bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1, first-in-human (FIH) study of autologous macrophages engineered to express an anti-HER2 chimeric antigen receptor (CAR) in participants (pts) with HER2-overexpressing solid tumors.
Authors: Abdou Yara , Dees Elizabeth Claire , Mortimer Joanne E. , Pohlmann Paula R , Johnson Melissa Lynne , Maziarz Richard T. , Specht Jennifer M. , Yuan Yuan , Ueno Naoto T. , Angelos Mathew , Gill Saar , Ronczka Amy , Condamine Thomas , Cushing Daniel , Barton Debora , Klichinsky Michael , Swaby Ramona F. , Reiss Kim Anna 
Published: June 2023

TPS2666 Background: Macrophages are abundant in the solid tumor microenvironment (sTME) and can promote tumor growth (M2) or enhance anti-tumor immunity (M1). CAR expression can redirect macrophage function to selectively target and phagocytose antigen overexpressing cancer cells. CAR-M can reprogram the sTME and present neoantigens to T cells, leading to epitope spreading and anti-tumor immunity. CT-0508 is comprised of autologous monocyte-derived proinflammatory macrophages expressing an anti-HER2 CAR. Pre-clinical studies showed that CT-0508 induced targeted cancer cell phagocytosis while sparing normal cells, decreased tumor burden, prolonged survival, and was safe. Notably, anti-HER2 CAR-M treatment led to activation of the sTME, with infiltration of CD8+ and CD4+ T cells, NK cells, dendritic cells, and increased activated CD8+ tumor infiltrating lymphocytes. In a pre-clinical anti-PD1 resistant solid tumor model, mice that received anti-HER2 CAR-M and anti-PD1 demonstrated improved tumor control, overall survival, and TME activation compared to single treatment alone, indicating synergy and capacity for CAR-M to sensitize solid tumors to checkpoint blockade. Methods: This Phase 1, First in Human study evaluates the safety, tolerability, cell manufacturing feasibility, trafficking, TME activation, and preliminary evidence of efficacy of investigational product CT-0508 in 18 participants (pts) with locally advanced (unresectable) /metastatic solid tumors overexpressing HER2. Pts previously treated with anti-HER2 therapies are eligible. Filgrastim mobilized autologous CD14+ monocytes are collected by apheresis, followed by manufacturing and cryopreservation. Group 1 pts (n = 9; enrollment complete) received fractionated doses of CT-0508 over Days 1, 3, and 5. Group 2 pts (n = 9) receive CT-0508 as a single infusion on D1. Additional cohorts include: CT-0508 co-administered with pembrolizumab and CT-0508 monotherapy administered intraperitoneally in pts with peritoneal predominant disease. Correlative assessments include pre- and post-treatment biopsies and blood samples for safety (immunogenicity), trafficking (PCR, RNA scope), CT-0508 persistence in blood and tumor, target antigen engagement, TME modulation (single cell RNA sequencing), immune response (TCR sequencing) and others. Clinical trial information: NCT04660929 .
Phase 2, multicenter, open-label basket trial of nab-sirolimus for patients with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 genes (PRECISION I).
Authors: Iyer Gopa , Deming Dustin A. , Demeure Michael J. , Federman Noah , McKean Meredith , Lee Elizabeth Katherine , Spira Alexander I. , Kwiatkowski David J. , Hussein Maen A. , Gordon Erlinda Maria , Crockett David G. , Ganjoo Kristen N. , Schulte Brian , Cranmer Lee D. , Ding Li , Schmid Anita N. , Navarro Willis H. , Rodon Ahnert Jordi 
Published: June 2023

TPS3168 Background: nab-Sirolimus is a novel albumin-bound mTOR inhibitor (mTORi) approved in the US for adult patients with malignant PEComa. In an exploratory analysis of the pivotal AMPECT trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with inactivating alterations in TSC2 and TSC1, respectively, had confirmed response (Wagner, J Clin Oncol, 2021). TSC1 and TSC2 alterations have been observed in patients with a broad variety of cancers. Most treatment-related adverse events in AMPECT were grade 1/2 (none were grade ≥4) and were consistent with mTORi class adverse events. Methods: PRECISION I (NCT05103358) will evaluate efficacy and safety of nab-sirolimus in patients with TSC1 (Arm A) and TSC2 (Arm B) alterations. Eligible patients are ≥12 y old and mTORi-naïve, possess malignant solid tumors with TSC1/TSC2 inactivating alterations (confirmed by central review of sequencing reports), and have received appropriate standard treatments, per investigator. nab-Sirolimus 100 mg/m2 will be given weekly intravenously over 30 min on Days 1 and 8 of each 21-d cycle. The primary endpoint is overall response rate per independent radiographic review (IRR) using RECIST v1.1. Other endpoints include duration of response, time to response, progression-free survival by IRR, overall survival, patient-reported quality of life, and safety. Enrollment began March 2022. Collaboration with leading next-generation sequencing vendors will expedite the identification of patients with qualifying TSC1/TSC2 mutations; study access will be facilitated through a just-in-time approach to trial location activation. Based on the prevalence of TSC1/TSC2 inactivating alterations, the most frequent tumor types expected are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric (Table). Clinical trial information: NCT05103358 . [Table: see text]
An open-label clinical trial of RP2 and RP3 oncolytic immunotherapy in combination with atezolizumab and bevacizumab for the treatment of patients with advanced colorectal carcinoma.
Authors: Shepard Dale Randall , Ahmed Muneeb , Bekaii-Saab Tanios S. , Wolff Johannes 
Published: June 2023

TPS3628 Background: Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality worldwide. PD-1/PD-L1 inhibition, in combination with other modalities, has demonstrated significant benefit in patients (pts) with microsatellite instability-high or mismatch repair deficient CRC. However, these agents have limited, if any, clinical benefit in pts with microsatellite stable (MSS) or mismatch repair proficient (pMMR) CRC. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 which expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), granulocyte-macrophage colony-stimulating factor (GM-CSF), and an anti–CTLA-4 antibody-like molecule; RP3 additionally expresses 4-1BB and CD40 activating ligands, but does not express GM-CSF. Both agents have demonstrated preliminary safety and efficacy in pts with solid tumors. This study will evaluate the safety and efficacy of RP2 and RP3 in combination with atezolizumab (Atezo) and bevacizumab (Bev) in pts with advanced MSS and pMMR CRC. Methods: Pts with a histologic diagnosis of unresectable and/or metastatic CRC, with documented MSS or pMMR status, and previously treated with up to 3 standard-of-care systemic regimens will be enrolled in the RP2 + Atezo + Bev or RP3 + Atezo + Bev treatment groups (30 pts per group). Further key inclusion criteria include Eastern Cooperative Oncology Group performance status 0–1 and adequate hepatic, renal, and hematologic function. RP2/RP3 will be injected into tumors by direct (including via colonoscope) or image-guided injection. Pts will receive 8 total doses of up to 10 mL of RP2 or RP3, with a first dose concentration of 1 × 106 plaque-forming units (PFU)/mL, followed by 3 doses of 1 × 107 PFU/mL every 2 weeks, and then 4 doses of 1 × 107 PFU/mL every 3 weeks. Pts may receive a second course of up to 8 injections of RP2/RP3 if study criteria are met. Bev will be administered starting on day 1 (with first dose of RP2/RP3); Atezo will be administered starting week 7 on the same days as RP2/RP3. The primary endpoint is objective response rate; secondary endpoints are safety, overall survival, progression-free survival, duration of response, and complete response rate. Antitumor activity will be evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 as modified for this study. Safety will be assessed by physical examination, clinical laboratory evaluations, vital signs, and monitoring for adverse events (AEs; including serious AEs). Clinical trial information: NCT05733611 .
A phase 1/2a, multicenter, open-label study of CNA3103 (LGR5-targeted, autologous CAR-T cells) in patients with metastatic colorectal cancer (mCRC).
Authors: Desai Jayesh , Iglesias Jose Luis , Jablonskis Lina T , McColl Shaun , Barry Simon C , Morelli Maria Pia 
Published: June 2023

TPS3632 Background: Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a cancer stem cell (CSC) marker that is abundant in solid tumors, highly expressed in colorectal cancer and involved in tumor initiation, growth, and metastasis. Its expression is linked to poor survival and poor patient response to therapy in mCRC, and presents an attractive opportunity for selectively targeting a highly specific, functional CSC receptor in this disease. CNA3103 is a first-in-class cell product consisting of autologous T cells transduced to express a CAR to target LGR5. It contains the antigen-biding domain of BNC101, a humanized monoclonal LGR5 antibody previously tested in Phase 1 in mCRC subjects and demonstrated to be safe and well tolerated with no off-target binding activity. Methods: This is a first in human, multicenter, open label, Phase 1/2a dose escalation and expansion study to determine the safety of and overall best response to CNA3103 in subjects with mCRC. Up to 44 subjects (24 in Phase 1 and 20 in Phase 2a) will be enrolled. The trial follows a BOIN design with a minimum of 3 consecutively enrolled subjects per cohort, and a 28-day DLT evaluation period. Four cell dose levels (5 × 107, 1.5 × 108, 4.5 × 108, 1.5 × 109) of CNA3103 will be evaluated. A Safety Monitoring Committee (SMC) will oversee the conduct of the study. The pharmacokinetic (PK) profile of CNA3103 in blood will be assessed. Exploratory objectives include evaluation of LGR5+ cells and CNA3103 in tumor biopsies, immune cellular profile, cytokine levels and circulating tumor DNA in blood, and immunogenicity of CNA3103. Main inclusion criteria: mCRC subjects positive for LGR5 expression and failing prior treatment with 5-FU, oxaliplatin and irinotecan-based regimens for metastatic disease; >1 radiologically measurable lesion per RECISTv1.1; >1 biopsiable lesion at baseline; ECOG 0 or 1; serum albumin >3 g/dL; and normal organ and marrow function. Main exclusion criteria: BRAF-mutated disease, clinical ascites/ pleural effusions; active autoimmune/ connective tissue disease; history of inflammatory bowel disease or active peptic ulcer disease. The trial is sponsored by Carina Biotech. Phase 1 enrolment is limited to Australian sites. Phase 2a enrolment will take place in Australia and the US. For information, contact Lina Jablonskis lina@carinabiotech.com or +61 437 891 563.
PACE: A phase III trial of CAPOX versus anti-PD-1 inhibitor as adjuvant therapy for patients with dMMR/MSI-H stage III colon cancer.
Authors: Hou Zhenlin , Jiang Wu , Tang Jinghua , Xiao Binyi , Li Yuan , Li Dandan , Zhang Xiaoshi , Pan Zhi-Zhong , Ding Peirong 
Published: June 2023

TPS3637 Background: Approximately 12% of stage III colon cancer are deficient mismatch repair (dMMR), leading to high levels of microsatellite instability (MSI-H). In the KEYNOTE-177 study, the anti–PD-1 inhibitor Pembrolizumab alone significantly improved progression free survival (PFS) versus chemotherapy as first-line therapy for metastatic colorectal cancer (mCRC) patients with MSI-H/dMMR. We are conducting a phase III randomised trial to determine whether anti-PD-1 inhibitor Sintilimab monotherapy can improve disease free survival (DFS) compared with standard adjuvant chemotherapy in stage III colon cancer patients with dMMR. Methods: This is an open-label, multicentre, randomised phase III study. Patients aged ≥ 18 years with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H and ECOG performance status 0-1 are eligible. Approximately 323 patients will be randomly assigned 1:1 to either Sintilimab monotherapy (200 mg IV every 3 weeks for 8 cycles) or CAPOX regimen (capecitabine, oxaliplatin for 4 or 8 cycles according to current standard practice). Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary endpoint is 3-year DFS. The study was estimated to provide approximately 80% power to detect a hazard ratio of 0.56 for DFS at a two-sided alpha of 0.05. Secondary endpoints include OS, safety profile, toxicity, and quality of life. Archived tumor tissue and blood samples will be collected for correlative studies. Study enrollment is ongoing. Clinical trial information: NCT05236972 .
Phase 2 trial of zolbetuximab in combination with mFOLFOX6 and nivolumab in patients with advanced or metastatic claudin 18.2-positive, HER2-negative gastric or gastroesophageal junction adenocarcinomas.
Authors: Shitara Kohei , Yamaguchi Kensei , Shoji Hirokazu , Matsangou Maria , Bhattacharya Pranob P. , Park Jung Wook , Klempner Samuel J 
Published: June 2023

TPS4173 Background: Zolbetuximab, a chimeric immunoglobulin G1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In the pivotal phase 3 SPOTLIGHT study, zolbetuximab with modified FOLFOX6 (mFOLFOX6; leucovorin [folinic acid], fluorouracil [5-FU], and oxaliplatin) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction (G/GEJ) adenocarcinomas. The phase 2 ILUSTRO trial is investigating the efficacy and safety of zolbetuximab, alone and in multiple combinations, in patients with CLDN18.2-positive, HER2-negative advanced/metastatic G/GEJ adenocarcinomas. Methods: The ILUSTRO trial is enrolling two new cohorts, 4A (safety cohort) and 4B, with approximately 12 and 50 patients planned, respectively, to assess safety and efficacy of the first-line combination of zolbetuximab, mFOLFOX6, and nivolumab in G/GEJ adenocarcinomas. Both cohorts are enrolling patients whose tumors are HER2-negative with high or intermediate CLDN18.2 positivity (moderate to strong immunohistochemistry staining intensity in ≥75% of tumor cells [high] or ≥50% but <75% of tumor cells [intermediate]). In Cohort 4A, patients will receive a loading dose of 800 mg/m2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 on cycle 1 day 1, followed by 400 mg/m2 of zolbetuximab with 240 mg of nivolumab and mFOLFOX6 every 2 weeks (on days 15 and 29 of each 42-day cycle). Up to 12 mFOLFOX6 treatments (4 cycles) will be administered; patients may continue to receive folinic acid and 5-FU alongside zolbetuximab and nivolumab. Tolerability and safety of the combination of zolbetuximab, mFOLFOX6, and nivolumab will be evaluated during a 2-week dose-limiting toxicity assessment period. If the 800 mg/m2 loading dose of zolbetuximab was assessed as not tolerable, patients were to be de-escalated to 600 mg/m2 as their loading dose but received the same subsequent 400 mg/m2 doses of zolbetuximab every 2 weeks. Cohort 4B will receive this combination at the dose level determined in Cohort 4A. Efficacy endpoints include objective response rate, disease control rate, duration of response, PFS, and OS. Safety and tolerability, pharmacokinetics, immunogenicity, and health-related quality of life will also be evaluated. Currently, 20+ sites are recruiting in 6 countries (France, Italy, Japan, Korea, Taiwan, United States); more US sites are planned. Clinical trial information: NCT03505320 .
Alliance A022102: Randomized phase III trial of mFOLFIRINOX +/- nivolumab vs. FOLFOX +/- nivolumab for first-line treatment of metastatic HER2-negative gastroesophageal adenocarcinoma (GEA).
Authors: Park Haeseong , Geyer Susan Michelle , Klute Kelsey , Bleeker Jonathan , King Daniel , Strickland Matthew , Goodrich Austin , Carlisle Destin , Shergill Ardaman , O'Reilly Eileen Mary , Meyerhardt Jeffrey A. , Shah Manish A. 
Published: June 2023

TPS4175 Background: Platinum/fluoropyrimidine (FP) with PD-1 inhibitor is now established as the standard first-line therapy for most patients with advanced HER2 negative gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinoma. The FP doublet chemotherapy backbone, most commonly FOLFOX, is recommended based on marginal survival benefits of taxane-containing triplet therapy at the cost of increased toxicity. Although several agents are approved as standard treatment options in later lines, only about 10% of patients in the US receive a third line of therapy, and very few have the opportunity to benefit from all approved agents in this disease. This challenge will only increase as more agents and targeted therapies are approved. FOLFIRINOX is a triplet regimen commonly used in gastrointestinal malignancies with established safety and often with superior efficacy. Two single arm phase II trials of FOLFIRINOX have reported promising activity in GEA with manageable toxicities. Reported median overall survival (OS) from these trials is around 15 months, which is superior to what is expected from FP doublet first-line chemotherapy (about 11 months). We hypothesize that using upfront triplet therapy with a more effective and less toxic triplet combination will result in improved patient outcomes by optimization of available therapies in GEA. Methods: This study is a randomized phase III, open-label, multicenter clinical trial with the primary objective to determine whether modified FOLFIRINOX (FU 2400 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, irinotecan 150 mg/m2 every 2 weeks) as first-line treatment improves OS compared to mFOLFOX in patients with advanced HER2 negative GEA. Eligible patients will have unresectable or metastatic adenocarcinoma of esophagus, GEJ, or stomach with no prior systemic treatment. Patients must have adequate organ function, and measurable or evaluable disease as defined by RECIST 1.1. Prior neoadjuvant or adjuvant therapy is allowed if completed at least 1 year prior to registration. Patients who will receive nivolumab (mandatory for PD-L1 combined positive score > 5) in addition to chemotherapy must not have any contraindications to immune checkpoint inhibitors. Patients with treated, asymptomatic and stable brain metastases are eligible. The total sample size is 382 evaluable patients for this study (191 patients per arm). The study accrual began January 2023. Clinical trial information: NCT05677490 .
Randomized phase 2 study of maintenance olaparib vs olaparib plus durvalumab for DNA damage repair (DDR) gene mutated unresectable or metastatic biliary tract cancer (BTC) with durable response to first-line platinum-based chemotherapy: OPTIMUM trial.
Authors: Kim YunJung , Ok Boram , Park Inkeun , Ryoo Baek-Yeol , Kim Kyu-Pyo , Yoo Changhoon 
Published: June 2023

TPS4180 Background: BTC is rare and aggressive disease with heterogeneous genetic profiles. Gemcitabine plus cisplatin (GemCis) with or without durvalumab is the standard first-line therapy but further improvement in survival outcomes is needed. In a prior study (Chae HJ et al, Eur J Cancer 2019), germline or somatic mutations in DDR genes including BRCA are detected more than half of BTC patients and associated with better survival outcomes with platinum-based chemotherapy. As the potential efficacy of Olaparib in DDR-mutated cancers and synergism between PARP inhibitors and immune checkpoint inhibitors, we designed randomized phase 2 trial investigating the efficacy and safety of olaparib monotherapy vs olaparib plus durvalumab in BTC patients as maintenance therapy for BTC patients who showed durable response to first-line platinum-based chemotherapy. Methods: This is a randomized, open-label phase 2 study conducted in a single center (Asan Medical Center, Seoul, Korea). Key eligibility criteria include histologically documented locally advanced unresectable or metastatic BTC, no progression at least 16 weeks with first-line platinum-based chemotherapy, DDR mutations on targeted sequencing of tumor tissues and ctDNA, ECOG performance status 0–1, and adequate organ function. Eligible patients will be randomized 1:1 into olaparib monotherapy arm (300 mg twice daily, every 4 weeks) or olaparib plus durvalumab (1,500 mg intravenous, every 4 weeks) arm. Study treatment is continued until disease progression, unacceptable toxicity, withdrawal of consent, or death. Response evaluation is performed every 8 weeks (fixed). Stratification factors are tumor location (intrahepatic vs extrahepatic/gallbladder) and best response to platinum-based chemotherapy (CR/PR vs SD). The six-month progression-free survival rates are the primary endpoint and overall survival, progression-free survival, response rates, and safety profiles are secondary endpoints. A total of 62 patients (31 for each arm) are planned, and 23 (37%) patients (ATM [n=6], BRCA2 [n=7], CHEK2 [n=2], BRCA1 [n=1], RAD51C [n=1], and PBRM1 [n=1]) are enrolled as of Jan 2023. Clinical trial information: NCT05222971 .
ABC-12: Exploring the microbiome in patients (pts) with advanced biliary tract cancer (BTC) in a first-line study of durvalumab in combination with cisplatin/gemcitabine (cis/gem).
Authors: McNamara Mairead Geraldine , Timmins Hayley , Osborne Ashley , Cox Rebecca , Wasan Harpreet Singh , Corrie Pippa , Gillmore Roopinder , Sivakumar Shivan , Ma Yuk Ting , Faluyi Olusola Olusesan , Arora Arvind , Arif Seema , Canham Jo , Hurt Chris , Hubner Richard , Bridgewater John A , Adams Richard , Valle Juan W. 
Published: June 2023

TPS4183 Background: Durvalumab/cis/gem improved overall survival (OS) in pts with advanced BTC versus placebo/cis/gem (Oh et al. NEJM Evid 2022). Disruption of the microbiota may impair tumour response to immunotherapy and chemotherapy and a better understanding of its role in the efficacy of these therapeutics in advanced BTC is required. Methods: This is a multi-centre, single arm trial exploring the microbiome in pts receiving durvalumab 1500 mg intravenously (IV) Q3w, in combination with cis 25 mg/m2, gem 1000 mg/m2 (Days 1 and 8, Q3w) up to 8 cycles, followed by durvalumab 1500 mg as monotherapy Q4w, until progression or intolerable toxicity. Pts with an ECOG performance status of ≤1 and histologically-proven BTC, including cholangiocarcinoma and gallbladder carcinoma, who have had no prior systemic chemotherapy for locally advanced or metastatic disease are eligible. Pts must provide a saliva and stool sample prior to commencement of durvalumab/cis/gem and at 18 weeks, or at progression (if earlier than 18 weeks). Taxonomic profiling via 16S Ribosomal ribonucleic acid gene sequencing will examine the differences in the diversity and composition of the pt gut microbiome. Pts must also have availability of a tumour biopsy. This study plans to recruit 70 pts from 10 UK centres (over 12 months). The primary objective is to determine the difference in baseline alpha diversity between “responders” (partial or complete response) and “non-responders” at 18 weeks (RECIST 1.1) in patients treated with durvalumab/cis/gem. Secondary objectives include investigation of the association between microbiome parameters and objective response rate, tumour control (partial + complete response + stable disease), progression-free and OS, and to investigate the interaction between treatment effect and microbiome parameters on clinical outcomes. The tumour biopsy will be used for research into the tumour microbiome and/or factors that may influence response to chemotherapy/immunotherapy, including, but not limited to tumour mutation burden, programmed cell death 1/programmed death-ligand 1 status, and microsatellite instability status. Clinical trial information: ISRCTN11210442 .