bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of moderate dose omega-3 acid ethyl esters for colorectal cancer prevention in patients with lynch syndrome (COLYNE).
Authors: Choucair Khalil , Dixon Dan , Bansal Ajay , Klemp Jennifer R. , Abdulateef Yazan , Chalise Prabhakar , Al-Rajabi Raed Moh'd Taiseer , Kasi Anup , Williamson Stephen K. , Baranda Joaquina Celebre , Sun Weijing , Saeed Anwaar 
Published: January 2022

TPS209 Background: Lynch syndrome (LS) is the most common inherited colorectal cancer (CRC) syndrome and is responsible for about 3% of newly diagnosed CRC. It is caused by germline mutations in one of the DNA mismatch repair (MMR) genes, and patients with LS carry a lifetime risk of CRC ranging between 10% and 70%. The role of inflammation in driving this malignant transformation is now well established and retrospective studies have revealed a potential chemo-preventative role for omega-3 (ω-3) polyunsaturated fatty acids (PUFAs), possibly via inhibition of inflammatory pathways associated with the development of defective MMR CRC tumors. While patients with LS have the highest risk of developing CRC, the majority of chemoprevention trials are focused on sporadic CRC. Effective interventions to reduce the risk of developing CRC in this population are limited to close surveillance and surgical prophylaxis. There is an unmet need for safe, effective, and non-invasive chemo-preventive interventions in patients with LS. Methods: This pilot study is a single-arm, open-label, phase 2 clinical trial of omega-3 acid ethyl esters (generic Lovasa; 2 grams orally once daily) for adult patients (≥ 18 years of age) with confirmed LS (based on germline testing of the MMR genes panel: MLH1, MSH2, MSHS6, PMS2 or deletion in EPCAM gene). Patients who are not candidate for elective endoscopy and/or with prior history of right sided or pan-colectomy are excluded. Thirty-four patients are expected to enroll, with a primary objective to determine the feasibility (defined as 80% retention rate) of 12 months of treatment with 2 grams capsules of omega-3 acid ethyl esters daily. Secondary endpoints include safety and tolerability of the intervention. Correlative aims include pre and post treatment assessment of colon mucosal tissue proliferation (right sided colon specimens will be evaluated for markers of proliferation (Ki-67) and apoptosis (Caspase-3)), the effect of omega-3 acid ethyl esters on inflammatory markers in serum, urine and feces (PGE-2, COX-2, β-catenin levels, and EPA:AA ratios), and gene expression related to proliferation, apoptosis and cell survival in colon tissue (NF-κB/Wnt pathways). The impact of omega-3 acid ethyl esters on intestinal microbiota will also be assessed (16S rRNA-based profiling). Correlative Colon tissue, serum, urine and feces samples are collected at baseline and at 12 months. The study is actively enrolling with 20 patients enrolled at the time of submission. Clinical trial information: NCT03831698.
NRG-GI008: Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US).
Authors: Dasari Arvind , Lin Yan , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Sahin Ibrahim Halil Halil , Deming Dustin A. , Philip Philip Agop , Hong Theodore S. , Wolmark Norman , Yothers Greg , George Thomas J. , Lieu Christopher Hanyoung 
Published: January 2022

TPS212 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach (especially with serial monitoring) for identifying microscopic or residual tumor cells in CC patients (pts) and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may not need AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose colon cancer has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using Natera’s Signatera assay, those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP + Ox vs more intensive AC with addition of irinotecan (I) for 6 mos. The primary objectives for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs delayed AC arms. The primary objective for Cohort B is DFS in the FP + Ox vs FP + Ox + I arms for both phase II and phase III portions of the trial. Secondary objectives include prevalence of detectable ctDNA post-operatively, time-to event outcomes (overall survival & time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/ normal blood samples will be collected for exploratory correlative research. Study will activate in early 2022 across the NCTN. NCT#: Pending. Support: U10-CA-180868, -180822; UG1CA-189867; Natera.
A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in advanced colorectal cancer (CRC) and other solid tumors (CodeBreaK 101).
Authors: Hong David S. , Yaeger Rona , Kuboki Yasutoshi , Masuishi Toshiki , Barve Minal A. , Falchook Gerald Steven , Govindan Ramaswamy , Sohal Davendra , Kasi Pashtoon Murtaza , Burns Timothy F. , Langer Corey J. , Puri Sonam , Chan Emily , Jafarinasabian Pegah , Ngarmchamnanrith Gataree , Rehn Marko , Tran Qui , Gandara David R. , Strickler John H. , Fakih Marwan 
Published: January 2022

TPS214 Background: Approximately 3% of patients (pts) with CRC have the oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation. Sotorasib, a small molecule that specifically and irreversibly inhibits the KRAS G12C mutant protein, has demonstrated modest clinical activity and no dose-limiting toxicities as a single agent in heavily pretreated pts with KRAS p.G12C-mutated CRC. The combination of sotorasib with other anticancer therapies, such as EGFR or MEK inhibitors, may enhance antitumor efficacy and counteract potential escape mechanisms. Other attractive partners for sotorasib in CRC include biologics and chemotherapy combinations. The CodeBreaK 101 master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib-based combinations in pts with KRAS p.G12C mutated solid tumors. Key subprotocols with CRC combination treatment arms are highlighted here. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens in pts with advanced KRAS p.G12C mutated CRC, NSCLC, and other solid tumors. Key regimens being explored in CRC include (1) Subprotocol A: Sotorasib + trametinib (MEK inhibitor) +/- panitumumab (EGFR inhibitor), (2) Subprotocol H: Sotorasib + panitumumab and sotorasib + panitumumab + FOLFIRI, and (3) Subprotocol M: Sotorasib + bevacizumab-awwb + FOLFIRI or FOLFOX. Key eligibility criteria include advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in treatment-naïve and pretreated patients depending on cohort. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (objective response, disease control, duration of response, time to response, and progression-free survival assessed per RECIST 1.1, and overall survival). Enrollment is ongoing. Contact Amgen Medical Information for more information: medinfo@amgen.com (NCT04185883). Abbreviations: EGFR = epidermal growth factor receptor; FOLFIRI = 5-fluorouracil + leucovorin + irinotecan; FOLFOX = 5-fluorouracil + leucovorin + oxaliplatin; MEK = mitogen-activated protein kinase. Clinical trial information: NCT04185883.
Anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pretreated with bevacizumab plus standard chemotherapy: A single-arm, phase IB/II study.
Authors: Qu Xin , Chen Xian , Li Yong , Liu Li-rong , Qu Yan-chun , Hou Fang-fang , Li Wen-zhu , Liu Yi-hong , Zhu Yan-juan , Zhang Haibo 
Published: January 2022

TPS220 Background: For advanced colorectal cancer (CRC), fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin) with VEGF inhibitors (bevacizumab) is standard first-line treatment. However, once this treatment had been used, the second line treatment is limited. Although continuation of bevacizumab after first progression can improve PFS and OS, the benefit of bevacizumab may be reduced compared with who never pre-treated with bevacizumab (the ML18147 study). Anlotinib is an oral small molecule tyrosine kinases inhibitor, targeting VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α/β and c-kit. mXELIRI is a chemotherapy regimen consisting of irinotecan and capecitabine. The trial is to investigate the efficacy and safety of anlotinib combined with mXELIRI as second-line treatment in advanced colorectal cancer pre-treated with bevacizumab plus standard chemotherapy. Methods: This is a multi-center, prospective, single-arm, 2-part, phase Ib/II study. Eligible pts are aged 18-75 years with histologically and radiographically confirmed mCRC who had progressed or intolerant with bevacizumab plus FOLFOX or CAPEOX regimen chemotherapy treatment. ECOG performance status 0 - 1, and adequate organ function. Treatment: anlotinib (8mg, 10mg or 12mg), po, qd, on days 1-14 every 3 weeks; irinotecan 180-200 mg/m2, iv, on day 1 every 3 weeks; capecitabine, 800 mg/m2, po, bid, on days 1-14 every 3 weeks. For the phase 1b segment, a standard 3+3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of anlotinib. 3 patients are enrolled and treated per dose level (8mg,10mg,12mg). If no DLT, dose is escalated for the next cohort of 3 patients; If 1 DLT, 3 additional patients are treated at this level with dose escalation only if no additional DLTs；If ≥ 2 DLTs, prior dose level is defined as MTD. MTD decided when 6 patients are treated at a dose level with < 2 DLTs. Primary endpoint is objective response rate (ORR) according to RECIST v1.1. Secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and quality of life (QoL). Based on a one-sided one sample log-rank test with 2.5% Type I error, 80% power to detect an improvement in ORR from 5.4% to 15%, there will be 94 patients consider 20% of patients fall off. Research Sponsor: Guangdong Provincial Hospital of Chinese Medicine Clinical trial information: NCT05035914.
An open-label, single-center, phase II study of exploration on optimizing the administration time of fruquintinib combined with camrelizumab in the third-line treatment of MSS advanced colorectal cancer.
Authors: He Yifu 
Published: January 2022

TPS225 Background: Immune checkpoint inhibitors monotherapy has limited clinical benefits in patients with MSS or pMMR metastatic colorectal cancer (CRC), which may be attributed to low level of tumor-infiltrating lymphocytes in MSS advanced CRC. Combination immunotherapy is changing the landscape of cancer treatment, especially combination of immunotherapy with small molecule angiogenesis inhibitors. Preclinical studies have shown that there is a time window from anti-angiogenesis to vascular normalization and this has been initially demonstrated in the clinical study of breast cancer. However, the time window is rarely considered in clinical practice. It is necessary to explore the optimal administration timing of angiogenesis inhibitors when combined with immunotherapy. Here, we conduct an open-label, single-center, phase II study to explore the issue. Methods: Patients eligible for the trial are included: 1) pathologically confirmed advanced colon or rectal adenocarcinoma, MSS or pMMR; 2) previously received only 2 standard regimens after recurrence or metastasis; 3) aged 18-70 years (boundary value included); 4) ECOG performance status of 0 or 1; 5) at least 3 months of survival expectations; 6) patient must present with measurable lesions according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST version 1.1; 7) patients with asymptomatic central nervous system metastases or asymptomatic brain metastases after treatment, with stable disease for at least 3 months, and need not be treated with steroids for at least 4 weeks; 8) had adequate organ function before the enrollment; 9) patients of reproductive age should agree to use effective contraceptive measures from the time of signing the informed form until 3 months after the last dose; 10) sign an informed consent form voluntarily, and be willing to and be able to follow and complete all experimental procedures. The patients enrolled were given oral fruquintinib (3 mg, qd, for 2 consecutive weeks, and then discontinued for 1 week, in 3 weeks [21 days] cycle); on the day 5, administered with intravenous camrelizumab (200mg, once every 3 weeks). The treatment was administered continuously until disease progression, unacceptable toxicity, or required withdrawal from patients. The primary endpoint is progression free survival (PFS), and the secondary endpoints are overall survival (OS), objective response rate (ORR), disease control rate (DCR) and drug safety. As of September 23, 2021, a total of 21 patients have been enrolled. Clinical trial information: ChiCTR2100048528.
mFOLFOXIRI+Bev vs. mFOLFOX6+Bev for RAS mutant unresectable colorectal liver-limited metastases: A study protocol of a multicenter randomized controlled phase 3 (BECOME2) trial.
Authors: Tang Wentao , Wei Ye , Ren Li , Ye Qing-Hai , Liu Tianshu , Xu Jianmin 
Published: January 2022

TPS228 Background: Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by conversion therapy. However, the optimal regimen of conversion therapy for RAS mutant patients has not been defined. Methods: BECOME2 is a multicenter, randomized, phase 3 clinical study. RAS mutant and BRAF wild type colorectal cancer patients with initially unresectable liver-limited metastases are eligible. The (un)resectability status is prospectively assessed by a central multidisciplinary team (MDT) consisting of at least one radiologist and three liver surgeons, according to predefined criteria. RAS and BRAF mutation status were evaluated according to primary tumor. Patients with RAS mutant and BRAF wild type will be randomized between modified FOLFOXIRI (IRI, 165mg/m2; Oxa, 85mg/m2; LV, 400mg/m2; 5-FU 2400mg/m2) plus bevacizumab (5mg/kg) and modified FOLFOX6 (mFOLFOX6) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central MDT every eight weeks. The primary study endpoint is conversion resection rate. Secondary endpoints are the ETS, DpR, ORR, PFS, OS, toxicity, perioperative complication, and the proportion of no evidence of disease. Clinical trial information: NCT04781270.
Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomized phase II trial (PRIME-RT).
Authors: Hanna Catherine Ruth , O'Cathail Sean Michael , Graham Janet , Saunders Mark P. , Samuel Leslie M. , Devlin Lynsey , Edwards Joanne , Maka Noori , Kelly Caroline , Dempsey Laura , Jones Leia , Lewsley Liz-Anne , Morrison Paula , Atherton Peter , Dillon Susan , Gourlay Jacqueline , Platt Jonathan , Tiplady Ellie , Adams Richard , Roxburgh Campbell SD 
Published: January 2022

TPS231 Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. The PRIME-RT trial tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in (n≥6) which is recruiting patients with metastatic disease. After opening in January 2021, three patients have been treated within the safety run-in; 2 in Arm A and 1 in Arm B. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Funding information Core funding (Glasgow CRUK CTU) and trial specific funding (Astrazeneca). Trial registration Clinicaltrials.gov NCT04621370 (Registered 9 Nov 2020) ISRCTN18138369 (Registered 27 October 2020) Clinical trial information: NCT04621370.
Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Hong Theodore S. , Wolmark Norman , George Thomas J. 
Published: January 2022

TPS233 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N = 1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for active surveillance (i.e., not needing adjuvant chemotherapy) will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the Guardant Reveal assay, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Enrollment continues across North America to the 540-patient phase II endpoint. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.
Examination of the functional and diagnostic potential of methylation-sensitive enhancers in metastatic colorectal cancer.
Authors: Carroll Hailey Kathryn , Harrold Emily , Greally Megan , Aird John , O'Donoghue Niamh , Finnegan Ellen , Shields Conor J , Brannigan Ann E , Mulsow Jurgen , Cahill Ronan , Toomey Des , Das Sudipto , McCaffrey John 
Published: January 2022

TPS237 Background: Molecular characterisation of colorectal cancer (CRC) has demonstrated the regulatory role of epigenetic alterations, such as DNA methylation, in CRC tumorigenesis(1). Robust molecular profiling of CRC has the potential to provide critical diagnostic and prognostic information. The establishment of 4 consensus molecular subtypes (CMSs), developed initially for primary CRC tumours, resulted in the evolving framework for molecularly targeted interventions; the molecular genetic profile characterising mCRC is less well defined(3, 4). Previous pilot work identified a unique tumour-specific methylation sequence, at 376 sites within the DNA of mCRC cells(5). This study will assess whether this methylation sequence drives mCRC pathogenesis and underpins disease phenotype. The primary aim of this study is validation of the diagnostic utility of this novel enhancer signature and identification of key enhancers with the potential to direct targeted treatment development. Secondary aims include CRISPR knockdown library development targeting the enhancers in CRC cells in vitro, evaluating the impact of the knockdown on phenotype in vitro, and identifying the mechanisms by which methylation-sensitive enhancers regulate the mCRC phenotype. Methods: This is a retrospective, non-interventional, single-centre clinical study, including patients > 18 years, with (group A) de novo mCRC (n = 100), (group B) stage III colorectal cancer that subsequently relapsed (n = 100) or (group C) stage III colorectal cancer without radiological evidence of relapse at study enrolment (n = 100). Formalin-fixed, paraffin-embedded ( FFPE) tissue obtained at diagnosis will be analysed. Additionally, 50 stage III patients who have relapsed (group B) will have blood samples collected prospectively at time of consent to enable assessment for the presence of the methylation signature on ctDNA. The presence or absence of the novel methylation signature will be evaluated via the application of a targeted bisulfite sequencing panel consisting of the previously identified differentially methylated enhancer (DME) signature to both tissue and plasma samples; results will be correlated with conventional histological parameters, systemic therapy, and overall survival. Quantitative statistical analysis will be performed using SPSS with linear regression analysis for survival data. Ethical approval was obtained from the MMUH Institutional Review Board; reference 1/378/2188. This study is open and recruiting. Clinical trial information: 1/378/2188.