR, RECIST v1.1 per central review). Secondary endpoints include overall survival and overall response rate (per investigator). Safety, pharmacokinetics, and exploratory genetic alterations/biomarkers will also be measured. The study was initiated in 2014 and has a planned enrollment of up to 160 patients across all 3 cohorts (120 in Cohort 1, 20 in Cohort 2, and 20 in Cohort 3). Cohort 1 has completed enrollment and findings from this Cohort are the focus of a separate abstract submitted to the meeting. Results are not currently available from Cohorts 2 and 3 (trial in progress). Clinical trial information: NCT02150967.
Systemic therapy with a loco-regional treatment in patients with locally advanced pancreatic cancer: The SMART study.
Authors: Ahmed Shahid , Ahmed Osama , Anderson Deborah , Beck Gavin , Chalchal Haji I. , Dwernychuk Lynn , Gitlin Josh , Hammond Austin , Iqbal Mussawar , Lim June , Pati Sukanya , Sari Nazmi , Shaw John , Souied Osama , Wall Christopher , Zaidi Adnan , Moser Michael 
Published: January 2021

TPS445 Background: Pancreatic cancer is a major cause of cancer-related death. About 40% of patients with pancreatic cancer present with locally advanced disease and are not candidates for curative surgery. Most patients are treated with chemotherapy with a limited life expectancy. The role of local treatment such as radiation is not well defined. Other conventional ablative therapies, such as thermal or cryoablation have limited role due to the risk of collateral damage to the adjacent structures. Irreversible electroporation (IRE) is a novel non-thermal ablation technology that does not cause injury to nearby blood vessels, ducts, and bowel and has the potential to provide longer disease control and thereby better overall survival. We hypothesized that addition of IRE to combination chemotherapy in patients with locally advanced pancreatic cancer will improve their outcomes, and patients with undetectable 12-week post IRE circulating tumor cell DNA will have better prognoses. Methods: It is a prospective, multicenter, single-arm phase II study. The primary objective is to determine 12-month PFS rate of patients with locally advanced pancreatic cancer who are treated with combination chemotherapy and IRE. Secondary objectives include identification of prognostic and predictive biomarkers, 24-months survival rate, quality of life of subjects, as well as cost-effectiveness and complication rates of IRE. Based on the assumption that treatment with IRE and chemotherapy would result in doubling of PFS versus chemotherapy alone a sample of n = 27 of patients with locally advanced pancreatic adenocarcinoma is estimated. Eligible patients will be recruited at the two major cancer centers in Saskatchewan. All IRE-eligible patients will receive 12 weeks of induction combination chemotherapy and will undergo IRE if there is no disease progression. An additional 12 weeks of chemotherapy will be recommended. Patients who are not eligible for IRE will receive chemotherapy at the discretion of treating oncologist until disease progression or until they become eligible for IRE. Circulating tumor DNA and a panel of genes will be examined using next-generation sequencing for their correlation with prognosis. Quality of life will be assessed, and cost-effectiveness analysis of IRE will be performed.The results of this study will be used to develop a future multicenter, national phase III trial. Clinical trial information: NCT04276857.
A phase III trial of tumor-treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma (LAPC): PANOVA-3.
Authors: Picozzi Vincent J. , Macarulla Teresa , Philip Philip Agop , Becerra Carlos Roberto , Dragovich Tomislav 
Published: January 2021

TPS448 Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma. TTFields at specific frequency (150-200 kHz) are delivered via transducer arrays placed on the skin in proximity to the tumor site. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The phase 2 PANOVA study, the first trial testing TTFields in pancreatic cancer patients, demonstrated the safety and preliminary efficacy of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and LAPC. The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy and safety of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Methods: Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields (150 kHz) will be delivered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q8w, including a CT scan of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint and progression-free survival, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%. Clinical trial information: NCT03377491.
Resection of Retro-Hepatic Vena Cava (RHVC) En-bloc with Caudate Lobe without Vascular Exclusion for a Low Grade Leiomyosarcoma of Inferior Vena Cava
Authors: Altomare Michele , Sposito Carlo , Regalia Enrico , Coppa Jorgelina , Flores Maria , Manzo Elena , Droz Dit Busset Michele , Mazzaferro Vincenzo 
Published: January 2021

Abstract
Background
Leiomyosarcomas (LMS) of the inferior vena cava (IVC) originate in the retrohepatic (RHVC) portion in 15% of cases.1 Due to complex anatomy and need to preserve venous outflow from the infra-diaphragmatic viscera, the operation may require total vascular exclusion, veno-venous bypass and hypothermic liver resections.2,3 In this video, virtual planning of the operation allowed a parenchyma-sparing radical resection in a patient with limited liver reserve.

Methods
A 12-cm LMS of RHVC invading the entire segment 1 (i.e., Spiegel’s lobe, paracaval portion, and caudate process) was diagnosed in a man with metabolic steato-hepatitis (BMI: 34). He had no response to previous chemotherapy. Major hepatectomy was excluded considering the high risk of postoperative liver failure. 3D-reconstruction of regional anatomy allowed planning of a parenchymal-sparing, en bloc resection of tumor, RHVC, and caudate lobe while avoiding hilar and suprahepatic venous clamping.

Results
The operation strategy relied on the en bloc separation of caudate lobe, RHVC, and tumor from the hepatic veins confluence and the posterior segments after complete mobilization of the liver. Vessel loop-assisted hanging maneuver, encircling tumor, and RHVC with superimposed 3D-reconstructions guided the parenchymal transection, while preserving the middle hepatic vein outflow. RHVC was replaced with prosthetic material.

Conclusions
Complex resection of primary tumor of the IVC en bloc with caudate lobe and RHVC can be attempted in chronic liver diseases at-risk of postoperative failure. Preservations of transhepatic flow and liver function depends on tumor size and preservation of noninvaded hepatic-veins confluence. Preoperative virtual 3D reconstruction is crucial in surgical planning.