bluuebunny/crossref_metadata_2025_split huggingface dataset:
nextHERIZON: A phase 2 study of HER-Vaxx, a HER2-targeting peptide vaccine, in combination with chemotherapy or pembrolizumab in patients with HER2 metastatic or advanced gastric/gastroesophageal adenocarcinoma that progressed on or after trastuzumab treatment.
Authors: Price Timothy Jay , Chong Leslie Mi Ok , Ede Nicholas , Nixon Bonnie , Withana Nimali , Yavrom Sharon , Selvaggi Giovanni , Good Anthony J. 
Published: January 2023

TPS481 Background: HER-Vaxx is a B-cell peptide vaccine composed of a fusion of 3 epitopes from the extracellular domain of HER2/neu conjugated to CRM197 with the adjuvant Montanide. Results from a phase 1b study revealed that active immunization with HER-Vaxx was well tolerated and induced HER2-dose dependent immune responses corresponding to tumor reduction in advanced gastric cancer (GC) or gastroesophageal adenocarcinoma (GEA) (Wiedermann, 2021). A phase 2 study, HERIZON, comparing HER-Vaxx plus standard chemotherapy or chemotherapy alone is currently enrolling. Pre-clinical data demonstrated a synergistic effect with combination of HER2 and PD-1 vaccines and 90% tumor growth inhibition (Kaumaya, 2020). Ramucirumab plus paclitaxel is an approved second-line treatment for patients with GC or GEA who have failed first-line treatment chemotherapy or trastuzumab (TRA) (Wilke, 2014). The nextHERIZON study seeks to evaluate the clinical benefit of adding HER-Vaxx to ramucirumab plus paclitaxel or pembrolizumab, following progression on TRA. Methods: nextHERIZON is phase 2, open-label, non-comparative, double arm, 2-stage design study in patients with confirmed AGC and HER2 overexpression following progression on or after TRA. Arm assignment depends on prior PD-1/PD-L1 inhibitor treatment. Arm 1 will receive HER-Vaxx + ramucirumab and paclitaxel. Arm 2 will receive HER-Vaxx + pembrolizumab. Up to 55 patients will be enrolled in each arm which includes a safety run-in phase. Arms will be analyzed independently. The key inclusion criteria are: patients ³ 18 year of age; ECOG 0 or 1; minimum life expectancy of 3 months; progressed on or after TRA; confirmed HER2 overexpression; at least one measurable lesion; adequate hematologic and organ function. Key exclusion criteria include previous treatment with trastuzumab-deruxtecan or any other anti-HER2 therapy other than trastuzumab. Arm 2 excludes prior therapy with anti- PD-1, PD-L1 or PD-L2 agents. The co-primary endpoints are safety and objective response rate (RECIST 1.1). Secondary objectives are efficacy and survival measures. HER-Vaxx is administered by intramuscular (IM) injection on Day 1, Day 15, and Day 29 and on Day 1 of each 2nd or 3rd cycle depending on arm. Dose-limiting toxicity (DLT) window is 29 days on treatment. Tumor assessment is evaluated at Day 43 then every 6 weeks until progression or withdrawal. This study is currently enrolling patients in Australia and US (Q1 2023). Clinical trial information: NCT05311176 .
An open-label, multi-center phase IIIb study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma (TREMENDOUS study).
Authors: Fan Jia , Qin Shukui , Sun Hui-Chuan 
Published: January 2023

TPS628 Background: Hepatocellular carcinoma (HCC) is of high incidence and mortality rate in China, with nearly half of them are diagnosed as advanced or metastatic stage at the initial diagnosis. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors and immune checkpoint inhibitors in combination with vascular endothelial growth factor. Recently, the phase III HIMALAYA trial investigated the STRIDE regimen, tremelimumab 300mg × 1 dose and durvalumab 1500mg every 4 weeks, compared to sorafenib in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved overall survival (OS) (16.4 mos vs 13.8mos, HR=0.78) and a well-tolerated safety profile (≥grade 3 treatment-related adverse events 25.8% vs 36.9% ). Notably, the HIMALAYA trial did not enroll subject from mainland China and excluded patients with class Child-Pugh B liver dysfunction or ECOG performance status (PS) 2. We hypothesize the STRIDE regimen will be safe and well tolerated in Chinese patients with locally advanced or metastatic HCC with Child-Pugh class A or B liver dysfunction or ECOG PS 0-2. In addition, the study will also assess efficacy and explore biomarkers. Methods: This will be an open label, multi-center phase IIIb study investigating the safety and efficacy of the STRIDE regimen in Chinese unresectable HCC patients without prior systemic therapy. Patients with Child-Pugh A liver dysfunction and ECOG PS 0-1 will be enrolled in cohort 1, while patients with Child-Pugh B liver dysfunction or ECOG PS 2 will be enrolled in cohort 2. Patients with main portal vein tumor thrombosis (Vp4), clinically significant ascites or hepatic encephalopathy, or active or prior documented gastrointestinal bleeding within 12 months will be excluded. We plan to enroll 300 patients with the primary endpoint of grade 3-5 adverse event (AE) rate by CTCAE v5.0 and adverse events of special interest (AESI). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), OS, OS rate at 6 months and 12 months. Patients of both cohorts will receive a single dose of tremelimumab 300 mg and durvalumab 1500 mg at Cycle 1 (Week 0), followed by durvalumab 1500 mg monotherapy every 4 weeks until confirmed disease progression or unacceptable toxicity. Archival or fresh tumor biopsy will be required at baseline. The trial is currently screening eligible subjects. Clinical trial information: CTR20222433 .
Phase II trial of durvalumab (MEDI4736) with/without tremelimumab for advanced hepatocellular carcinoma after palliative hypofractionated radiotherapy.
Authors: Andemicael Luchia , Chang Hewitt , Anwar Moshiur Mekhail , Bauer Kelly , Gordan John , Johnson Jamese , Keenan Bridget P , Venook Alan P. , Wang Chia-Ching Jackie , Zhang Karen , Fong Lawrence , Kelley Robin Kate , Feng Mary Uan-Sian 
Published: January 2023

TPS630 Background: Hepatocellular Carcinoma (HCC) is among the most common types and leading causes of cancer death globally, and the incidence is on the rise. For patients with advanced hepatocellular carcinoma (HCC), immune checkpoint inhibitors (ICI) in combination with anti-angiogenic agents or other ICI improve survival compared with tyrosine kinase inhibition. Though ICI-based regimens can achieve prolonged responses in some patients and prolong overall survival, only a subset of patients achieve durable responses. There is an urgent need for strategies to overcome primary and acquired resistance. Many of these patients have symptomatic sites of disease which could benefit from local palliative radiotherapy. Radiotherapy also has the potential to elicit an abscopal immune response when combined with ICI. We hypothesize that combining Radiation Treatment (RT) with Durvalumab or the combination of Durvalumab + Tremelimumab (combination D+T in STRIDE regimen showed OS improvement in HIMALAYA trial in 1st line HCC) will achieve a meaningful response rate in advanced HCC patients after progression on other ICI-based therapies. Methods: This is an open label, single center, two-arm, non-comparative phase II trial. Key eligibility criteria are; histologically-diagnosed HCC with progression during or after prior PD-(L)1 checkpoint inhibitor immunotherapy and at least 1 RECIST 1.1-measurable tumor present which has not received RT or other local therapy prior to enrollment, ECOG 0-1, and Child Pugh score of A, B7, or B8. Patients are assigned sequentially to either single-agent durvalumab initiated starting 3 to 10 days after completing RT (25 Gy in 5 fractions to 1-5 sites of disease), at fixed dose of 1500 mg IV every 28 days, or a single fixed dose of tremelimumab of 300 mg IV administered on Day 1, initiated within 3-10 days of completing RT, in combination with durvalumab at fixed dose of 1500 mg IV every 28 days; for up to 24 months or until confirmed radiographic progression. The primary end point is overall response rate (ORR) and secondary endpoints include proportion of participants with adverse events, overall survival, progression free survival and duration of response. Exploratory endpoints include profiling of peripheral blood mononuclear cell immune cells and plasma biomarkers. We plan to accrue 30 patients to this study, 15 to each Arm, to evaluate ORR which would allow us to detect at least a 20% ORR, which would be a clinically meaningful improvement in efficacy in this population with otherwise poor treatment options assuming a statistical power of 87% and a directional 5% statistical significance level based upon an exact binomial test. The trial is open and enrolling. Clinical trial information: NCT04430452 .
A randomized, multi-center phase III trial of adjuvant chemotherapy with gemcitabine and capecitabine (GemCap) compared to capecitabine (Cap) alone in curatively resected biliary tract cancer (BilGemCap Study): KCSG HB20-14.
Authors: Park Joon Oh , Park Joon Seong , Lee Choong-kun , Chon Hong Jae , Choi Sae Byeol , Hwang Dae Wook , Oh Do-Youn , Lee Myung Ah , Jang Jin-Young , Ryoo Baek-Yeol 
Published: January 2023

TPS633 Background: Biliary tract cancers (BTCs) are usually diagnosed at an advanced stage; thus, only 20% of the patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. Recent phase 3 trials using single agent such as Cap or S1 support the role of adjuvant chemotherapy as standard of care in patients with resected BTCs, but the efficacy still needs to be further improved. Therefore, we designed a randomized, multi-center, phase 3 trial comparing GemCap with Cap in curatively resected BTC patients. Methods: The primary endpoint is 24-month disease-free survival (DFS) and secondary endpoints are overall survival (OS), quality of life (QOL), toxicities and exploratory biomarker analysis. Referring to the recent results of BILCAP study, the sample size calculation is based on the assumption that the 24-month DFS would be 50% in the Cap arm, and that treatment with GemCap would improve the 24-months DFS by 10%, from 50% to 60%. As such, 490 patients and 337 events are needed to detect a HR of 0.737, with a two-sided significance level of 5% and 80% power. Patients aged 19 years or older with macroscopically resected intra- or extrahepatic cholangiocarcinoma and muscle-invasive gallbladder cancer (T2-4 or N1-2, M0) are eligible. The Eastern Cooperative Oncology Group (ECOG) performance status have to be 0-1, and adequate renal, hematological, and liver function is required. Patients who had not completely recovered within 12 weeks from surgery or who had previous history of chemotherapy or radiotherapy for BTC are also excluded. Patients are randomly assigned 1:1 to the GemCap arm or the Cap arm, stratified by LN status (N0 vs. N+), resection status (R0 vs. R1) and primary site. After randomization, either oral Cap (1250 mg/m²) twice a day on days 1 to 14 of a 3-weekly cycle (8 cycles), or oral Cap (830 mg/m²) twice a day on days 1 to 21 plus Gem (830 mg/m²) on days 1, 8 and 15 of a 4-weeky cycle (6 cycles) are given. As of September 2022, 147 patents have been randomized to each arm, and updated study status will be presented. This is a collaborative study with Korean Cancer Study Group (KCSG) and Korean Pancreas Surgery Club (KPSC), supported by a grant from the National R&D Program for Cancer Control through the National Cancer Center (NCC) funded by the Ministry of Health & Welfare, Republic of Korea (HA22C0053). This is prospectively registered on ClinicalTrials.gov, NCT0005056. Clinical trial information: NCT0005056 .
Trial in progress: A phase 2/3 randomized, controlled study of CTX-009 in combination with paclitaxel versus paclitaxel alone in adult patients with unresectable advanced, metastatic or recurrent biliary tract cancers who have received one prior systemic chemotherapy regimen.
Authors: Fontaine Marilyn , Pilgrim Sarah , Schuetz Thomas 
Published: January 2023

TPS640 Background: CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Presently, there is no consensus second-line therapy for patients with Biliary Tract Cancer (BTC) in whom first-line therapy has failed. In a Phase 1b study of CTX-009 in combination with paclitaxel, there were 4 patients with cholangiocarcinoma enrolled, and 2 of these 4 patients (both received CTX-009 at 10mg/kg + paclitaxel) had confirmed PRs with declines of 41.4% and 61.6% in their linear tumor burden from the baseline. Both of these patients had multiple prior therapies, and were on study for more than a year, with durable responses for more than 9 months each. Based on that observation, an adaptive Phase 2 cohort was added to the Phase 1b Study. There are currently 9 confirmed PRs among 24 patients treated for a 37.5% overall response rate in the ongoing Phase 2 Study of CTX-009 in combination with paclitaxel in patients with BTC treated in the second- or third-line setting. While there is anecdotal data suggesting that taxanes may have activity in BTC, the contribution of CTX-009 needs to be confirmed in a randomized study. Methods: CTX-009 is being evaluated in an open-label, randomized, controlled study in patients with previously treated, advanced or metastatic BTC. 120 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include sex, presence of disease inside the liver only (intrahepatic cholangiocarcinoma) vs. outside the liver (all extrahepatic BTC or metastatic disease), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. The study is currently activating sites with first patient in expected to be enrolled in 2022. Clinical trial information: NCT05506943 .
Greco-2: A randomized, phase 2 study of stereotactic body radiation therapy (SBRT) in combination with rucosopasem (GC4711) in the treatment of locally advanced or borderline resectable nonmetastatic pancreatic cancer.
Authors: Aguilera Todd Anthony , Parikh Parag , Ghaly Maged , Hoffe Sarah E. , Herman Joseph M. , Caster Joseph Michael , Kim Dae Won , Costello James , Malafa Mokenge Peter , Beg Muhammad S. , Moser Elizabeth Charlotte , Kennedy Eugene Paul , Terry Kara , Kurman Michael 
Published: January 2023

TPS766 Background: While treatment of pancreatic cancer has advanced, survival rates remain low. Stereotactic body radiotherapy (SBRT; high dose per fraction radiation) may exhibit improved clinical outcomes in locally advanced pancreatic cancer but carries potential gastrointestinal toxicity risks. Rucosopasem (GC4711) is one of a class of investigational selective dismutase mimetics that rapidly and specifically converts superoxide to hydrogen peroxide. Studies have shown that normal cells tolerate hydrogen peroxide fluxes better than cancer cells. As radiation response modifiers, dismutase mimetics have the potential to increase tumor control of SBRT without compromising radiation safety. In a pilot phase 1/2 trial in patients with pancreatic cancer, avasopasem, a dismutase mimetic related to rucosopasem, nearly doubled median overall survival in patients receiving SBRT vs placebo plus SBRT. Improvements versus placebo were also observed in local tumor control, time to metastases, and progression-free survival. Altogether, these data support the hypothesis that rucosopasem may improve survival and the benefit-risk ratio of SBRT by improving efficacy without increasing gastrointestinal toxicity. Methods: GRECO-2 is a phase 2, multicenter, randomized, double-blind, placebo-controlled study (NCT04698915) to determine the effect of adding rucosopasem to SBRT on overall survival in patients with borderline resectable or locally advanced, unresectable nonmetastatic pancreatic cancer following initial chemotherapy with a FOLFIRINOX-based regimen or a gemcitabine doublet. Approximately 160 patients will be randomized (approximately 35 sites) to receive rucosopasem 100 mg or placebo via IV infusion over 15 minutes, prior to each SBRT fraction (5 x 10 Gy). Patients judged to be resectable will undergo surgical exploration within 8 weeks after SBRT. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, locoregional control, time to metastasis, surgical resection rate, RO resection rate, best overall response, in-field local response, and safety (acute and late toxicities). Exploratory endpoints include PRO-CTCAE and CA19-9 normalization. This trial (NCT04698915) is now enrolling. Clinical trial information: NCT04698915 .
An adaptive approach to neoadjuvant therapy to maximize resection rates for pancreatic adenocarcinoma: A phase II trial.
Authors: Sohal Davendra , Kharofa Jordan , Olowokure Olugbenga Olanrele , Rojan Adam , Patel Sameer H. , Wilson Gregory C. , Sussman Jeffrey J. , Moreland Katie , Patra Krushna , Bogdanov Vladimir , Riall Taylor S , Zavros Yana , Shroff Rachna T. , Ahmad Syed A. 
Published: January 2023

TPS771 Background: Curative treatment for potentially resectable (resectable or borderline resectable) pancreatic adenocarcinoma, despite recent advances, leads to only suboptimal outcomes. Recent US national cooperative group trials have demonstrated the safety and feasibility of neoadjuvant chemotherapy (PMID 33475684, PMID 35834226), and also show that the two frontline regimens, FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin) and gemcitabine/nab-paclitaxel (GnP), are comparable in this setting. Finally, ability to undergo resection remains the key driver of cure. Therefore, an approach that selects chemotherapy based on early response assessment, to maximize the probability of resection, is likely to improve curative outcomes. Methods: This is a phase II study intended to maximize the probability of surgical resection for pancreatic cancer. Key eligibility requirements include adult patients with a confirmed histopathologic diagnosis of pancreatic carcinoma or adenocarcinoma, an ECOG PS ≤ 1, resectable or borderline resectable disease by central radiology review, no prior therapy for index pancreatic cancer, and adequate bone marrow, liver and kidney function. Treatment includes 4 doses (~ 2 months total treatment time) of FOLFIRINOX (“Chemo1”). After a re-evaluation, using radiologic response, CA19.9 response, and chemotherapy toxicity, patients will either continue with “Chemo1” for another 4 cycles (8 doses) or switch to GnP (“Chemo2”) which will be administered for 4 cycles (12 doses, for ~4 month total treatment time), followed by surgical resection. Primary outcome will measure the proportion of patients undergoing surgical resection using historical dated compared to 32 patients in a current study with a time frame of 16 months. Using historical data, the expected proportion of patients undergoing resection is ~60%. The goal of this study is to increase this to 80% or higher. With a one-sided of 0.05 and power of 80%, 32 patients will be needed to demonstrate this difference. Key translational correlatives will include serial circulating tumor DNA assessment and extensive tumor molecular profiling. Clinical trial information: NCT04594772 .
Unpredictability and basin entropy
Authors: Daza Alvar , Wagemakers Alexandre , Sanjuán Miguel A. F. 
Published: January 2023

Abstract
The basin entropy is a simple idea that aims to measure the the final state unpredictability of multistable systems. Since 2016, the basin entropy has been widely used in different contexts of physics, from cold atoms to galactic dynamics. Furthermore, it has provided a natural framework to study basins of attraction in nonlinear dynamics and new criteria for the detection of fractal boundaries. In this article, we describe the concept as well as fundamental applications. In addition, we provide our perspective on the future challenges of applying the basin entropy idea to understanding complex systems.
Prevalence of Admission Hyponatremia in Patients With Diabetes Treated With and Without an SGLT2 inhibitor
Authors: Monnerat Sophie , Atila Cihan , Refardt Julie , Christ-Crain Mirjam 
Published: January 2023

AbstractContextHyponatremia often reflects a free water excess. Sodium/glucose cotransporter 2 (SGLT2) inhibitors increase free water excretion through glucose-induced osmotic diuresis. In 2 randomized double-blind, placebo-controlled trials in patients with the syndrome of inappropriate antidiuresis (SIAD), we showed that empagliflozin increased plasma sodium concentration more effectively than placebo.ObjectiveWe hypothesized that long-term therapy with SGLT2 inhibitors might reduce the prevalence of hyponatremia on hospital admission.MethodsIn this retrospective analysis, we extracted data from adult patients with type 2 diabetes (T2DM) hospitalized at the University Hospital Basel between 2015 and 2020. Patients with an SGLT2 inhibitor on admission were matched 1:1 according to age, gender, diagnosis of heart failure, and principal diagnosis to patients without an SGLT2 inhibitor on admission. The primary outcome was the prevalence of hyponatremia (plasma sodium concentration corrected for glycemia &lt;135 mmol/L) on admission.ResultsWe analyzed 821 patients with T2DM treated with and 821 patients with T2DM without an SGLT2 inhibitor on admission. Hyponatremia prevalence on admission was 9.9% in the treated group, and 8.9% in the matched control group (P = .554), in other words, the risk for hyponatremia did not differ (multivariable adjusted odds ratio 1.08, 95% CI 0.72-1.44, P = .666). There was no difference in the median (interquartile range) plasma sodium concentration between the groups (treated 140 mmol/L [138-142], controls 140 mmol/L [138-142]; P = .1017).ConclusionBased on these retrospective findings, treatment with SGLT2 inhibitors does not prevent hyponatremia. However, prospective randomized data suggest their efficacy at a higher dosage in overt SIAD.