bluuebunny/crossref_metadata_2025_split huggingface dataset:
DELFI-L101: Development of a blood-based assay that evaluates cell-free DNA fragmentation patterns to detect lung cancer.
Authors: Mazzone Peter J. , Work Kyle , Velculescu Victor E. , Kotagiri Sonali , Sun Lee Ming , Dix Daniel , Jakubowski Debbie M , Leal Alessandro , Bach Peter Brian , Maddala Tara 
Published: June 2022

TPS3164 Background: Despite longstanding national recommendations, uptake of lung cancer screening in the US remains low. Barriers include access to lung cancer screening, costs, and concerns over potential harms like false-positives and radiation exposure. The DELFI technology evaluates fragmentation patterns of cfDNA using supervised machine learning to distinguish cancer from non-cancer [PMID30943338; 34417454; 31142840]. Methods: The DELFI-L101 is a case-control observational study (NCT04825834) prospectively enrolling at academic and community sites. Eligible participants (≥50 years of age) are individuals who currently smoke or previously smoked, with smoking histories of ≥20 pack-years. Individuals are ineligible if they had cancer treatment in the prior year or a history of hematologic malignancies or myelodysplasia. Cases are individuals with pathologically confirmed cancers (group A – lung, group C – non-lung). Controls are those without cancer (group B) as determined by low-dose computed tomography screening completed within 6 weeks of enrollment. Cases and controls are identified among enrollees from all participating sites. Total enrollment is estimated to be ̃2500 participants across all groups. Blood samples are collected at enrollment for DELFI analyses, which involves cfDNA isolation from plasma, low-coverage, whole-genome, next-generation sequencing, and machine learning methods. Clinical data (medical history, demographics, and diagnostic, surgery, imaging, and pathology reports, and/or other diagnostic information) are collected at enrollment and at 12 months post-enrollment. The primary objective is to train and test a classifier for the detection of lung cancer using the DELFI technology with other biomarkers and clinical features. Secondary objectives include the evaluation of classifiers to distinguish lung cancer from other cancers, modeling benefits and harms using performance estimates of these classifiers, and description of the analytical performance (eg, repeatability and reproducibility) of the DELFI technology and classifiers. The primary endpoint is the accuracy of lung cancer detection as measured by sensitivity, specificity, and the area under the receiver operating characteristic curve. Secondary endpoints include accuracy of tissue of origin classification, and adverse events associated with blood sample collection. The training and performance characterization of a DELFI classifier will further the development of an affordable, accessible, blood-based cancer detection tool with potential to overcome barriers to lung cancer screening. Clinical trial information: NCT04825834.
A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2).
Authors: Dumbrava Ecaterina Elena , Hanna Glenn J. , Cote Gregory Michael , Stinchcombe Tom , Johnson Melissa Lynne , Chen Christopher , Devarakonda Siddhartha , Shah Naisargee , Xu Feng , Doebele Robert Charles , Gounder Mrinal M. 
Published: June 2022

TPS3165 Background: Murine double minute 2 (MDM2) is a potent negative regulator of the tumor suppressor p53. MDM2 induces degradation of p53 and promotes tumorigenesis in solid tumors, and preclinical models have shown that inhibition of MDM2 can restore p53 tumor suppressor activity in TP53-wild type (WT), MDM2-amplified tumors. We performed a mutual exclusivity analysis of patients with solid tumors (n = 42,125; AACR Project GENIE) and found that the frequency of co-occurring TP53 mutations decreased with increasing MDM2 copy number. An MDM2 copy number of 12 was chosen as the threshold. An estimated 1.1% of solid tumors meet this molecular criteria, excluding glioblastomas, dedifferentiated liposarcomas, and intimal sarcomas where this signature is enriched. Milademetan (RAIN-32), an oral, selective MDM2 inhibitor, inhibits growth of TP53-WT/ MDM2-amplified cell lines and patient-derived xenograft models from varying tumor types. Furthermore, tumor regression was observed in 3/3 non-liposarcoma patients with MDM2 copy number > 12 in a phase 1 trial of milademetan. MANTRA-2 (RAIN-3202) is a phase 2, multicenter, single-arm, open-label, basket trial designed to evaluate the efficacy or clinical benefit of milademetan in TP53-WT solid tumors with MDM2 amplification (copy number ≥ 12). Methods: Eligible patients must be ≥ 18 years of age with histologically and/or cytologically confirmed locally advanced, incurable or metastatic solid tumors refractory to standard therapy. Local testing demonstrating TP53 WT and MDM2 amplification is required, defined as a MDM2 copy number ≥ 12 or 6-fold increase. Patients with well-differentiated/de-differentiated liposarcomas, intimal sarcomas, or primary central nervous system tumors are excluded. Prior treatment with an MDM2 inhibitor is not permitted. Patients receive milademetan 260 mg orally once daily on Days 1–3 and 15–17 of a 28-day cycle. Tumor response is evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: objective response rate. Secondary endpoints include: duration of response; progression-free survival; growth modulation index; disease control rate; overall survival; safety; health-related quality of life scores. Exploratory endpoints include: biomarkers in blood and/or tumor tissue; pharmacodynamics; pharmacokinetics. Enrollment of 65 patients is planned to ensure that 57 patients have centrally confirmed TP53 WT and MDM2 copy number ≥ 12. The trial opened in November 2021 and is actively enrolling patients. Clinical trial information: NCT05012397.
A phase I trial of elimusertib in combination with cisplatin or with cisplatin plus gemcitabine in advanced solid tumors with an emphasis on urothelial carcinoma.
Authors: Leibrandt Ryan , Frankel Paul Henry , Beumer Jan Hendrik , Takebe Naoko , Yin Ming , Emamekhoo Hamid , Lara Primo "Lucky" N. , Gore Steven , Parikh Mamta 
Published: June 2022

TPS3174 Background: Cisplatin, a well-established backbone of combination therapy of various advanced solid tumors, inhibits DNA synthesis by forming DNA cross-links and adducts. Despite the activity of cisplatin, tumor cells can either be refractory or develop resistance to treatment. Cisplatin has been demonstrated to cause cell cycle G2/M arrest, which may allow for DNA damage response (DDR) and repair. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad 3-related (ATR) protein kinases are key regulators of DDR, and contribute to maintaining genomic integrity in response to various exogenous and endogenous genotoxic insults like cytotoxic chemotherapy. In fact, cisplatin has been shown to transiently increase ATR expression. Inhibitors of ATR have been studied in combination with cisplatin both in vitro and in vivo, demonstrating enhanced activity. The oral small molecule ATR inhibitor elimusertib, which has been studied as a single agent in a Phase I study, has also demonstrated enhanced activity with cisplatin in vitro in lung cancer and bladder cancer cell lines. We sought to conduct a Phase I study evaluating the combination of elimusertib with cisplatin or with cisplatin and gemcitabine. Methods: In the first cohort, patients with histologically confirmed advanced solid tumors for which cisplatin-based therapy would be considered appropriate, who exhibit adequate organ function, and have received < 300 mg/m2 of cisplatin previously are treated with cisplatin on Day (D) 1 and with elimusertib on D2 & 9 of each 21-day cycle. The study follows a phase I queue (IQ) 3+3 dose escalation design, following standard practices for dose-limiting toxicity (DLT) impact on escalation, and when the maximum tolerated dose (MTD) is established with cisplatin alone, this will inform the first dose level of the next cohort, in which patients will be treated with cisplatin on D1, gemcitabine on D1 & 8, and elimusertib on D2 & 9 of each 21-day cycle. An expansion cohort will enroll urothelial carcinoma patients when the second MTD is established. The primary objective of the study is to evaluate the safety and MTD of elimusertib in combination with cisplatin, as well as in combination with cisplatin and gemcitabine. Secondary study objectives include evaluation of pharmacokinetics of elimusertib in these combinations, preliminary efficacy, and evaluating the association between ATM expression and responses to therapy. Currently, 6 patients have been enrolled to the first cohort of the study. Clinical trial information: NCT04491942.
A first-in-human phase I dose-escalation trial of the B7-H6/CD3 T-cell engager BI 765049 ± ezabenlimab (BI 754091) in patients with advanced solid tumors expressing B7-H6.
Authors: Falchook Gerald Steven , Patel Manish R. , Ulahannan Susanna Varkey , Maier Daniela , Hipp Susanne , Azuma Hisaya , Spigel David R. 
Published: June 2022

TPS3175 Background: B7-H6 is a member of the B7 family of immune receptors, which is expressed in several solid tumors, but with little to no expression detected in normal tissues[Brandt et al. J Exp Med 2009;206.1495–503; Boehringer Ingelheim. Data on file]. BI 765049 is a novel IgG-like bispecific T-cell engager (TcE) designed to bind simultaneously to B7-H6 on tumor cells and CD3 on T cells, resulting in cytolytic synapse formation and tumor lysis. Preclinical studies have demonstrated that BI 765049 monotherapy induced dose-dependent antitumor activity in humanized in vivo CRC tumor models. Consistent with the mode of action, treatment with BI 765049 led to profound infiltration of T cells into the tumor tissue, which correlated with apoptosis and tumor shrinkage. The inflammatory tumor microenvironment created by treatment with the B7-H6/CD3 TcE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells [Hipp et al. AACR Annual Meeting 2021]. This upregulation of PD-(L)1 provides the rationale for combining BI 765049 with a PD1 inhibitor. Methods: NCT04752215 is a first-in-human, open-label, dose-escalation trial of BI 765049 ± the PD-1 inhibitor, ezabenlimab. Adults with advanced, unresectable and/or metastatic CRC, NSCLC, HNSCC, hepatocellular, gastric or pancreatic carcinoma are eligible. Patients must have progressed on, or be ineligible for, standard therapies. B7-H6 positivity must be confirmed at screening by central review (immunohistochemistry assay) in archived tissues/fresh biopsies (except CRC). Patients must have ≥1 evaluable lesion (modified RECIST 1.1) outside of the central nervous system and adequate organ function. The primary objective is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 765049 ± ezabenlimab, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD, and preliminary efficacy of BI 765049 ± ezabenlimab. The trial will assess up to four intravenous dosing regimens: A (BI 765049 once every 3 weeks [q3w]); B1 (BI 765049 qw); B2 (BI 765049 qw with step-in dosing); C (BI 765049 + ezabenlimab q3w). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control that will be fitted to binary toxicity outcomes using a hierarchical modelling approach to jointly model all dosing regimens. Treatment will be allowed to continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria, or for a maximum duration of 36 months, whichever occurs first. Approximately 150–175 patients will be screened and ̃120 patients enrolled. As of January 2022, eight patients have been recruited in early dose-escalation cohorts. Clinical trial information: NCT04752215.
Phase III study to compare bevacizumab or cetuximab plus FOLFIRI in patients with advanced colorectal cancer RAS/BRAF wild type (wt) on tumor tissue and RAS mutated (mut) in liquid biopsy: LIBImAb Study.
Authors: Damato Angela , Damato Angela , Aschele Carlo , Ciardiello Fortunato , Maiello Evaristo , Siena Salvatore , Torri Valter , Dolcini Virginia , Gervasi Erika , La Grotteria Ilenia , De Simone Irene , Normanno Nicola 
Published: June 2022

TPS3636 Background: KRAS, NRAS, and BRAF mutations are well-established negative predictive biomarkers of response to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC) patients (pts). In clinical practice, RAS/BRAF wild-type (wt) patients receive first-line therapy regimens containing anti-EGFR agents. However, tumor heterogeneity might drive primary and acquired resistance to anti-EGFR MoAbs. In fact, circulating tumor DNA (ctDNA) testing reveals RAS/BRAF mutations in approximately 10% of pts who resulted in wt at tumor tissue. In addition, 30% to 50% RAS wt pts develop, during the treatment with anti-EGFR MoAbs, RAS mut can be detected in the ctDNA several weeks before clinical progression. As today, it is not known whether revealing RAS mut in liquid biopsy (LB) earlier than the appearance of a clinical/radiological disease progression, could impact pts’ outcomes. Similarly, there are no data suggesting the best therapeutic approach in patients with RAS/BRAF wt tissue and mutated ctDNA. Methods: This is a phase III, randomized, open-label, comparative, multicenter study to assess the superiority of Bevacizumab (BEV) compared to Cetuximab (CET) plus FOLFIRI in treatment naïve mCRC RAS/BRAF wt on tumor tissue (TT) and mutated in plasma samples. RAS/BRAF wt pts on TT will undergo the first LB, and RAS mut pts will be randomized 1:1 to receive FOLFIRI/CET (control arm) or FOLFIRI/BEV (experimental arm). Instead, RAS wt pts at first LB will be treated with FOLFIRI/CET up to 8 cycles. Pts who have not progressed after 8 cycles of treatment will undergo a second LB. If RAS mut was detected, pts will be randomized 1:1 to continue FOLFIRI/CET or switch to FOLFIRI/BEV. If not, pts will continue FOLFIRI/CET outside the clinical trial. Pts will be treated until disease progression, unacceptable toxicity, or withdrawal of consent. Among 26 pts screened at the first LB, actually 1 KRAS mut and 1 BRAF mut pts were detected. The primary endpoint is the PFS Plasma samples will be analyzed for KRAS, NRAS, and BRAF mutations by Idylla ctKRAS and Idylla ctNRAS-BRAF-EGFGR. All samples will be also analyzed by NGS, in order to better evaluate the correlation of tumor heterogeneity with pts’ outcomes. Clinical trial information: EudraCT Number: 2020-005078-82, NCT04776655.
A phase 2 multicenter, open-label, randomized, controlled trial in patients with stage II/III colorectal cancer who are ctDNA positive following resection to compare efficacy of autogene cevumeran versus watchful waiting.
Authors: Kopetz Scott , Morris Van K. , Alonso-Orduña Vicente , Garcia-Alfonso Pilar , Reboredo Margarita , Fernandez Montes Ana , Maurel Joan , Paez David , Reinacher-Schick Anke C. , Höhler Thomas , Carrasco Javier , Galligan Barbara Marie , Manning Luisa , Preußner Liane , Tureci Özlem , Sahin Ugur 
Published: June 2022

TPS3641 Background: Colorectal cancer (CRC) is one of the most commonly occurring cancers with high recurrence and mortality rate. Circulating tumor DNA (ctDNA) can be used as a marker of minimal residual disease after completion of surgical resection of stage II/III CRC, where detectable ctDNA levels (positive) post-AdCTx are associated with an increased risk of disease recurrence and novel therapies are needed. Autogene cevumeran is an investigational individualized neoantigen-specific immunotherapy that is designed to harness an immune response against patient-specific, tumor neoantigens. This clinical trial is in progress in patients with Stage II (high risk) / Stage III colorectal cancer who are ctDNA positive following resection. Methods: Autogene cevumeran is being evaluated in an open-label, Phase 2, randomized, controlled trial in patients with Stage II / III CRC patients who are ctDNA positive following resection. Patients are randomized to adjuvant therapy followed by autogene cevumeran compared to adjuvant therapy followed by watchful waiting. The primary endpoint is disease-free survival (DFS). The trial has a Biomarker Cohort of 15 patients who will receive autogene cevumeran irrespective of the ctDNA status to pursue exploratory objectives. The main study of the phase 2 trial consists of a randomized (1:1) design comparing the experimental arm (autogene cevumeran) with the observational arm (watchful waiting) in ctDNA positive CRC patients. A third Exploratory Cohort explores the efficacy and safety of autogene cevumeran in ctDNA positive CRC patients with early recurrence/relapse during or after completion of AdCTx. Patients enrolled onto the experimental group, the biomarker and exploratory cohorts will receive autogene cevumeran 6x q1w, followed by 2x q2w, followed by 7 “booster” doses q6w, to receive a total of 15 doses (dosed at 25μg). AEs are assessed according to CTCAE v5. DFS will be determined by an independent central radiology assessment. Key eligibility criteria include 1) Patients must have stage II/III rectal cancer or stage II (high risk)/III colon cancer that has been surgically resected (R0 confirmed by pathology report); 2) patients must be ctDNA positive following resection; and 3) at least 5 tumor neoantigens must be identified in the provided tumor sample for autogene cevumeran manufacturing (RNA lipoplex, RNA-LPX). ClinicalTrials.gov identifier: NCT04486378.
Blood-borne assessment of stromal activation in esophageal adenocarcinoma to guide tocilizumab therapy: A randomized phase II proof-of-concept study (NCT04554771).
Authors: Doeve Benthe , Pouw Roos E. , Van Berge Henegouwen Mark I. , Hulshof Maarten C.C.M. , Medema Jan Paul , Derks Sarah , Bijlsma Maarten F. , Van Laarhoven Hanneke W.M. 
Published: June 2022

TPS4166 Background: The tumor stroma is increasingly acknowledged to harbor tumor-promoting properties. Recently, we found that stroma activity measured by serum ADAM12 predicts response to chemoradiation in esophageal adenocarcinoma (Veenstra et al., Oncogenesis, 2018). Preclinically, the esophageal adenocarcinoma stroma was found to produce interleukin 6, which causes epithelial-to-mesenchymal transition of tumor cells. These mesenchymal tumor cells have a poor response to chemoradiation (Ebbing et al., PNAS, 2019). Therefore, stroma-derived interleukin 6 provides a potential new target to improve the treatment of esophageal adenocarcinoma. Tocilizumab is an interleukin 6 receptor inhibitor clinically used in rheumatoid arthritis and cytokine-release syndrome. In this phase II proof-of-concept clinical trial, we aim to demonstrate that stroma-targeting by tocilizumab in esophageal adenocarcinoma patients with highly activated stroma increases efficacy of chemoradiation measured by pathological response according to the Mandard criteria. Methods: BASALT is a multi-center, randomized, open-label phase II proof-of-concept clinical trial in patients with surgically resectable adenocarcinoma of the esophagus or gastroesophageal junction (NCT04554771). To assess efficacy of tocilizumab in addition to chemoradiation, 48 patients will be grouped for serum ADAM12 level with a cutoff of 203 pg/mL. Patients are then randomized in a 1:1:1:1 ratio to receive three cycles of tocilizumab every two weeks in addition to paclitaxel, carboplatin and radiation (Table). The sample size is based on the rule-of thumb estimate of 12 patients per arm. Tocilizumab will be given intravenously at a dose of 8 mg/kg with a maximum of 800 mg per dose. Efficacy will be assessed by pathological response to chemoradiation according to the Mandard criteria. Secondary endpoints are overall and progression free survival, safety and toxicity, feasibility and efficacy of interleukin 6 inhibition with serum interleukin 6 levels, immunohistochemistry and RNA-sequencing. Currently, 28 out of the 48 planned patients have been enrolled. Clinical trial information: NCT04554771. [Table: see text]
First-line lenvatinib plus pembrolizumab plus chemotherapy in esophageal squamous cell carcinoma: LEAP-014 trial in progress.
Authors: Sun Jong-Mu , Enzinger Peter C. , Adenis Antoine , Shah Manish A. , Kato Ken , Bennouna Jaafar , Doi Toshihiko , Hawk Natalyn Nicole , Yu Li , Shah Sukrut , Bhagia Pooja , Shen Lin 
Published: June 2022

TPS4167 Background: Recent data from the KEYNOTE-590 study demonstrated the superiority of pembrolizumab plus chemotherapy compared with chemotherapy as first-line treatment for unresectable locally advanced recurrent or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction. Prior data also suggest promising antitumor activity of lenvatinib plus pembrolizumab in advanced solid tumors. LEAP-014 (NCT04949256) is a randomized, 2-part, open-label, phase 3 study that will evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic esophageal squamous cell carcinoma (ESCC). Methods: Key eligibility criteria include histologically or cytologically confirmed metastatic ESCC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and Eastern Cooperative Oncology Group performance status 0 to 1. In part 1 (safety run-in), ̃6 patients will be treated for induction with intravenous (IV) pembrolizumab 400 mg every 6 weeks (Q6W) for 2 cycles plus oral lenvatinib 8 mg daily (QD) plus IV 5-fluorouracil (FU; 4000 mg/m2 on days 1-5) plus IV cisplatin (80 mg/m2) (FP) for 4 cycles and treated for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; patients will be closely monitored for 21 days after the first dose of study intervention for dose-limiting toxicities. In part 2 (main study), approximately 850 patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (FP or mFOLFOX6 [Q2W for 6 cycles {IV oxaliplatin 85 mg/m2 plus bolus IV 5-FU 400 mg/m2 plus continuous IV 5-FU 2400 mg/m2 plus IV leucovorin 400 mg/m2 or IV levoleucovorin 200 mg/m2}]) followed by consolidation with pembrolizumab plus lenvatinib (arm 1) or pembrolizumab plus chemotherapy (FP or mFOLFOX6; arm 2). Randomization will be stratified by PD-L1 combined positive score (CPS; ≥10 vs < 10), region (East Asia vs North America and Western Europe vs rest of world), and chemotherapy backbone (FP vs mFOLFOX6). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor imaging assessment will be performed Q6W for ≤1 year and Q9W thereafter. In part 1, the primary end point is safety and tolerability. In part 2, the dual primary end points are overall survival and progression-free survival (per RECIST v1.1 assessed by blinded independent central review [BICR]); secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) and safety and tolerability. Enrollment in this trial is ongoing. Clinical trial information: NCT04949256.