bluuebunny/crossref_metadata_2025_split huggingface dataset:
An observational study to evaluate RAS mutations in circulating tumor DNA after standard chemotherapies for metastatic colorectal cancer patients with tumors harboring RAS mutation: RASMEX study (JACCRO CC-17).
Authors: Izawa Naoki , Kagawa Yoshinori , Satake Hironaga , Sunakawa Yu , Takeuchi Masahiro , Ichikawa Wataru , Fujii Masashi 
Published: January 2022

TPS230 Background: RAS status in tumor tissue is a predictive factor for the efficacy of anti-epidermal growth factor receptor (EGFR) antibodies therapy in patients (pts) with metastatic colorectal cancer (mCRC). In mCRC pts with tumors harboring RAS mutation, anti-EGFR antibodies therapy has the lack of clinical benefit; thus, the survival of RAS mutant mCRC pts is shorter compared to RAS wild mCRC pts. Recently, several studies have shown that colorectal cancer tissue had heterogeneity of gene profiling, and the analysis of circulating tumor DNA (ctDNA) in blood samples could detect the change of gene alterations in tumors which were caused by chemotherapy. Bouchahda et al., demonstrated that nearly half of the pts with RAS mutant mCRC had no detectable RAS mutation in ctDNA after first-line chemotherapy; moreover, some of the pts had clinical benefits from post-anti-EGFR antibodies therapy. Therefore, anti-EGFR antibodies therapy might become a novel treatment option for RAS mutant mCRC pts without RAS mutations in ctDNA after chemotherapies. Other report also showed the frequency of no RAS mutations in ctDNA was about 1%. There have been few studies to prospectively evaluate the RAS status in ctDNA for mCRC pts with RAS mutant tumors treated with standard chemotherapies. We, therefore, conducted an observational study to evaluate RAS mutations and the mutation allele frequency in ctDNA for mCRC pts with RAS mutant tumors who were treated with first- or second-line chemotherapy. Methods: This study is a multi-center observational/translational study in 67 facilities. The key eligibility criteria are as follows: 1) Eastern Cooperative Oncology Group Performance status 0-1, 2) histologically proven unresectable mCRC, 3) RAS mutation in tumor tissue, 4) refractory or intolerable after response to prior fluoropyrimidine-containing regimen. OncoBEAM RAS CRC kit is used to investigate RAS status in ctDNA just after first- or second-line treatment in enrolled pts. The primary endpoint is the frequency of pts without RAS mutations in ctDNA. Secondary endpoints include mutation allele frequency of RAS in ctDNA and clinical outcomes of pre- and post-treatments (overall response rate, disease control rate, overall survival, and progression-free survival). As the exploratory analysis, gene alterations related to the resistant mechanism of anti-EGFR antibodies (BRAF, PIK3CA, ERBB2, MET) are analyzed in pts without RAS mutations in ctDNA. We assume that no RAS mutations are observed in ctDNA in at least 1 % pts. We expect that one patient with no RAS mutations in ctDNA is detected in 100 pts; thus, the sample size of 300 pts is set for our study. Accrual is starting in April 2021. Clinical trial information: UMIN000043442.
Prospective study of the co-relation of ctDNA with pathologic complete remission (pCR) and other efficacy outcomes in rectal cancer patients undergoing neoadjuvant chemotherapy and radiation.
Authors: Xue RuoBing , Sharma Vivek R. , Farmer Russell Ware , Rai Shesh , Wu Xiaoyong , Krainock Michael , Drummond Bridgette , Olshan Perry , Billings Paul R. , Aleshin Alexey 
Published: January 2022

TPS235 Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker for non-invasive longitudinal monitoring of tumor progression in cancer management. Through the recent advances in next generation sequencing (NGS) technologies and personalized assays, ctDNA has been heralded as a promising tool to detect residual disease, relapse, and monitor treatment response in hematologic malignancies and solid tumors. Our study aims to determine whether treatment related ctDNA dynamics can be used as a reliable indicator to predict pathologic complete response (pCR) in patients with rectal cancer receiving neoadjuvant treatment. Methods: This is a prospective observational cohort study. The primary aim is to estimate the sensitivity and specificity of ctDNA clearance in predicting pCR in patients undergoing neoadjuvant therapy. The secondary aim is to evaluate the feasibility of using ctDNA as a surveillance method to detect progression of rectal cancer during neoadjuvant therapy and relapse in the subsequent follow up period. ctDNA levels are collected from newly diagnosed rectal cancer patients at 7 discrete time points: at diagnosis or screening, during neoadjuvant therapy, after completion of neoadjuvant therapy and 1 month, 2 months, 4 months, 6 months after surgery. This will be followed by every 3 months ctDNA testing for surveillance for up to 2 years. We expect to enroll approximately 30 patients at our institution. The subjects will be sorted into two groups: responders and non-responders based on whether they achieve pCR. ctDNA level between two groups will subsequently be compared. The use of ctDNA to predict pCR in rectal cancer patients may allow for many of these patients to safely avoid surgery if undetectable ctDNA at the end of neoadjuvant therapy strongly correlates with pCR. We are actively enrolling patients into this prospective observational study and expect to report the data in the near future. The data we obtain will be combined with those from several institutions around the US doing similar studies with the same test. Data analysis will subsequently be conducted. [Table: see text]
A phase 3 randomized, double-blind, placebo-controlled, multicenter, global study of durvalumab with and after chemoradiotherapy in patients with locally advanced, unresectable esophageal squamous cell carcinoma: KUNLUN.
Authors: Wang Luhua , Chen Ming , Kato Ken , Wyrwicz Lucjan , Smyth Elizabeth Catherine , Jiang Anastasia , Zhang Di , Robbins Scott H. , He Philip , Negro Alejandra , Saba Nabil F. 
Published: January 2022

TPS373 Background: Esophageal cancer is the eighth most common cancer type and the sixth leading cause of cancer-related death worldwide, and esophageal squamous cell carcinoma (ESCC) is the most common type of esophageal cancer. For patients with locally advanced, unresectable ESCC (AJCC 8th Stage II–IVA), definitive chemoradiotherapy (dCRT) is the current standard of care; however, up to half of patients will experience disease progression within two years of dCRT, and overall survival rates remain suboptimal. The combination of immune checkpoint inhibitors with CRT has demonstrated synergistic antitumor activity in pre-clinical models, and recent clinical data has demonstrated clinical benefit of combined programmed cell death-1 inhibition and preoperative CRT in patients with locally advanced ESCC. KUNLUN (NCT04550260) is a Phase 3, multicenter, global study evaluating the efficacy and safety of durvalumab, a programmed cell death ligand-1 (PD-L1) inhibitor, given concurrently with, and after, dCRT in patients with locally advanced, unresectable ESCC. Methods: Approximately 600 patients will be randomized 2:1 to receive either durvalumab with dCRT (cisplatin plus fluorouracil or cisplatin plus capecitabine, with a total dose of 50–64 Gy radiation), followed by durvalumab for up to approximately 24 months, or placebo with dCRT, followed by placebo for up to approximately 24 months. Eligible patients will have histologically or cytologically confirmed ESCC, and present with locally advanced, unresectable ESCC that is deemed suitable for dCRT. Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1, and have not received prior anti-cancer treatment. The co-primary endpoint of the study is progression-free survival according to RECIST v1.1 as assessed by blinded independent central review in all randomized patients and in patients with PD-L1-high tumors. Additional endpoints include overall survival and safety. Study enrollment is ongoing. Funding: This study was sponsored by AstraZeneca. References: Hong MH, et al. J Clin Oncol 2019;37(15 suppl). Abs 4027. Clinical trial information: NCT04550260.
AdvanTIG-206: Anti-TIGIT monoclonal antibody (mAb) ociperlimab (BGB-A1217; OCI) plus anti-programmed cell death protein 1 (PD-1) mAb tislelizumab (TIS) plus BAT1706 versus (vs) TIS plus BAT1706 as first-line treatment for advanced hepatocellular carcinoma (HCC).
Authors: Fan Jia , Ren Zhenggang , Hsu Chiun , Guo Yabing , Song Tianqiang , Wang Wentao , Chao Yee , Gao Yujuan , Li Bai , Ferro Salvatore , Yen Chia-Jui 
Published: January 2022

TPS488 Background: Treatment with PD-1/programmed death-ligand 1 (PD-L1) inhibitors and anti-angiogenic agents has demonstrated significant survival improvements in patients with untreated HCC. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is a co-inhibitory immune checkpoint receptor upregulated on T cells and natural killer cells in multiple solid tumors. OCI is a novel, humanized mAb that binds TIGIT with high specificity and affinity, blocking interaction with its ligands on tumor cells. TIS is an anti-PD-1 mAb that has demonstrated clinical activity in patients with previously treated, unresectable HCC (NCT03419897). BAT1706 is a similar biological product to the anti-angiogenic agent bevacizumab. OCI combined with TIS and BAT1706 could further enhance both anti-angiogenic and anti-PD-1 therapies for patients with HCC. Methods: AdvanTIG-206 is a phase 2, randomized, open-label clinical study (NCT04948697). Patients aged ≥ 18 years with histologically confirmed advanced HCC that is not amenable to a curative treatment approach are eligible. Patients must have a Child-Pugh A score, ECOG PS ≤ 1, and have received no prior systemic therapy for HCC. Approximately 90 patients will be randomized 2:1 to OCI 900 mg combined with TIS 200 mg plus BAT1706 15 mg/kg (Arm A) or TIS 200 mg plus BAT1706 15 mg/kg (Arm B), all administered intravenously (once every 3 weeks [Q3W]). The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Radiological assessment of tumor response status will be performed Q6W for the first 48 weeks and Q12W thereafter. Secondary endpoints include duration of response, time to response, disease control rate, clinical benefit rate, and progression-free survival (all investigator-assessed overall survival), safety, pharmacokinetics, and immunogenicity. Study enrollment is ongoing. Clinical trial information: NCT04948697.
Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: The DEMAND randomized phase II clinical trial.
Authors: De Toni Enrico N. , Kubisch Ilja , Ben Khaled Najib , Ricke Jens , Mayerle Julia , Ehmer Ursula , Waldschmidt Dirk , Rössler Daniel Christoph , Oehrle Bettina , Bitzer Michael , Kandulski Arne , Reuken Philipp A. , Wege Henning , Seidensticker Max 
Published: January 2022

TPS492 Background: Atezolizumab and bevacizumab is the first approved immunotherapeutic regimen for first-line treatment of patients with advanced hepatocellular carcinoma (HCC). The efficacy and tolerability of this regimen suggests that its use could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The effect of TACE combined with atezolizumab and bevacizumab could improve response and tumor control as well as prevent disease progression in non-responders to TACE. Response to the early use of immunotherapy could also reduce the number and extent of TACE cycles needed to achieve tumor control, thereby contributing to the prevention of collateral damage to the liver parenchyma and preservation of liver function. Initiating immunotherapy first may also promote the access of circulating lymphocytes into tumor lesions. The DEMAND study investigates the efficacy and ideal sequence of TACE and immunotherapy in intermediate stage HCC. Methods: This investigator-initiated, multi-center, randomized, open-label phase 2 trial is the first study to evaluate the safety and efficacy of atezolizumab and bevacizumab prior to, or in combination with TACE in patients with unresectable HCC. 106 patients (Barcelona Clinic Liver Cancer Stage A not amenable to curative therapy or B, Child-Pugh A or B7, Eastern Cooperative Oncology Group performance status 0 or 1, no prior TACE) will be randomized in a 1:1 ratio to receive either up-front atezolizumab and bevacizumab followed by TACE selectively directed against progressive lesions (Arm A, 53 patients), or TACE and synchronous treatment with atezolizumab and bevacizumab (Arm B, 53 patients). Patients receive study treatment until loss of clinical benefit or unacceptable toxicity for up to 24 months. The use of local ablation is allowed for the treatment of lesions which cannot be targeted sufficiently selectively by TACE, or of de-novo lesions. The primary endpoint is the 24-month survival rate; secondary endpoints include objective response rate, progression-free survival, safety and quality of life. Translational analyses aim at identifying predictive biomarkers and focus on immune cell phenotyping in tumor and peripheral blood, circulating tumor DNA and changes in the diversity of the gut microbiome. Recruitment is ongoing in 15 German centers with 21 of 106 patients randomized. Clinical trial information: NCT04224636.
LEAP-012 trial in progress: Transarterial chemoembolization (TACE) with or without lenvatinib plus pembrolizumab for intermediate-stage hepatocellular carcinoma (HCC)
Authors: El-Khoueiry Anthony B. , Llovet Josep M , Vogel Arndt , Madoff David C. , Finn Richard S. , Ogasawara Sadahisa , Ren Zhenggang , Mody Kalgi , Li Jerry J. , Siegel Abby B. , Dubrovsky Leonid , Kudo Masatoshi 
Published: January 2022

TPS494 Background: Limited treatment options are available for patients with intermediate HCC. Lenvatinib, a potent multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, are approved first- and second-line therapies for advanced HCC, respectively. The LEAP-012 study (NCT04246177) is investigating lenvatinib plus pembrolizumab in combination with TACE versus placebo plus TACE in patients with intermediate-stage HCC. Methods: LEAP-012 is a randomized, double-blind, phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥1 measurable lesion per RECIST v1.1, Eastern Cooperative Oncology Group performance status of 0 or 1, and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to receive lenvatinib 8 mg (body weight < 60 kg) or 12 mg (body weight ≥60 kg) orally once daily plus pembrolizumab 400 mg intravenously (IV) every 6 weeks (Q6W) plus TACE or placebo orally once daily plus placebo IV Q6W plus TACE. Response will be assessed by imaging every 9 weeks; safety will be assessed throughout the study and up to 90 days after the end of treatment. Dual primary end points are overall survival and progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are PFS, objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and time to progression (TTP) per modified RECIST by BICR; ORR, DCR, DOR, and TTP per RECIST v1.1 by BICR; and safety. Exploratory end points are PFS, ORR, DCR, DOR, TTP, and time from randomization to second/subsequent disease progression after initiation of new anticancer therapy or death from any cause, whichever occurs first, per RECIST v1.1 by investigator review, identification of molecular biomarkers, and health-related quality of life. Recruitment began in April 2020, and the planned sample size is 950 patients. The results of the LEAP-012 study will show the clinical benefit of adding lenvatinib plus pembrolizumab to the current standard of care TACE for patients with intermediate-stage HCC not amenable to curative treatment. Clinical trial information: NCT04246177.
A phase II, open-label pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
Authors: Rogers Sherise C. , Lee Ji-Hyun , Ramnaraign Brian Hemendra , Hitchcock Kathryn , Hughes Steven J. , Turk Anita Ahmed , Russell Karen Bullock , El-Far Ahmad , Thomas Ryan M. , Fabregas Jesus C. , Sahin Ilyas , Allegra Carmen Joseph , DeRemer David L. , George Thomas J. 
Published: January 2022

TPS619 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) in combination with 5FU/LV is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Exploratory ctDNA and stool microbiome analyses are also planned. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]
A phase 1/2 study to evaluate the safety, tolerability, and preliminary efficacy of GP-2250 in combination with gemcitabine for advanced or metastatic pancreatic adenocarcinoma.
Authors: Kasi Anup , Iglesias Jose Luis 
Published: January 2022

TPS620 Background: GP-2250 is a metabolic enzyme inhibitor that selectively induces oxidative stress, mitochondrial dysfunction, and apoptosis in cancer cells by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and limiting aerobic glycolysis, an essential process for energy production in cancer cells. In vitro, increasing concentrations of GP-2250 induced proportional dose-response effects in 5 different pancreatic cancer cell lines (Buchholtz BMC Cancer 2017). Patient-derived pancreatic xenograft studies in mice demonstrated tumor growth inhibition with GP-2250 monotherapy (Braumann J Clin Oncol 2020). In combination with gemcitabine, a synergistic effect was shown with greater inhibition of pancreatic tumor growth than with either gemcitabine or GP-2250 alone. These findings support the assessment of the therapeutic potential of GP-2250 in combination with gemcitabine in patients with pancreatic cancer. Methods: This open-label phase 1/2 trial will evaluate the safety and tolerability of escalating doses of GP-2250 and the preliminary efficacy of GP-2250 in combination with gemcitabine in patients with advanced unresectable or metastatic pancreatic adenocarcinoma who have progressed on prior treatment with FOLFIRINOX chemotherapy. In phase 1, Bayesian Optimal Interval design will be used for GP-2250 dose escalation. The dose-limiting toxicity (DLT)–assessment period will be 5 weeks at each dose level (starting dose 250 mg once weekly intravenously), consisting of a 1-week run-in period with GP-2250 monotherapy, followed by a full cycle of GP-2250 plus standard dose and schedule of gemcitabine. Single patient cohorts (100% dose escalation between cohorts) will be enrolled until the occurrence of the first DLT (or cohort 4 if no DLTs occur in cohorts 1−3), after which, cohorts will be expanded to 3 patients with 35%−45% dose escalations between cohorts. Patients will receive treatment until disease progression or development of unacceptable toxicity. Primary study endpoints include safety and tolerability of GP-2250, tumor response (RECIST 1.1), disease control rate (complete response, partial response, stable disease), and duration of response. Pharmacokinetics, incidence and severity of laboratory abnormalities and treatment-emergent adverse events, progression-free survival, and overall survival will also be assessed. As of September 2021, 19 patients have been enrolled. Following completion of the phase 1/2 trial, a phase 3 first-line maintenance study will be initiated. This study is funded by Geistlich Pharma AG. Clinical trial information: NCT03854110. Clinical trial information: NCT03854110.
Phase Ib/II trial of siltuximab and spartalizumab in patients in metastatic pancreatic cancer.
Authors: Akce Mehmet , Shaib Walid Labib , Diab Maria , Alese Olatunji B. , Wu Christina , Thomas Sunisha , Greene Emily , Herting Cameron , Lesinski Gregory B. , El-Rayes Bassel F. 
Published: January 2022

TPS626 Background: Interleukin-6 (IL-6) is associated with carcinogenesis, immune suppression, and poor prognosis in pancreatic adenocarcinoma (PDAC). Preclinical data demonstrated dual inhibition of IL-6 and (programmed death ligand-1) PD-L1 facilitates CD8+ T cell migration into pancreatic tumors and was effective in controlling tumor growth in syngeneic and genetically engineered PDAC mouse models. Siltuximab is a chimeric monoclonal antibody which targets the IL-6 molecule specifically and spartalizumab is a high-affinity ligand-blocking humanized IgG4 antibody against the PD-1 receptor. Based on this preclinical rationale, we developed a phase Ib/II trial to determine the recommended phase II dose (RP2D), evaluate the safety, toxicity profile, preliminary antitumor activity, and immunogenicity of the siltuximab and spartalizumab in patients with previously treated metastatic PDAC. Methods: The phase Ib trial design is standard 3+3. Primary endpoint is to determine RP2D. Siltuximab is administered intravenously (IV) in three dose levels of 6 mg/kg (DL1), 11 mg/kg (DL2), 9 mg/kg (only if 2 DLTs observed on DL2) every 3 weeks with spartalizumab at 300 mg IV every 3 weeks. Eligible patients must have stage IV PDAC who have failed at least one prior therapy age ≥18 years, ECOG PS 0-1, no prior anti PD-1 or anti-PD-L1 agent. After RP2D is established, an expansion phase will enroll 24 patients with PDAC. Pre and on-treatment biopsy will be performed in 24 patients in the expansion cohort for correlative analysis. Pre-treatment and on-treatment peripheral blood samples will be collected from all patients. In the expansion phase patients will receive initial cycle (every 3 weeks) treatment with either spartalizumab or spartalizumab plus siltuximab and then starting cycle 2 all patients receive the combination following the on-treatment research biopsy. This design will enable us to evaluate the immunological effects of spartalizumab alone versus the combination in the tumor microenvironment and peripheral blood. This study was activated in January 2020 and to date 12 patients were enrolled in dose escalation phase. The dose expansion phase has recently started accrual. Clinical trial information: NCT04191421.