bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I clinical trial of stereotactic body radiotherapy with atezolizumab and bevacizumab in advanced hepatocellular carcinoma.
Authors: Brown Timothy J , Minn Andy J , Carpenter Erica L. , Ben-Josef Edgar , Karasic Thomas Benjamin 
Published: January 2023

TPS626 Background: Systemic therapy with atezolizumab and bevacizumab (atezo/bev) has improved outcomes for advanced HCC, but results in objective responses in fewer than 30% of patients. Stereotactic body radiotherapy (SBRT) is currently used for small HCC tumors that do not require systemic therapy but has also been shown in a number of clinical trials of other solid tumors to enhance the anti-cancer immune response. Of particular interest, our prior experience with SBRT in a 17Gy fraction has demonstrated the ability to restore sensitivity to immunotherapy in advanced solid tumors, even those previously refractory to immunotherapy. We hypothesize that repeated high dose fractions of radiation will act as an immune booster and will improve on outcomes of patients with advanced HCC. Since the combination of SBRT and atezo/bev has not yet been tested prospectively in patients with HCC, and because bevacizumab is a known radiosensitizer, we are conducting a phase I trial to evaluate the safety of repeated SBRT doses. Methods: This is a single-site phase I clinical trial utilizing a Rolling 6 design to determine the safety of 1, 2, or 3 doses of SBRT fractions in combination with atezo/bev. Up to 18 total patients will be enrolled (n=6 per cohort). Patients must be naïve to systemic therapy with Child-Pugh A or B liver function, at least one lesion amenable to radiation, and a measurable lesion that will not receive radiation. Patients with uncontrolled ascites or hepatic encephalopathy are excluded. Atezo/bev is administered at the standard doses every 21 days. SBRT will start 1 week after the first infusion of this combination. Patients will receive 1, 2, or 3 17Gy fractions of SBRT at 4-week intervals (cohorts 2 and 3 only). Patients will undergo serial collections of circulating cell-free DNA (ccfDNA), methylated DNA, and peripheral blood mononuclear cells to investigate the application of these markers as a predictor of response. Following completion of SBRT, patients will continue with atezo/bev until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the proportion of patients experiencing dose-limiting toxicities (grade 3 or higher radiation-related toxicities graded by the Common Terminology Criteria for Adverse Events, Version 5). Secondary endpoints are overall survival, progression-free survival, objective response rate, duration of response, and toxicity rates. Enrollment began 9/2022 and complete accrual is expected by June 2024. NCT05488522. Clinical trial information: NCT05488522 .
A phase 1/2 open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of OTX-2002 as a single agent and in combination with standard of care in patients with hepatocellular carcinoma and other solid tumor types known for association with the MYC oncogene (MYCHELANGELO I).
Authors: Rodriguez-Rivera Ildefonso I , Wu Ting-Hui , Ciotti Rachel , Senapedis William , Sullivan Kaitlyn , Gao Jeff Z , Palakurthi Sangeetha , McCauley Thomas , Moore Yan 
Published: January 2023

TPS627 Background: MYC, or c-MYC, is a master regulator of gene expression that controls cell growth and proliferation. Dysregulation of MYC is frequently identified in various cancer types, including hepatocellular carcinoma (HCC), where it is overexpressed in up to 70% viral and alcohol-related disease.1 While MYC represents an attractive therapeutic target, it has historically been considered undruggable due to a lack of a structured binding pocket and its tightly autoregulated expression. OTX-2002 is a first-in-class, engineered and programable mRNA therapeutic called Omega Epigenomic Controllers (OECs) that modulates MYC gene expression pre-transcriptionally by creating epigenetic marks at two different structural and regulatory elements within the insulated genomic domain where MYC resides. In vitro studies have demonstrated that downregulation of MYC through OTX-2002 led to loss of viability in HCC cells while sparing normal hepatocytes. In HCC xenograft mouse models, OTX-2002 demonstrated anti-tumor activity as monotherapy and in combinations with standard of care therapies in HCC.2 Methods: OTX-2002 is being evaluated in an open-label, non-randomized, phase 1/2 study (MYCHELANGELO I) in patients with HCC and other advanced solid tumor types (NCT05497453). The study consists of two parts. Part 1 dose escalation explores ascending doses of intravenous OTX-2002 monotherapy given every 2 weeks to identify dose limiting toxicities, maximum tolerated dose, and recommended dose for expansion (RDE) in patients with HCC and other solid tumors using a classic 3+3 design. Upon identification of the RDE, a monotherapy expansion in advanced HCC patients is planned to explore the preliminary anti-tumor activity of OTX-2002. Part 2 will evaluate OTX-2002 in combination with HCC standard of care in the same HCC population as that of Part 1 expansion. The safety of OTX-2002 at the selected dose in combination with a tyrosine kinase inhibitor or immune checkpoint inhibitor will be evaluated in a safety run-in; expansion will follow to identify the preliminary anti-tumor activity of the combinations. Key eligibility criteria for HCC patients include: 1) Barcelona Clinical Liver Cancer (BCLC) stage B or C disease, 2) Child-Pugh A liver function, 3) received at least 1 prior systemic therapy. The MYCHELANGELO I study began enrollment in August 2022, and Part 1 dose escalation is ongoing in the US. References: 1. Lin et al. World J Hepatol. 2010; 2: 16–20. 2. Senapedis et al. Ann Oncol. 2022; 33: S355. Clinical trial information: NCT05497453 .
ALTER-H006: A phase II study of TQB2450 plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after surgical resection.
Authors: Mao Xianhai , Duan Xiaohui , Wu Dongde , Zhou Cuncai , Tian Yifeng , Zheng Jinfang , Fu Changbo , Xu Guohui , Bai Yannan , Wu Changxiong 
Published: January 2023

TPS632 Background: Recurrence rate at 5 years for patients with early-stage HCC undergoing resection is between 50% and 70%. The optimal adjuvant treatment strategy for patients with resected HCC has not been proved and there is limited evidence to support a standard regimen for adjuvant treatment. Anlotinib, an oral small molecule antiangiogenic inhibitor, has shown promising anti-tumor activity and manageable toxicity as first or second-line treatment for patients with advanced HCC in an open-label phase II trial (NCT02809534). Anlotinib plus TQB2450, an anti-PD-L1 mAb, has shown anti-tumor activity in some solid tumors, such as biliary tract cancer (NCT03996408) and non-small cell lung cancer (NCT03910127). Here we investigate the efficacy and safety of this regimen as an adjuvant treatment for HCC with a high risk of recurrence after surgical resection. Methods: This is a single-arm, multicenter phase II trial. A total number of 37 patients with histologically or cytologically confirmed HCC will be enrolled. Eligible patients are aged 18-75, ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b)portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Patients enrolled receive anlotinib (12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurs first. Tumor assessment is performed at the end of the second cycle and every four cycles since that, according to RECIST v1.1. The primary endpoint is 1-year recurrence-free survival (RFS) rate. Secondary endpoints include RFS, 1-year overall survival (OS) rate, and safety. Recruitment for this study began in January 2022. Clinical trial information: NCT05111366 .
Durvalumab and tremelimumab for hepatocellular carcinoma in patients listed for a liver transplant.
Authors: Sohal Davendra , Moreland Katie , Quillin Ralph , Lemon Kristina , Rojan Adam , Olowokure Olugbenga Olanrele , Shah Shimul 
Published: January 2023

TPS638 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy, developing most often in the setting of liver cirrhosis (Sohal et al Current Oncol Rep 2011; Gordan et al JCO 2020). For advanced disease, immunotherapy has now become standard of care – a combination of atezolizumab and bevacizumab has shown the best overall survival outcome so far (Finn et al NEJM 2020). For earlier stage disease, however, there is no systemic therapy standard. The best treatment for HCC in the setting of cirrhosis is a liver transplant allowing potential cure for both the cancer and cirrhosis. Nonetheless, 25-35% of patients fail to reach liver transplant because of disease progression while waiting for a transplant (Sinha et al, Hepatology 2019) and approximately 15% experience HCC recurrence after transplant (Mehta et al, Transplantation 2020). Taken together, this constitutes a large subset of this patient population who cannot achieve a cure. Given the success of immunotherapy in the advanced setting, it is imperative to study this in the pre-transplant setting, to improve the outcomes cited above. However, there is a theoretical risk of graft rejection with immunostimulatory treatment. Methods: This is a single-arm, open-label, Phase II, multicenter study designed to evaluate the safety and efficacy of durvalumab and tremelimumab for the treatment of HCC patients who have cirrhosis or portal hypertension and are eligible for listing for a liver transplant. Eligibility requirements include adult patients with HCC within UCSF criteria, a Child-Pugh score of up to 7, and ECOG PS of 0 or 1. Treatment includes an immunotherapy combination of 1 dose of tremelimumab and 5 doses of durvalumab for up to 4 months. After a minimum 28-day gap following the final durvalumab dose, patients undergo locoregional therapy per institutional standards. After a minimum 72-day gap from the end of immunotherapy, patients undergo liver transplant. Primary outcome is a binary endpoint, and it will be assessed in patients undergoing liver transplant. Historically, 10-20% of patients are expected to experience acute cellular rejection within 30 days of transplant. We propose that an observed proportion of 20% treatment failure will be a clear indicator of safety in this pilot study, whereas an observed proportion of 50% failure will be a clear indicator of failure. Using these guardrails, with at least 20 patients going to transplant, we will have 80.6% power to demonstrate a failure proportion of 20% (4 patients experiencing failure) versus a null of 50% (10 patients experiencing failure), with a one-sided alpha of 0.05. With 25 patients going to transplant, the power will increase to 86% (other parameters being the same). Correlative studies include tumor molecular profiling, peripheral blood immunophenotyping, and circulating tumor DNA for early recurrence detection. Clinical trial information: NCT05027425 .
A phase I study of a mutant KRAS-targeted long peptide vaccine in patients at high risk of developing pancreatic cancer.
Authors: Haldar Saurav Daniel , Judkins Carol , Ferguson Anna , Abou Diwan Elizabeth , Lim Su Jin , Wang Hao , Nauroth Julie , Goggins Michael , Laheru Dan , Jaffee Elizabeth M. , Azad Nilofer Saba , Zaidi Neeha 
Published: January 2023

TPS758 Background: KRAS mutations are identified in the majority of premalignant lesions that precede pancreatic ductal adenocarcinoma (PDAC). Arising during tumorigenesis, mutant KRAS (mKRAS) neoantigens are less susceptible to central tolerance mechanisms and serve as ideal vaccine targets. Indeed, targeting mKRAS neoantigens with vaccines has shown promising anti-tumor activity in the preclinical setting. For instance, our group previously demonstrated that a Listeria-based vaccine targeting mKRAS G12D combined with Treg-depleting agents can prevent the progression of early pancreatic intraepithelial neoplasia to overt PDAC in a mouse model (Keenan et al, 2014). Building upon this work, the current study aims to determine the safety and immunogenicity of a pooled synthetic long peptide (SLP) mKRAS vaccine in patients identified as high risk for developing PDAC based on family history and germline mutation testing. Methods: This is a single-arm, open-label phase I trial evaluating a pooled SLP mKRAS vaccine in patients at high risk of developing PDAC ( n = 20). The vaccine consists of poly-ICLC adjuvant admixed with SLPs corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. A four-dose series of the mKRAS vaccine is administered on weeks 1, 3, 4, and 17. Following completion of the treatment phase, all patients have the option to continue annual follow-up visits until study closure. Eligible patients must have radiographic evidence of a premalignant pancreatic lesion and fall under at least one of the following three high-risk groups: 1) ≥ 2 familial pancreatic cancer relatives, 2) germline mutation carriers with ≥ 10% lifetime PDAC risk and 3) germline mutation carriers with ~5% lifetime PDAC risk. The co-primary endpoints of this study are safety and T cell response. Safety will be assessed by the frequency and grading of adverse events per NCI CTCAE v5.0. T cell response will be determined by the maximal percent change in IFNγ-producing mKRAS-specific T cell density within 16 weeks post-vaccination compared to baseline. Correlative studies will explore vaccine-associated changes in T cell quality (e.g., memory, exhaustion, poly-functionality, and activation) using mass cytometry analysis of peripheral blood samples. Patient accrual began in April 2022 and is currently ongoing. Clinical trial information: NCT05013216 .
A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic adenocarcinoma.
Authors: Kamgar Mandana , Khan Husain Yar , Aboukameel Amro , Bannoura Sahar , Chung Brian Y. , Szabo Aniko , Li Yiwei , Al Hallak Mohammed Najeeb , Philip Philip Agop , George Ben , Christians Kathleen K. , Evans Douglas B. , Tsai Susan , Erickson Beth , Luther Sanjeev , Azmi Asfar S. , Hall William A. 
Published: January 2023

TPS760 Background: Local tumor progression is a cause of significant mortality and morbidity in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function, both hallmarks of PDAC, are known contributors to chemo- and radio-resistance. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation therapy (gem-RT). Methods: We describe a single-arm, single-center, open-label, phase I study designed to determine the maximum tolerated dose of CPI-613 when used concomitantly with gemcitabine and intensity modulated radiation therapy (IMRT) for local control of PDAC. CPI-613 will be administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2 and dose-escalated/de-escalated using a Bayesian optimal interval design. Gemcitabine will be given once weekly at 400 mg/m2 dosage and IMRT as 54 Gray (Gy) in 30 fractions (1.8 Gy per fraction) with five fractions given per week. Up to 24 patients will be enrolled for the study after meeting the following main eligibility criteria, which include: pathologically confirmed PDAC; inoperable disease that by institutional pancreatic multidisciplinary tumor board or multidisciplinary review are considered to benefit from definitive local control of the primary tumor; ECOG of 0-2; and adequate organ and marrow function after completion of intended systemic chemotherapy. The secondary objectives are to determine the recommended phase II dose of CPI-613 when used with gem-RT, safety and tolerability of CPI-613-gem-RT, overall survival, local progression-free survival (PFS), overall PFS, patient-reported quality of life after treatment, and late gastrointestinal toxicities following treatment with CPI-613-gem-RT. Clinical trial information: NCT05325281 . Support: Cornerstone Pharmaceuticals. [Table: see text]
Phase I study of autologous transgenic T cells expressing high affinity mesothelin-specific T-cell receptor (TCR; FH-TCR TMSLN) in patients with metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Chiorean E. Gabriela , Chapuis Aude , Coveler Andrew L. , Yeung Cecilia CS , Gooley Ted , Zhen David Bing , King Gentry Teng , Hannan Lindsay Marie , Cohen Stacey A. , Safyan Rachael A , Germani Anthony , Ra Susan , Casserd Jennifer , Schmitt Thomas , Greenberg Philip D 
Published: January 2023

TPS779 Background: PDA has a low tumor mutational burden and an immunosuppressive microenvironment. Targeting overexpressed self-antigens with adoptive, genetically engineered, high affinity T cells may overcome immunosuppression (Stromnes I, Immunol Rev 2014). We previously engineered murine CD8+ T cells to express a high affinity MSLN-specific TCR in the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48Cre/+ ( KPC) mouse model, with highest efficacy observed following serial infusions (Stromnes I, Cancer Cell 2015). We developed an autologous TCR-T cell therapy targeting MSLN, which is overexpressed by 80% of PDAs. In this first-in-human phase I trial, we seek to determine the safety, preliminary efficacy, as well as the persistence, activation, localization, and functional capacity of FH-TCR TMSLN in chemotherapy refractory, MSLN+ mPDA. Methods: Eligible pts have ECOG PS 0-1, ≥ 1 prior therapy for mPDA, life expectancy ≥ 12 wks, able/willing to undergo biopsies (at baseline, and after 3 and 6 wks of treatment), MSLN 2+ expression in ≥ 30% tumor cells by IHC, HLA-A*02:01, no HLA-B*13:02. Patients undergo leukapheresis, and approximately 3-4 weeks later, receive the first TCR-TMSLN cell infusion. Three TCR-TMSLN cell infusions given q21 days (d) are planned to be administered to each patient. Patients are enrolled in 4 cohorts by dose level (cohort 1: 1 x 109; cohort 2: 3.3 x 109; cohorts 3 and 4: 10 x 109 T cells), with a 3+3 design. Dose limiting toxicities (DLTs) are assessed during 21d after each TCR-TMSLN cells infusion. Lymphodepleting chemotherapy with fludarabine/cyclophosphamide is administered prior to the third TCR-TMSLN infusion (cohorts 1-3) or prior to the first TCR-TMSLN infusion (cohort 4). Primary endpoint is safety and DLTs. Secondary endpoints are ORR, PFS, OS. Exploratory endpoints are translational tumor and blood TCR-TMSLN cells biomarkers. Safety is assessed by CTCAE v5.0, with a goal of grade ≥ 3 TCR-TMSLN cells unexpected toxicity rate <35%; stopping rate if toxicity is ≥20% is 0.06. Response is assessed by RECIST 1.1. Enrollment of 15 patients allows >80% power to observe a statistically significant (one-sided alpha level 0.05), meaningful efficacy signal of ORR 20%. Secondary and exploratory endpoints will be descriptive and hypothesis generating. The study was activated in December 2021 and is open to accrual; 4 patients have been enrolled as of 24 Sept 2022. Clinical trial information: NCT04809766 .
Activism for Abortion Rights and Access Is Global: What the United States Can Learn from the Rest of the World
Authors: Kumar Anu 
Published: January 2023

Abstract
While the US Supreme Court's 1973 ruling in Roe v. Wade guaranteed a legal right to abortion, universal access to legal abortion has never been achieved in the United States. At the same time, the Helms Amendment, a US foreign-assistance policy, is keeping millions of people around the world, particularly Black and Brown people, from receiving abortion-related information and services. As abortion-rights advocates in the United States look for ways to move forward in the post-Roe era, two sources can offer insights and inspiration: the inclusive, human rights–based reproductive justice framework, and some of the strategies and approaches being used to expand access in countries around the world with restrictive abortion laws.
Abortion as a Public Health Risk in COVID-19 Antiabortion Legislation
Authors: Carson Saphronia , Carter Shannon K. 
Published: January 2023

AbstractDuring the early months of the COVID-19 pandemic, 12 states banned or restricted abortion access under elective-procedure restrictions. The rationale was preserving hospital capacity and personal protective equipment (PPE); however, abortions commonly take place in clinics and use less PPE than childbirth. This paper investigates the discursive construction of abortions, the people who get them, and the fetuses in this legislation. The authors analyzed 13 antiabortion documents using an iterative process of thematic coding and memo writing. Twenty-three percent of the legislation listed abortion as banned, whereas the remaining laws implied abortion within the terms “elective” or “nonessential.” Legislation used common antiabortion tactics, such as the trivialization of abortion, risk discourses, and constructions of motherhood and fetal personhood. Discourses delegitimized abortion providers and used quasi-medical justifications for banning abortion. Finally, legislation constructed abortion clinics as sites of contagion and waste and consequently as risks to public health. The results highlight the vulnerability of abortion and the connection between abortion policy and other conservative policies, and they gesture toward a strategic attempt to ban abortion federally. These findings have several implications for a post-Roe United States and for stakeholders wishing to increase abortion access.
Introduction: The Politics of Abortion 50 Years afterRoe
Authors: Kimport Katrina , Kreitzer Rebecca 
Published: January 2023

AbstractAbortion is central to the American political landscape and a common pregnancy outcome, yet research on abortion has been siloed and marginalized in the social sciences. In an empirical analysis, the authors found only 22 articles published in this century in the top economics, political science, and sociology journals. This special issue aims to bring abortion research into a more generalist space, challenging what the authors term “the abortion research paradox,” wherein abortion research is largely absent from prominent disciplinary social science journals but flourishes in interdisciplinary and specialized journals. After discussing the misconceptions that likely contribute to abortion research siloization and the implications of this siloization for abortion research as well as social science knowledge more generally, the authors introduce the articles in this special issue. Then, in a call for continued and expanded research on abortion, the introduction to this special issue closes by offering three guiding practices for abortion scholars—both those new to the topic and those deeply familiar with it—in the hopes of building an ever-richer body of literature on abortion politics, policy, and law. The need for such a robust literature is especially acute following the US Supreme Court's June 2022 overturning of the constitutional right to abortion.