bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fruquintinib with PD-1 inhibitors versus TAS-102 with bevacizumab in late-line mCRC: A retrospective cohort study based on propensity score matching.
Authors: Li Rongrong , Yang Xiao-Lin , Liu Zhen-yang , Zhou Hui-Jun , Yin Xian-Li , Zeng De-Yu , Shen Hua , Zeng Yi-Dong , Xiang Fang , Li Ke , Jiang Shao-Feng , Liu Wu 
Published: January 2024

95 Background: Fruquintinib with PD-1 inhibitors (FP) and TAS-102 with bevacizumab (TB) are two common therapies for patients with previous-treated metastatic colorectal cancer (mCRC). However, it’s still not clear that which therapy can bring better prognosis. Methods: This is a retrospective cohort study conducted in Hunan Cancer Hospital. Patients (pts) with mCRC who had received at least the 2nd line treatment were eligible. Propensity score (PS) would be calculated to balance the baseline characteristics of two arms. Overall survival (OS) was set as the primary endpoint. Results: From July 2019 to October 2022, 106 eligible pts in total were enrolled. According to the treatment received, 72 and 34 pts were respectively allocated into FP cohort and TB cohort. With a global median follow-up of 14, the crude OS was 19.4 (95% CI: 17.9-NA) mo in FP cohort vs. 11.6 (10.0-17.2) mo in TB cohort. The HR of FP was 0.384 (95% CI: 0.192-0.769, TB as reference). Multivariate Cox regression showed that the adjusted HR was 0.323 (95% CI: 0.149-0.704), which was adjusted with sex, age greater than 65 yr, ECOG-PS, resection of primary lesion, radiotherapy history, location of lesion (left or right), metastases (liver, lung, and bone), and current line (3 or later). With PS, we performed three statistical methods, namely inverse probability weighting, PS matching (the sample size was 49 vs. 29 after matching), and additional adjustment for PS with multivariate cox regression. The HRs of FP were 0.437 (95% CI: 0.200-0.953), 0.446 (95% CI: 0.201-0.990), and 0.339 (95% CI: 0.153-0.748), respectively. Subgroup analysis indicated that FP demonstrated lower HR in subgroup of male (0.296, 95% CI: 0.117- 0.753), right-sided lesion (0.177, 95% CI: 0.043- 0.736), liver metastasis (0.291, 95% CI: 0.112- 0.756), and current line greater than 3 (0.303, 95% CI: 0.113- 0.812). Additionally in the raw set, the ORR was 16.67% vs. 8.82% (ORFP=2.067, 95% CI: 0.602-9.559), and the DCR was 93.06% vs. 73.53% (ORFP=4.824, 95% CI: 1.518-17.030). Conclusions: FP demonstrated robustly lower HRs for OS in both crude and PS analysis. Likewise, FP showed better OS and DCR in pts with late-line mCRC than TB, which suggested FP might be a better therapy in late-line mCRC.
A phase 1b study of the OxPhos inhibitor ME-344 in combination with bevacizumab in refractory metastatic colorectal cancer.
Authors: Boland Patrick M , Lenz Heinz-Josef , Cusnir Mike , Florou Vaia , Pishvaian Michael J. , Cohen Deirdre J. , Ciombor Kristen Keon , Winer Arthur , Guo Jessie Yanxiang , Algaze Sandra , Wiley Sandra E , Ghalie Richard , Hochster Howard S. 
Published: January 2024

TPS222 Background: ME-344 is a synthetic small molecule that inhibits oxidative phosphorylation, resulting in energy starvation and cell death via caspase-dependent and -independent mechanisms. The activity of mitochondrial inhibitors is enhanced when mitochondrial respiration is upregulated, a situation achieved in solid tumors by inducing vascular normalization and hypoxia correction with antiangiogenics. In a CT26 colon carcinoma syngeneic murine model, ME-344 in combination with regorafenib showed significantly reduced tumor growth compared to regorafenib alone (Navarro et al. Cell Reports. 2016;15:2705). A randomized phase 0/1 window of opportunity study in HER2-negative breast cancer showed significant decrease in the proliferation marker Ki67 in patients administered ME-344 plus bevacizumab vs. bevacizumab alone (Quintela-Fandino et al, Clin Cancer Res. 2020;26:35). The current study evaluates the safety and efficacy of ME-344 in combination with bevacizumab in refractory metastatic colorectal cancer, a clinical setting where continued antiangiogenic inhibition has established benefit. Prior phase 1-1b studies of ME-344 as a single agent and in combination have established the RP2D at 10 mg/kg when administered intravenously weekly. Methods: This is an open-label phase 1b study in patients ≥18 years old with metastatic colorectal cancer after failure of standard therapies, including fluoropyrimidine-, irinotecan-, and oxaliplatin-based regimens, anti-EGFR if RAS wild-type, PD/L-1-blocking antibody if MSI-H/dMMR, and BRAF-targeted therapy if BRAF V600E mutated. Other key eligibility criteria include measurable disease, ECOG performance status 0-1, adequate bone marrow, liver and renal function, no uncontrolled brain metastatic disease, no peripheral neuropathy grade ≥2, no uncontrolled hypertension or diabetes, and no increased hemorrhagic risk. Enrollment will proceed in 2 cohorts of 20 patients each. Cohort 1 will be administered ME-344 at 10 mg/kg on days 1, 8, and 15 of a 28-day cycle and bevacizumab 5 mg/kg on days 1 and 15. Cohort 2 will be administered ME-344 at 10 mg/kg and bevacizumab 5 mg/kg both on days 1 and 15 of a 28-day cycle. Treatment will continue until disease progression or intolerance. Tumor assessment is performed every 8 weeks for 6 months and then every 3 months using RECIST-1 criteria. The primary endpoint is 16-week PFS. Secondary endpoints are PFS, response rate, and safety. Correlative analysis will evaluate treatment-related metabolic response. The study is actively enrolling, funded by MEI Pharma, and registered under NCT02100007. Clinical trial information: NCT02100007 .
Neoadjuvant anti-programmed death 1 (PD-1) therapy in patients (pts) with resectable mismatch repair–deficient (dMMR) locally advanced rectal cancer (LARC): EPOC2201.
Authors: Bando Hideaki , Tsukada Yuichiro , Taketomi Akinobu , Yuki Satoshi , Komatsu Yoshito , Akiyoshi Takashi , Shinozaki Eiji , Kanemitsu Yukihide , Takashima Atsuo , Shiozawa Manabu , Shiomi Akio , Yamazaki Kentaro , Matsuhashi Nobuhisa , Hasegawa Hiroko , Kato Takeshi , Oki Eiji , Wakabayashi Masashi , Fuse Nozomu , Ito Masaaki , Yoshino Takayuki 
Published: January 2024

TPS226 Background: Neoadjuvant radiotherapy and chemotherapy followed by surgical resection is a standard treatment for LARC. As anti-PD-1 therapy for patients with dMMR colorectal cancer is responsive in the context of metastatic disease, several clinical trials which evaluate the efficacies of anti-PD-1 therapy in patients with dMMR LARC are on-going and suggested the outstanding responses (Cercek A. et al., N Engl J Med 2022). Methods: We initiated the EPOC 2201 VOLTAGE-2 study, which is an ongoing, non-randomized, single-arm phase II trial. The major eligibility criteria were as follows: treatment-naïve with rectal cancer located 12 cm from the anal verge; confirmed dMMR; clinical stage II/III in primary cohort (N=35) and stage I in exploratory cohort (N=20); age ≥ 18; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and presence of sufficient organ function. The study treatments include 12 cycles of nivolumab (NIVO) monotherapy (240 mg every 2 weeks) followed by assessment using Memorial Sloan Kettering (MSKCC) Regression Schema (Smith J.J. et al., BMC Cancer 2015). If clinical complete response (cCR) or near complete response (nCR) are observed, non-operative management with additional 12 cycles of NIVO will be performed. If incomplete response (IR) is observed, standard chemoradiotherapy with 50.4Gy of radiation plus capecitabine followed by surgery will be performed. The primary endpoint is the 2-year cCR rate in primary cohort. Various survival endpoints including progression-free survival (PFS) and overall survival (OS) are assessed as secondary endpoints. Safety analyses are performed using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, and the Clavien‒Dindo classification (ver. 2.0) is added for postoperative complications. Assuming null and alternative hypotheses, cCR rates of 23% and 45%, the planned sample size for primary cohort was set at 35, with a one-sided alpha of 5% and power of 80%. An exploratory biomarker study was also conducted using serially collected tumor and blood samples. Whole genome-based minimal residual disease (MRD) assay and whole exome/whole transcriptome-based tumor and immune microenvironment analyses are performed. As of August 2023, patient’s enrollment is ongoing. Clinical trial information: jRCT2031220484 .
FOENIX-CCA4: A phase 2 study of futibatinib 20 mg and 16 mg in patients with advanced cholangiocarcinoma (CCA) and fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements.
Authors: Macarulla Teresa , Mizuno Takashi , Brandi Giovanni , Li Jin , Chen Ming-Huang , Kang Jung Hun , Abdalla Kathia Cristina , Wysocki Piotr Jan , Couto Nuno , Anderson Bailey , Elsayed Hamdy , Mantry Parvez 
Published: January 2024

TPS572 Background: In 2022, the U.S. FDA approved futibatinib, a covalently binding inhibitor of FGFR1–4, for previously treated patients with advanced intrahepatic CCA and FGFR2 fusions/rearrangements. In the pivotal phase 2 FOENIX-CCA2 study, futibatinib 20 mg once daily (QD) resulted in an objective response rate (ORR) of 42% by independent review and a median duration of response (DOR) of 9.7 months. Futibatinib was tolerable and had a manageable safety profile.1 Limited phase 1 data suggest futibatinib may also have antitumor activity at a lower dose (16 mg QD), with fewer dose modifications required for adverse events.2 The aim of FOENIX-CCA4is to confirm the clinical benefit of futibatinib 20 mg QD and explore the safety and efficacy of futibatinib 16 mg QD in previously treated patients with advanced CCA and FGFR2 fusions/rearrangements. Methods: In this global, phase 2, randomized, open-label study (NCT05727176), patients with CCA harboring FGFR2 fusions/rearrangements who have received ≥1 line of gemcitabine/platinum-based therapy for advanced/metastatic disease will be randomized 1:1 to futibatinib at a starting dose of 20 mg or 16 mg QD continuously on a 21-day cycle. Randomization will be stratified by the number of prior lines of systemic therapy for advanced disease (1 vs ≥2). Futibatinib will be continued until progressive disease or unacceptable toxicity. Tumor response will be assessed at baseline, every 6 weeks for the first 12 weeks, and every 9 weeks thereafter until radiographic progressive disease or initiation of new anticancer therapy. The primary endpoint is ORR according to Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by blinded independent central review (analyzed when all patients responding to futibatinib have ≥6 months’ follow-up from the first onset of response). DOR is a key secondary endpoint. Other secondary endpoints are progression-free survival, overall survival, safety, and quality of life. Sample size (120 patients) was estimated on the assumption that if the lower ORR between futibatinib 16 mg and 20 mg is 32% (with ≥60 patients per arm), the probability of correctly selecting the treatment arm with a true ORR of 42% is 0.87. Enrollment is ongoing in Europe, the US, and Asia-Pacific. 1. Goyal L et al. N Engl J Med. 2023;388:228–39. 2. Meric-Bernstam F et al. Cancer Discov. 2022;12:402–15. Clinical trial information: NCT05727176 .
Lenvatinib in recurrent hepatocellular carcinoma after liver transplantation.
Authors: Akce Mehmet , Gbolahan Olumide B. , Switchenko Jeffrey M. , Sonbol Mohamad B. , Roccaro Giorgio , Cannon Robert M , Sheikh Saulat S , Alese Olatunji B. , Bekaii-Saab Tanios S. , El-Rayes Bassel F. 
Published: January 2024

TPS578 Background: Liver transplantation is a curative treatment option in hepatocellular carcinoma (HCC) however; up to 20% of patients develop recurrent disease. HCC recurrence post-transplant is usually extrahepatic (up to 67%) hence requires effective systemic therapy options. Available data are limited and restricted to small non-randomized studies and case series. Lack of prospective clinical trial data and limited data indicates an area of unmet need in treatment of recurrent HCC after liver transplantation. This phase II study aims evaluate the safety and efficacy of lenvatinib in patients with recurrent HCC after liver transplantation. Methods: This is a multi-institutional phase II trial with lenvatinib in patients with recurrent HCC after transplantation. Lenvatinib is administered 12 mg daily orally in patients ≥60 kg, and 8 mg daily orally in patients <60 kg. Each cycle is 28 days. Restaging scans will be performed every 8 weeks. Eligible patients must have histologically proven HCC that has recurred after liver transplantation and not amenable for surgical resection, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST version 1.1, adequate organ function, no prior systemic therapy with lenvatinib or another systemic therapy in the post-transplant setting. Prior liver directed therapy is allowed, should be at least >28 days prior to the study enrollment, and should have at least one measurable untreated lesion by RECIST 1.1 Primary endpoint is overall response rate (ORR). Secondary endpoints are safety/tolerability, progression free survival, and overall survival. Pre-treatment and on-treatment peripheral blood samples will be collected for correlative research. A Simon`s two stage Minimax design is employed (H0: ORR = 5%; H1: ORR = 24%; Type I error = 0.05; power = 80%). In the first stage, 11 patients will be accrued, and if there is no objective response among them, the study will be stopped for futility. Otherwise, additional 6 patients will be accrued for a total of 17 patients. This study is currently enrolling patients. Clinical trial information: NCT05103904 .
Anlotinib combined with penpulimab and hepatic artery infusion chemotherapy (HAIC) in the first-line treatment of unresectable hepatocellular carcinoma.
Authors: Chen Gong-Rang , Zhong Ting , Cai Jian-Hua , Liang Juan 
Published: January 2024

TPS579 Background: Hepatic arterial infusion chemotherapy (HAIC) is recommended as a treatment option in patients with advanced hepatocellular carcinoma (HCC). Anlotinib plus penpulimab, a humanized anti-PD-1 IgG1 antibody, has shown encouraging activity in the treatment of advanced HCC in an open-label phase II trial (NCT 04172571). Considering different anti-malignancy mechanisms, combining systemic and locoregional therapies may show a potential synergic effect and promising preliminary efficacy results in advanced HCC. Consequently, the aim of this study is to assess the efficacy and safety of Anlotinib, Penpulimab, plus HAIC for advanced HCC. Methods: Trial design: This single-arm, prospective, phase II study will include treatment-naive adult (≥18 years) patients with advanced HCC, ECOG PS 0-2, and Child-Pugh class A-B. A total number of 26 patients will be enrolled for treatment until disease progression or intolerable toxicity. Patients will receive anlotinib(10 mg, p.o., qd, d1-14, q3w), penpulimab (200 mg, i.v., d1, q3w) and HAIC (d1- d2) with the FOLFOX regimen (oxaliplatin 85-130 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 hours) for 4-6 cycles, followed by maintenance therapy with anlotinib and penpulimab for up to 2 years. The primary endpoint is objective response rate (ORR)), evaluated using RECIST 1.1. Secondary endpoints are median PFS and overall survival (OS), disease control rate (DCR) per RECIST 1.1, quality of life (QOL) and safety. Recruitment for this study will complete in December 2024.
Phase I/II clinical trial of regorafenib plus durvalumab (MEDI4736) in patients with chemotherapy-refractory advanced biliary tract cancers.
Authors: Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Baranda Joaquina Celebre , Saeed Anwaar , Li Haoran , Bruey Collin , Best Shaun , Phadnis Milind A. , Sun Weijing 
Published: January 2024

TPS581 Background: Biliary tract cancers (BTC) are a heterogeneous group of cancers affecting the epithelial lining of the intra- and extrahepatic portions of the biliary tree, ranking as the second most prevalent primary liver cancer after hepatocellular carcinoma. A subgroup of BTC was found to have an abundant tumor specific neoantigen expression, enriched expression of immune related genes and genes regulating inhibitory immune checkpoint proteins. Recent advancements in BTC treatment include the TOPZ-1 trial, which established the survival advantage of adding durvalumab to the gemzar + cisplatin regimen with an estimated 24-month overall survival rate of 24.9% versus 10.4% for placebo. The hazard ratio for progression-free survival favored durvalumab at 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates also showed improvement, with 26.7% for durvalumab and 18.7% for placebo. Furthermore, single agent regorafenib has exhibited efficacy in patients with refractory advanced metastatic cholangiocarcinoma, particularly in terms of progression-free survival, favoring regorafenib over placebo, the overall toxicity profile was as expected. Regorafenib targets multiple tyrosine kinases and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with checkpoint inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like regorafenib will have synergistic effect when combined with checkpoint-based immunotherapy like durvalumab in patients with chemo refractory BTC. Methods: This study comprises a single-arm, unblinded Phase I/II trial designed to assess the safety and efficacy of the combination therapy involving regorafenib and durvalumab in patients with chemo-refractory advanced BTC. The Phase I portion employed a 3 + 3 design with two dose levels of regorafenib (80 mg and 120 mg) administered in conjunction with 1500 mg IV durvalumab every 28 days. Phase I successfully completed, and the Data Monitoring Committee (DMC) endorsed the continuation of the trial as planned. Eligibility: Histologically confirmed unresectable or metastatic disease. Progressed on at least one line of therapy. May have received checkpoint inhibitor in the past. Inclusion criteria also include ECOG PS 0-1. Objectives:Primary Phase I: Safety of regorafenib in combination with durvalumab.Phase II: Progression-free survival (PFS).Secondary:Disease Control Rate (DCR), Overall response rate (ORR), Overall survival (OS). Statistical Plan: Interim futility testing after one year, halting if conditional power < 20%. Final analysis: PFS and OS via Weibull Regression. Enrollment is currently ongoing with 8 out of 40 patients enrolled.
Phase 1/2 trial of vesicular stomatitis virus expressing human interferon-β and NIS (VSV-IFNβ-NIS), with ipilimumab and nivolumab, in patients with neuroendocrine carcinoma.
Authors: McGarrah Patrick Walsh , Naik Shruthi , Halfdanarson Thorvardur Ragnar , Peng Kah Whye , Russell Stephen J. , Molina Julian R. , Adjei Alex A. 
Published: January 2024

TPS602 Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of dual immune checkpoint inhibitor (ICIs) therapy in NEC shows some promise, but most tumors do not respond. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety and efficacy of VSV-IFNβ-NIS in combination with dual ICI therapy, ipilimumab and nivolumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. After a safety run-in, we will be testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated with ipilimumab and nivolumab on day 1, followed by one RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 4, followed by nivolumab every 3 weeks and ipilimumab every 6 weeks until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .