An Open Labelled Phase III Adjuvant Trial of Disease-free Survival in Patients With Resected Pancreatic Ductal Adenocarcinoma Randomized to Allocation of Oxaliplatin- or Gemcitabine-based Chemotherapy by Standard Clinical Criteria or by a Transcriptomic Treatment Specific Stratification Signature

This is a multicentre open labelled phase III adjuvant trial of disease-free survival in patients with resected pancreatic ductal adenocarcinoma randomized to allocation of oxaliplatin- or gemcitabine-based chemotherapy by standard clinical criteria (control arm) or by a transcriptomic treatment specific stratification signature or TSS (test arm).

开始日期2025-01-15

申办/合作机构

Heidelberg University, U.S.

[+3]

NCT04516681 / Recruiting临床3期IIT

Vitamin C Intravenously With Chemotherapy and Adebrelimab in Metastatic Colorectal Cancer With High Expresison Level of GLUT3

Previous preclinical study has shown that high levels of ascorbic acid (AA) possesses the ability to kill human colorectal cancer cells and high expression of GLUT3 will augment the efficacy of AA. To date, no previous studies have investigated the combination of therapeutic role of AA and PD-L1 antibody in metastatic colorectal cancer with high expression of GLUT3. This protocol is a randomized controlled study of AA infusions combined with Adebrelimab and FOLFOX +/- bevacizumab versus treatment with FOLFOX +/- bevacizumab alone in metastatic colorectal cancer patients with high expression of GLUT3.

开始日期2024-12-01

申办/合作机构

复旦大学

NCT06490536 / Recruiting临床3期IIT

A Precision Medicine Trial Leveraging Blood-Based Tumor Genomics to Optimize Treatment in Operable Stage III and High-Risk Stage II Colon Cancer Patients

Background & Rationale:
Colon cancer is a leading cause of cancer deaths, with a high recurrence rate in stage II high-risk and stage III patients due to undetectable micro-metastases. Liquid biopsy (LB) detects residual cancer DNA post-surgery and monitors treatment response.
Primary Objective:
Show that therapy based on tumor genetics and LB improves outcomes and quality of life for high-risk stage II and stage III colon cancer patients compared to conventional therapy.
Secondary Objectives:
Compare recurrence times. Evaluate side effects and quality of life. Assess cost differences. Validate LB accuracy.
Study Design: Patients are randomized into standard or personalized treatment groups based on LB results.
For positive LB results:
Randomized to standard or customized therapy. Monitor treatment response with LB.
For negative LB results:
Randomized to standard chemotherapy or follow-ups, starting treatment if a positive result appears.
Treatments:
Standard Chemotherapy:
CAPOX (capecitabine and oxaliplatin) FOLFOX (folinic acid, fluorouracil, and oxaliplatin)
Personalized Treatments:
Customized chemotherapy with CAPOX. Immunotherapy with nivolumab and ipilimumab. Targeted therapy with trastuzumab and pertuzumab. FOLFOX with anti-EGFR (epidermal growth factor receptor) therapy (panitumumab).
Population: 700 patients with operable stage III and high-risk stage II colon cancer.
Inclusion Criteria:
Aged 18 or older. Confirmed diagnosis. Tumor tissue sample available.
Exclusion Criteria:
History of other tumors within five years. Incomplete colonoscopy or recent polyp removal. Metastatic disease or recent experimental study participation. Major cardiovascular diseases, intestinal obstruction, autoimmune diseases, neuropathy, HIV (Human Immunodeficiency Virus), active TB (Tuberculosis), or hepatitis B/C infection.
Medical conditions contraindicating treatment.
Endpoints:
Primary:
Evaluate disease recurrence after two years.
Secondary:
Assess disease recurrence and overall survival at 3 and 5 years. Measure treatment safety and tolerability. Validate LB accuracy. Monitor quality of life using questionnaires.
The study will last 5 years and be conducted in 25-30 hospitals across Italy, Spain, and Germany.

开始日期2024-10-22

申办/合作机构-

100 项与亚叶酸相关的临床结果

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100 项与亚叶酸相关的转化医学

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100 项与亚叶酸相关的专利（医药）

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6,959

项与亚叶酸相关的文献（医药）

2025-01-01·PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY

The pediatric psychopharmacology of autism spectrum disorder: A systematic review - Part II: The future

Review

作者: Arango, Celso ; Asta, Lisa ; Cortese, Samuele ; Persico, Antonio M. ; Persico, Antonio M ; Vitiello, Benedetto ; Chehbani, Fethia ; Parlatini, Valeria ; Mirabelli, Silvestro

Part I of this systematic review summarized the state-of-the-art of pediatric psychopharmacology for Autism Spectrum Disorder (ASD), a severe and lifelong neurodevelopmental disorder. The purpose of this Part II follow-up article is to provide a systematic overview of the experimental psychopharmacology of ASD. To this aim, we have first identified in the Clinicaltrials.gov website all the 157 pharmacological and nutraceutical compounds which have been experimentally tested in children and adolescents with ASD using the randomized placebo-controlled trial (RCT) design. After excluding 24 drugs already presented in Part I, a systematic review spanning each of the remaining 133 compounds was registered on Prospero (ID: CRD42023476555), performed on PubMed (August 8, 2024), and completed with EBSCO, PsycINFO (psychology and psychiatry literature) and the Cochrane Database of Systematic reviews, yielding a total of 115 published RCTs, including 57 trials for 23 pharmacological compounds and 48 trials for 17 nutraceuticals/supplements. Melatonin and oxytocin were not included, because recent systematic reviews have been already published for both these compounds. RCTs of drugs with the strongest foundation in preclinical research, namely arbaclofen, balovaptan and bumetanide have all failed to reach their primary end-points, although efforts to target specific patient subgroups do warrant further investigation. For the vast majority of compounds, including cannabidiol, vasopressin, and probiotics, insufficient evidence of efficacy and safety is available. However, a small subset of compounds, including N-acetylcysteine, folinic acid, l-carnitine, coenzyme Q10, sulforaphane, and metformin may already be considered, with due caution, for clinical use, because there is promising evidence of efficacy and a high safety profile. For several other compounds, such as secretin, efficacy can be confidently excluded, and/or the data discourage undertaking new RCTs. Part I and Part II summarize "drug-based" information, which will be ultimately merged to provide clinicians with a "symptom-based" consensus statement in a conclusive Part III, with the overarching aim to foster evidence-based clinical practices and to organize new strategies for future clinical trials.

2025-01-01·ANALYTICA CHIMICA ACTA

Therapeutic drug monitoring of methotrexate by disposable SPCE biosensor for personalized medicine

Article

作者: Zhang, Chen-Zhi ; Liu, Hui ; Liu, Ai-Lin ; Huang, Pin-Fang ; Yu, Zi-Wei ; Liu, Yi-Wei ; Liu, Meng-Meng ; Wu, Mei-Juan ; Han, Jing-Wen ; Yang, Ruo-Yu

BACKGROUND:

Methotrexate (MTX) is widely used in clinical practice for the treatment of malignant tumors and autoimmune diseases. High-dose MTX has been shown to be an effective approach for treating various malignant tumors, but it is accompanied by numerous toxic side effects, necessitating therapeutic drug monitoring (TDM) for patients and timely "folinic acid rescue." High-performance liquid chromatography and fluorescent immunoassay (FIA) are currently used to detect MTX, but these methods are limited by complex sample preparation, time consumption, and high cost. Therefore, a simple, rapid, and cost-effective MTX measurement method is required.

RESULTS:

We developed a flexible and inexpensive electrochemical sensor using a stearyl trimethyl ammonium bromide (STAB)-modified, screen-printed carbon electrode to directly detect MTX in human serum. Assay performance was validated via detection of MTX in spiked buffer. The sensor was capable of measuring MTX concentrations ranging from 0.01 to 1 μM and 1-1500 μM, with a limit of detection of 3.1 nM and a limit of quantitation of 3.5 nM. For the samples simulating combined medication, the sensor exhibited outstanding selectivity, in cross-reactivity, with the maximum response value of interferents reaching only 3.49 %. Additionally, the sensor shows reliable repeatability with a relative standard deviation of 3.8 % and remarkable stability. Recovery in human serum validated the clinical utility of the sensor in point-of-care testing conditions. The sensor's applicability to personal medicine was confirmed by detecting MTX blood concentration in patients with different diseases. The results obtained by the sensor were compared with those obtained by the FIA technique, a method commonly used in hospitals, showing a high level of consistency between both methods.

SIGNIFICANCE:

To meet the requirements of personalized medicine for MTX-patients, we developed a disposable biosensor with wide detection range from 0.01 to 1 μM and 1-1500 μM. Owing to the effective enrichment of STAB, the electrochemical response was sensitive, selective, stable, and rapid. As per the clinical test results, our sensor has shown a high level of consistency with the FIA method, indicating its potential to replace FIA as a cost-effective platform for MTX-TDM.

2024-12-01·Recent patents on anti-cancer drug discovery

Targeted Regulation of Osteoblasts and Osteoclasts in Osteosarcoma Patients by CSF3R Receptor Inhibition of Osteolysis Caused by Tumor Inflammation Based on Transcriptional Spectrum Analysis and Drug Library Screening

Article

作者: Duan, Wei ; Shan, Jinlu ; Chen, Yu ; Li, Qian

Background::

Osteosarcoma (OS) is a common primary malignant bone tumor that mainly occurs in children and adolescents. The use of IL-8 inhibitor compounds has been reported in patents, which can be used to treat and/or prevent osteosarcoma, but the pathogenesis of osteosarcoma remains to be investigated. At present, osteoblasts and osteoclasts play an important role in the occurrence and development of OS. However, the relationship between osteoblasts and osteoclasts in the specific participation mechanism and inflammatory response of OS patients has not been further studied.

Methods::

The transcriptome, clinical data, and other data related to OS were downloaded from the GEO database to analyze them with 200 known inflammatory response genes. We set the screening conditions as p < 0.05 and | log2FC| > 0.50, screened the differentially expressed genes (DEGs) related to OS, tested the correlation coefficient between the OS INF gene and clinical risk, and analyzed the survival prognosis. We further enriched and analyzed the DEGs and inflammatory response genes of OS with GO/KEGG to explore the potential biological function and signal pathway mechanism of OS inflammatory response genes. Moreover, the virtual screening of drug sensitivity of OS based on the FDA drug library was also carried out to explore potential therapeutic drugs targeted to regulate OS osteogenesis and osteoclast inflammation, and finally, the molecular dynamics simulation verification of OS core protein and potential drugs was carried out to explore the binding stability and mechanism between potential drugs and core protein.

Results::

Through differential analysis of GSE39058, GSE36001, GSE87624, and three other data sets closely related to OS osteoblasts and osteoclasts, we found that there was one upregulated gene (CADM1) and one down-regulated gene (PHF15) related to OS. In addition, GSEA enrichment analysis of the DEGs of OS showed that it was mainly involved in the progress of OS through biological functions, such as oxidative photosynthesis, acute junction, and epithelial-mesenchymal transition. The enrichment analysis of OS DEGs revealed that they mainly affect the occurrence and progress of OS by participating in the regulation of the actin skeleton, PI3K Akt signal pathway, complement and coagulation cascade. According to the expression of CSF3R in OS patients, a risk coefficient model and a diagnostic model were established. It was found that the more significant the difference in the CSF3R gene in OS patients, the greater the risk coefficient of disease (p < 0.05). The AUC under the curve of the CSF3R gene was greater than 0.65, which had a good diagnostic significance for OS. The above results showed that the prognosis risk gene CSF3R related to OS inflammation was closely related to the survival status of OS patients. Finally, through the virtual screening of the ZINC drug library and molecular dynamics simulation, it was found that the docking model formed by the core protein CSF3R and the compounds, Leucovorin and Methotrexate, were the most stable, which revealed that the compounds Leucovorin and Methotrexate might play a role in the treatment of OS by combining with the inflammatory response related factor CSF3R of OS.

Conclusion::

CSF3R participates in the occurrence and development of OS bone destruction by regulating the inflammatory response of osteoblasts and osteoclasts and can affect the survival prognosis of OS patients.

112

项与亚叶酸相关的新闻（医药）

2024-12-10

·GlobeNewswire-Health Care

Cardiff Oncology Announces Positive Initial Data from First-line RAS-mutated mCRC Clinical Trial

- Initial results from randomized Phase 2 CRDF-004 trial evaluating onvansertib + standard of care in RAS-mut mCRC demonstrated 64% ORR in the 30mg onvansertib dose arm versus 33% ORR in the control arm - - In the experimental arms, 30mg dose of onvansertib demonstrated a higher ORR compared to 20mg dose of onvansertib (64% vs. 50%) with deeper tumor regression in the 30mg arm - - Onvansertib was well tolerated at both doses - - Additional clinical data from CRDF-004 trial expected in 1H 2025 - - Company will hold a conference call today at 8:00 a.m. ET / 5:00 a.m. PT - SAN DIEGO, Dec. 10, 2024 (GLOBE NEWSWIRE) -- Cardiff Oncology, Inc. (Nasdaq: CRDF), a clinical-stage biotechnology company leveraging PLK1 inhibition to develop novel therapies across a range of cancers, today announced positive initial data from CRDF-004, a randomized, Phase 2 clinical trial evaluating onvansertib in combination with standard-of-care (SoC) in patients with first-line RAS-mutated metastatic colorectal cancer (mCRC). Efficacy and safety data are for all evaluable patients as of a November 26, 2024 data cut-off date, and all efficacy data are determined by a blinded, independent central review (BICR) of each patient’s tumor scan. “We are highly encouraged by the robust efficacy signal and favorable safety profile observed with onvansertib plus standard-of-care from the first 30 evaluable patients in our randomized first-line RAS-mutated mCRC CRDF-004 trial,” said Fairooz Kabbinavar, MD, FACP, Chief Medical Officer of Cardiff Oncology. “Our data shows an objective response rate of 64% in patients receiving the 30 mg dose of onvansertib in combination with standard of care, significantly higher than the 33% objective response rate observed in the control arms of standard of care alone. In addition, as can be seen in the spider plots, we are observing deeper tumor response in patients receiving the 30mg dose of onvansertib compared to those receiving the 20mg dose with similar safety profiles for both doses.” Study Design The CRDF-004 phase 2 trial is currently enrolling patients with mCRC who have a documented KRAS or NRAS mutation. Onvansertib is added to SoC consisting of FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab. Patients are being randomized in a 1:1:1 ratio to either 20mg of onvansertib plus SoC, 30mg of onvansertib plus SoC, or SoC alone. The primary endpoint is objective response rate (ORR), and the secondary endpoints include progression-free survival (PFS), duration of response (DOR) and safety. Efficacy Data Objective Response Rates observed in the CRDF-004 clinical trial, as of the data cut-off date of November 26, 2024, are shown below. Control Arm(SoC alone)20mg dose of onvansertib + SoC30mg dose of onvansertib + SoCAll onvansertib patients33% ORR(3 of 9)50% ORR(5 of 10)64% ORR(7 of 11)57% ORR(12 of 21) Spider Plots, displaying the change in tumor size from baseline for each patient over time, demonstrate deeper responses observed in patients receiving the 30mg dose of onvansertib in combination with the SoC compared to both the control arms and 20mg dose of onvansertib arms. Note: Radiographic response determined per RECIST 1.1 by blinded independent central review. Spider plot reflects interim data as of November 26, 2024 from an ongoing trial and unlocked database. Safety and Tolerability Onvansertib in combination with chemo/bevacizumab was well-tolerated and there have been no major or unexpected toxicities observed. “Overall, these data support our belief that onvansertib has potential to change the treatment paradigm for the entire first-line RAS-mutated mCRC patient population of almost 50,000 new patients diagnosed in the U.S. annually,” said Mark Erlander, Chief Executive Officer of Cardiff Oncology. “In addition to the efficacy signal observed, the data demonstrate that onvansertib can safely be combined with the two different chemo backbones that are currently approved as standard of care in the first-line setting, thus providing a key differentiated profile over previous generation PLK1 inhibitors. We look forward to providing additional clinical updates from our CRDF-004 trial in the first half of 2025.” Upcoming expected milestones Additional clinical data from CRDF-004 trial expected in 1H 2025 Conference Call and Webcast Cardiff Oncology will host a conference call and live webcast at 8:00 a.m. ET / 5:00 a.m. PT on December 10, 2024. Individuals interested in listening to the live conference call may do so by using the webcast link in the "Events" section of the company's website. A webcast replay will be available in the investor relations section on the company's website following the completion of the call. About Cardiff Oncology, Inc. Cardiff Oncology is a clinical-stage biotechnology company leveraging PLK1 inhibition, a well-validated oncology drug target, to develop novel therapies across a range of cancers. The Company's lead asset is onvansertib, a PLK1 inhibitor being evaluated in combination with standard of care (SoC) therapeutics in clinical programs targeting indications such as RAS-mutated metastatic colorectal cancer (mCRC), as well as in ongoing and planned investigator-initiated trials in metastatic pancreatic ductal adenocarcinoma (mPDAC), small cell lung cancer (SCLC) and triple negative breast cancer (TNBC). These programs and the Company's broader development strategy are designed to target tumor vulnerabilities in order to overcome treatment resistance and deliver superior clinical benefit compared to SoC alone. For more information, please visit https://www.cardiffoncology.com. Forward-Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified using words such as "anticipate," "believe," "forecast," "estimated" and "intend" or other similar terms or expressions that concern Cardiff Oncology's expectations, strategy, plans or intentions. These forward-looking statements, including statements regarding Cardiff Oncology’s plans to provide additional clinical updates from our CRDF-004 trial in the first half of 2025, are based on Cardiff Oncology's current expectations and actual results could differ materially. There are several factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, clinical trials involve a lengthy and expensive process with an uncertain outcome, and results of earlier studies and trials may not be predictive of future trial results; our clinical trials may be suspended or discontinued due to unexpected side effects or other safety risks that could preclude approval of our product candidate; results of preclinical studies or clinical trials for our product candidate could be unfavorable or delayed; our need for additional financing; risks related to business interruptions, including the outbreak of an epidemic or pandemic such as the COVID-19 coronavirus and cyber-attacks on our information technology infrastructure, which could seriously harm our financial condition and increase our costs and expenses; uncertainties of government or third party payer reimbursement; dependence on key personnel; limited experience in marketing and sales; substantial competition; uncertainties of patent protection and litigation; dependence upon third parties; and risks related to failure to obtain FDA clearances or approvals and noncompliance with FDA regulations. There are no guarantees that our product candidate will be utilized or prove to be commercially successful. Additionally, there are no guarantees that future clinical trials will be completed or successful or that our product candidate will receive regulatory approval for any indication or prove to be commercially successful. Investors should read the risk factors set forth in Cardiff Oncology's Form 10-K for the year ended December 31, 2023, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Cardiff Oncology does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances. Cardiff Oncology Contact: James Levine Chief Financial Officer 858-952-7670jlevine@cardiffoncology.com Investor Contact: Kiki Patel, PharmD Gilmartin Group 332-895-3225Kiki@gilmartinir.com Media Contact: Grace Spencer Taft Communications 609-583-1151 grace@taftcommunications.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/22880436-fc66-4f63-8937-5e69de0ce613

临床结果临床2期ASCO会议临床1期

2024-12-02

·access wire

Alligator Sharpens Focus on Mitazalimab and Announces Cost Reduction Program to Maximize Long-Term Value Creation

Sharpening focus on preparing mitazalimab for Phase 3 and continuing partnering discussionsPlanned reduction of workforce, mainly within Discovery and Non-Clinical unitExpected annual cash savings of at least SEK 65 millionWill continue to conduct limited research activities, primarily related to mitazalimabLUND, SE / ACCESSWIRE / December 02, 2024 / Alligator Bioscience AB ("Alligator" or the "Company") announced today that it is sharpening its primary focus on its lead asset mitazalimab, and, given current capital restraints, plans to adjust the size of its organization and scope of operations to reflect that. All other assets under development are under strategic evaluation.Given the unprecedented survival benefits observed in first line metastatic pancreatic cancer, including a near doubling of the overall survival rate at 18 months compared to FOLFORINOX alone, Alligator believes that mitazalimab should advance into Phase 3 for metastatic pancreatic cancer as soon as possible.The planned restructuring remains subject to negotiation with the relevant trade unions and may result in a reduction of approximately 70% of the current workforce, mainly affecting the discovery and non-clinical operations. Once implemented, the restructuring is expected to reduce operational costs by at least SEK 65 million annually. Going forward Alligator will focus on late-stage development with an adequate workforce of approximately 15 FTEs. Furthermore, Alligator will continue to be able to conduct limited research activities, primarily related to mitazalimab, through internal and external resources.Alligator has separately announced the plans for a Rights issue to be completed in Q1 2025. If the Rights issue is fully subscribed, Alligator will have secured financing up until the end of 2025.Alligator is continuing to prepare mitazalimab for Phase 3 development, in parallel with ongoing partnership discussions. It expects to report 24 months follow-up data from the mitazalimab OPTIMIZE-1 Phase 2 trial in Q1 2025. The 24-month timepoint is longer than many other treatments in metastatic pancreatic cancer have shown, as most trials have been stopped earlier as the clinical efficacy was no longer evident and patients had relapsed or died."Being able to report the OPTIMIZE-1 24-month timepoint sets mitazalimab apart and is a clear testimony to its clinical benefit. Because Alligator at that timepoint expects to continue to deliver additional outstanding Phase 2 clinical data for mitazalimab in 1st line pancreatic cancer, we remain laser focused on mitazalimab development and it is our objective to deliver outstanding returns to our shareholders. The cost savings announced today will strengthen our ability to continue developing mitazalimab and enhance the chances to unlock its value by making it more attractive for partnership," said Søren Bregenholt, CEO of Alligator Bioscience. "In order to focus our current resources on mitazalimab, our most important asset,we have no other option than to reduce our earlier stage research and development activities and workforce. We thank our colleagues, who have strived professionally and with great dedication to innovate and deliver on Alligator'smission to develop drugs for patients with hard-to-treat cancers since the Company's inception. We will make the utmost efforts to support the highly talented people affected by this initiative. I am confident they will prove to be important contributors to other innovative organizations."Alligator will notify the Swedish Public Employment Service (Sw. Arbetsförmedlingen) and seek consultations with trade unions regarding the reorganization. Decisions regarding specific employee reductions will take place after the change consultations have been concluded according to local regulations.For further information, please contact:Søren Bregenholt, CEOE-mail: [email protected] Phone: +46 (0) 46 540 82 00Johan Giléus, CFOE-mail: [email protected] Phone: +46 (0) 46 540 82 00This information is information that Alligator Bioscience is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact persons set out above, at 2024-12-02 08:35 CET.About Alligator BioscienceAlligator is a clinical-stage biotechnology company developing tumor-directed immuno-oncology antibody drugs focused on the CD40 receptor. This validated approach promotes priming of tumor-specific T cells and reversing the immunosuppressive nature of the tumor microenvironment, with significant potential benefits for cancer patients across multiple types of cancer. Its portfolio includes lead drug candidate mitazalimab, for which the company reported unprecedented survival data at 18-months follow up in first-line metastatic pancreatic cancer patients in Phase 2 testing and is in preparation for Phase 3 development. The follow-on bispecific antibody ATOR-4066 is in preclinical testing. Alligator has a proprietary technology platform, comprised of two antibody libraries, ALLIGATOR-GOLD® and ALLIGATOR-FAB™, the powerful protein optimization strategy FIND® and the bispecific antibody format RUBY™, which drives rapid design and development of innovative drugs.Alligator is listed on Nasdaq Stockholm (ATORX) and headquartered in Lund, Sweden.For more information, please visit alligatorbioscience.com .AttachmentsAlligator sharpens focus on mitazalimab and announces cost reduction program to maximize long-term value creationSOURCE: Alligator Bioscience

临床2期临床3期

2024-11-29

·肿瘤界

盘点2024丨刘宝瑞教授：2024年度肿瘤治疗性疫苗临床研究进展

点击蓝字关注我们余玥霖，刘宝瑞（南京大学医学院附属鼓楼医院肿瘤中心，江苏南京 210008）通信作者：刘宝瑞 E-mail ：baoruiliu@nju.edu.cn 通讯作者刘宝瑞教授主任医师，教授，博导南京大学临床肿瘤研究所所长南京大学医学院鼓楼医院肿瘤中心主任/免疫治疗中心主任《中国肿瘤生物治疗杂志》副主编《肿瘤综合治疗电子杂志》副主编中国临床肿瘤学会胃癌专委会副主任委员江苏省抗癌协会整合肿瘤学专委会主任委员江苏省医师协会肿瘤化疗与生物治疗医师分会主任委员中国医师奖获得者江苏省突贡专家南京大学首届十佳研究生导师临床重点：难治性肿瘤个体化免疫整合治疗科研方向：恶性肿瘤个体化与靶向免疫治疗新技术主持课题：国家自然科学基金重点项目、国际合作重大项目等国家省市课题30余项【摘要】近年来，随着肿瘤免疫治疗的蓬勃发展，肿瘤疫苗已经由动物实验研究阶段进入临床转化阶段。伴随2024年各大国际肿瘤年会的召开，肿瘤疫苗的众多试验成果也进入了公众视野，引起了人们的广泛关注。肿瘤疫苗又可分为预防性疫苗和治疗性疫苗。本文重点关注肿瘤治疗性疫苗中的信使RNA疫苗、树突状细胞疫苗、合成肽疫苗和病毒载体疫苗，论述2024年度国内外肿瘤治疗性疫苗相关的临床试验，旨在为肿瘤治疗性疫苗未来的发展方向提供思路启迪新思维，开辟新路径。【关键词】肿瘤治疗性疫苗；肿瘤预防性疫苗；免疫治疗；临床试验近年来，随着各种组学和生物信息学技术的不断进步，肿瘤疫苗的研发和临床转化已成为最令人瞩目的研究方向。肿瘤疫苗主要分为预防性疫苗和治疗性疫苗。流行病学调查显示，人群罹患传染病或接种疫苗可降低肿瘤发生的风险，接种疫苗可以作为肿瘤高风险人群的预防措施，如乙型病毒性肝炎疫苗已证实对原发性肝癌具有预防作用，人乳头瘤病毒（human papillomavirus，HPV）疫苗能预防宫颈癌，均已上市并得到广泛应用[1]。肿瘤治疗性疫苗的原理是将肿瘤抗原以多种形式，如肿瘤细胞、多肽、表达肿瘤抗原的基因等，注射入患者体内，增强免疫原性，激活人体自身特异性免疫反应，从而达到控制或清除肿瘤的目的[2]。随着2024年美国癌症研究协会（American Association for Cancer Research，AACR）年会、美国临床肿瘤学会（American Society of Clinical Oncology，ASCO）年会、欧洲肿瘤内科学会年会等重要国际肿瘤会议的召开，更多肿瘤治疗性疫苗的研究成果于大会上公布。本文旨在论述2024年度国内外肿瘤治疗性疫苗相关的临床试验，以期为相关领域的研究奠定理论基础。 1 2024年度肿瘤治疗性疫苗相关临床试验 2024年肿瘤治疗性疫苗相关的临床试验正在有条不紊地开展（表1）。通过国际著名的临床试验注册中心（https://clinicaltrials.gov/）检索肿瘤疫苗与肿瘤相关临床试验发现，截至2024年11月，于2024年立项及开展的临床试验立项总数已达114项，其中55项正在招募，59项未招募及状态未知（检索条件为“vaccine”and“cancer”and“Study start on or after 01/01/2024”）。表1 2024年度肿瘤治疗性疫苗相关的临床试验注：NCT编号为试验登记号；mRNA为信使RNA；DC为树突状细胞；GM-CSF为粒细胞-巨噬细胞集落刺激因子。 2 信使RNA（message RNA，mRNA）肿瘤疫苗 mRNA肿瘤疫苗是通过体外转录，获得编码肿瘤特异性抗原或肿瘤相关抗原的mRNA序列，制备成疫苗后注射入人体，翻译产生抗原蛋白，从而诱导机体产生特异性免疫应答[3]。与传统疫苗相比，mRNA肿瘤疫苗的优势主要在于其耐受性良好、成本较低、生产较快且能编码全长肿瘤抗原，具有良好的临床应用前景[4]。美国BioNTech公司开发的autogene cevumeran是基于BioNTech的个体化新抗原特异性免疫疗法癌症疫苗技术平台生成的个体化新抗原疫苗。该疫苗的抗原是autogene cevumeran，其含有高达20种主要组织相容性复合体（major histocompatibility complex，MHC）Ⅰ类和MHCⅡ类分子限制的新抗原，佐剂为脂质纳米颗粒（lipid nanoparticle，LNP）。2023年6月，BioNTech在Nature上发布了autogene cevumeran个体化治疗胰腺癌Ⅱ期临床试验（NCT05968326）结果[5]。2024年AACR年会上，BioNTech公布了autogene cevumeran治疗胰腺导管腺癌的Ⅰ期临床试验（NCT04161755）的进一步进展。按照临床试验设计，受试者依次接受阿替利珠单抗、autogene cevumeran和mFOLFIRINOX化疗，此次公布的结果显示，在中位随访时间36个月时，获得新抗原特异性免疫反应患者的无复发生存（recurrence free survival，RFS）时间显著长于无疫苗激发免疫反应的患者；获得免疫反应组体内的T细胞免疫应答持续激活，中位RFS时间尚未达到（n＝8，P＝0.003），而未获得免疫反应组患者中位RFS时间为13.4个月（n＝8，P＝0.007）。 2024年3月，美国生物技术公司Gritstone bio公布了肿瘤疫苗GRANITE治疗转移性微卫星稳定型结直肠癌（microsatellite stability colorectal cancer，MSS CRC）患者Ⅱ/Ⅲ期临床试验（NCT05141721）的研究数据。GRANITE是一款个体化新抗原mRNA癌症疫苗，其新抗原是根据每例患者活检得到的肿瘤组织，进行肿瘤组织测序筛选出。GRANITE利用自扩增mRNA载体递送表达新抗原的mRNA，引发显著的CD8+细胞毒性T淋巴细胞反应，从而产生抗肿瘤效应。该疫苗目前已获得美国食品药品监督管理局（Food and Drug Administration，FDA）的快速通道资格，用于治疗MSS CRC患者。截至2024年3月8日，67例可评估疗效的转移性MSS CRC患者被随机分为GRANITE组（n＝39例，接受化疗方案FOLFOX或FOLFOXIRI＋贝伐珠单抗诱导治疗）和对照组（n＝28，接受化疗方案FOLFOX或FOLFOXIRI＋贝伐珠单抗诱导治疗）。研究结果显示，与对照组患者相比，GRANITE组的疾病进展和死亡风险降低了18%，高危患者的疾病进展和死亡风险降低了48%。GRANITE组患者的中位无进展生存时间为11.57个月，对照组仅为7.06个月。该研究结果提示，GRANITE在转移性MSS CRC患者的治疗中展现出了积极的疗效[6]。 mRNA-4157/V940是美国Moderna公司开发的一款个体化mRNA肿瘤疫苗，其抗原为包含编码最多34种新抗原的单一合成mRNA分子，佐剂为LNP[7]。其Ⅱb期临床试验（NCT03897881）3年随访数据首次在2024年ASCO年会上公布[8]。数据显示，中位随访时间约34.9个月，与单独使用帕博利珠单抗相比，mRNA-4157与帕博利珠单抗联用可使黑色素瘤患者复发和死亡风险降低49%，远处转移的风险降低了62%，且与单独使用帕博利珠单抗相比，mRNA-4157联合帕博利珠单抗的总生存（overall survival，OS）时间的探索性终点更有利，2.5年OS率分别为96.0%和90.2%，其RFS时间显著延长，RFS率提高了19.2%。Moderna公司目前启动了另一项Ⅲ期临床试验（NCT05933577），主要评估mRNA-4157联合帕博利珠单抗治疗肿瘤完全切除后、复发风险较高的ⅡB～Ⅳ期黑色素瘤患者的联合疗效。截至2024年4月，已在伦敦大学学院医院招募了首批患者[9]。虽然截至目前尚未有临床上市的mRNA肿瘤疫苗，早期临床试验的结果也仅显示出适度的临床疗效[10]。但随着mRNA疫苗在肿瘤治疗领域展现出的广阔前景，mRNA疫苗作为未来癌症治疗关键策略的潜力巨大。数据显示，mRNA肿瘤疫苗mRNA-4157在临床试验中疗效显著且耐受性良好，预计最早可能于2025年上市，这将会是全球首款mRNA肿瘤疫苗[11]。目前国内mRNA肿瘤疫苗也已有多个产品处于临床及临床前研究阶段，如成都威斯津生物医药科技有限公司自主研发的WGc-043，可用于治疗EB病毒阳性的肿瘤，目前已通过美国FDA临床试验审批。我国自主研发的mRNA肿瘤疫苗JCXH-211也在实体瘤中开展了Ⅰ期临床试验（NCT05727839）。 3 病毒载体肿瘤疫苗病毒载体疫苗是利用改造后具有复制缺陷或减毒的病毒作为载体，将编码肿瘤抗原的遗传信息传递给宿主细胞，促使其表达这些抗原，从而激活特异性抗肿瘤免疫反应[12]。由于病毒载体肿瘤疫苗发展相对成熟，安全性良好，传递肿瘤抗原高效，无需佐剂就能诱导强烈的特异性免疫反应，因而受到临床广泛关注[13]。 2024年4月，世界疫苗大会上公布了新型癌症疫苗VBI-1901的Ⅰ/Ⅱ期临床试验（NCT03382977）研究结果。VBI-1901是一款由美国生物制药公司VBI研发的新型癌症疫苗，其采用VBI的包膜病毒样颗粒技术进行设计，旨在通过靶向gB和pp65这2种高免疫原性的巨细胞病毒抗原，激发免疫系统的反应。该临床试验是一项多中心、随机、对照、开放标签的研究，旨在评估VBI-1901作为单药治疗复发性胶质母细胞瘤患者的疗效，包括OS率、客观缓解率以及安全性和耐受性。结果显示，接受VBI-1901治疗的5例可评估患者的疾病控制率为40%，与接受卡莫司汀或洛莫司汀标准治疗的6例可评估患者相比，平均OS时间提高了约5个月。VBI-1901在治疗复发性胶质母细胞瘤中展现出了令人鼓舞的疗效，有效控制了患者的疾病进展。目前该试验的后续研究正在持续招募患者，研究人员的目标是每组招募30人，截至2024年4月，共有14个研究中心正在积极招募患者，预期于2024年12月公布更多的中期数据[14]。肿瘤疫苗TG4050是利用非致病型痘病毒提供的30种个性化的新抗原，激活和扩增T细胞的疫苗[15]。2024年AACR年会上公布了一项Ⅰ期临床试验（NCT04183166），目的是评估TG4050的安全性及有效性。该试验招募了口腔、口咽、下咽或喉部完全切除的Ⅲ期或Ⅳ期HPV阴性头颈鳞状细胞癌患者，将患者随机分为A组（n＝17，标准护理后立即接受TG4050治疗）和B组（n＝16，仅接受标准护理，若出现肿瘤复发，则加用TG4050治疗）。在中位随访18.6个月时，A组可评估患者（n＝16）仍处于缓解期，均未出现肿瘤复发。而B组患者中，有3例患者分别在6.2、8.8、18.5个月后出现肿瘤复发。初步试验结果表明，TG4050能激发HPV阴性头颈鳞状细胞癌患者的肿瘤特异性免疫反应，从而降低肿瘤复发率，具有抗肿瘤活性[16]。 4 新抗原树突状细胞（dendritic cell，DC）疫苗肿瘤细胞疫苗是由来源于患者自体或同种异体的肿瘤细胞作为免疫源，经照射、加热、冷冻等处理使其失活，并辅以佐剂以提高其免疫原性，注射入患者体内激活抗肿瘤免疫反应[17]。其中DC是目前认为机体中功能最强大的专职抗原递呈细胞（antigen presenting cells，APC）[18]，其能高效摄取、加工处理和递呈抗原，从而激活T细胞介导的抗肿瘤免疫反应[19]。迄今为止，DC肿瘤疫苗已在黑色素瘤、结直肠癌、非小细胞肺癌等多种实体肿瘤的临床研究中被证实了其安全性和临床疗效[20]。 2024的AACR年会上，美国Diakonos Oncology公司公布了其DC疫苗DOC1021用于治疗多形性胶质母细胞瘤（glioblastoma，GBM）患者的Ⅰ期临床试验的中期分析结果。DOC1021疫苗是由患者自身的免疫细胞及患者肿瘤样本中提取的RNA和蛋白质结合制成，可以个性化靶向患者完整的癌症抗原谱而无需进行任何基因修饰。中期分析结果显示，接受疫苗治疗患者的中位OS时间尚未达到，但有望大幅超过接受标准治疗患者的预期中位OS时间（12.7个月）。目前可评估GBM患者的1年OS率为88%，而接受标准化治疗的GBM患者的1年OS率仅为53%[21]。 5 多肽疫苗肿瘤多肽疫苗是基于肿瘤抗原表位氨基酸序列设计并化学合成的多肽生产的疫苗。多肽疫苗由专职APC摄取、加工、处理并进行提呈，结合T淋巴细胞抗原识别受体和共刺激分子的作用使特异性T淋巴细胞活化，从而激活强烈的抗肿瘤免疫反应[22]。多肽疫苗制备简单，生产成本低廉，化学性质稳定，具有显著优势，因而受到肿瘤生物治疗研究领域的高度重视。 Elicio Therapeutics开发的ELI-002是一种淋巴结靶向的肿瘤疫苗，包括两亲分子修饰的KRAS G12D和KRAS G12R长肽和两亲分子修饰的Toll样受体9，目前已进入Ⅰ期临床试验阶段（NCT04853017）[23]。临床前研究结果显示，注射经两亲分子修饰后的ELI-002与直接注射未经修饰的抗原肽相比，KRAS G12D免疫强度提高了400倍以上，KRAS G12R免疫强度提高了60倍以上[24]。2024年1月Nature Medicine上发表了该Ⅰ期临床试验最新研究成果，所有接受疫苗治疗的胰腺癌和结直肠癌的患者中，84%的患者出现了T淋巴细胞免疫应答，T淋巴细胞免疫反应水平高于中位数的患者中位RFS时间显著短于T淋巴细胞免疫反应水平低于中位数的患者（未达到∶4.01个月，P＜0.05），为Ⅱ期临床试验奠定了基础[25]。 2024年3月，Nature Communications上发表了一项随机多中心Ⅱ期临床试验（NCT 00118274）的长期研究结果。该研究中所有高危黑色素瘤患者均接受靶向CD8+淋巴T细胞的多肽疫苗（12MP），且随机接受了6MHP（6种黑色素瘤特异性肽抗原的混合物）或tet（破伤风类毒素肽）2种CD4+T淋巴细胞疫苗，并在研究中评估环磷酰胺（cyclophosphamide，Cy）预处理对疫苗疗效的影响。临床试验共纳入167例ⅡB～Ⅳ期黑色素瘤患者，中位年龄为55～60岁，其中82例患者接受12MP＋tet治疗，85例患者接受12MP＋6MHP治疗。所有患者的中位随访时间为8.6年，结果显示，2种疫苗方案的预计OS时间在早期相似，之后逐渐分离，事后分析表明，12MP＋6MHP的疫苗方案改善了长期OS时间。研究结果还表明，Cy预处理未产生显著效益，但多变量分析表明，Cy预处理与12MP＋6MHP的疫苗方案接种之间存在有利相互作用的可能性。表明在ⅡB～Ⅳ期黑色素瘤患者中，辅助12MP＋6MHP疫苗，可显著延长OS时间。对于部分复发可切除的患者可能会获得长期无病生存[26]。 6 总结与展望目前，肿瘤治疗性疫苗的临床试验数量正在迅速增加，尽管取得了实质性进展，但其仍然面临着许多挑战。随着高通量基因测序和大数据分析技术的应用，新抗原疫苗备受大众关注。与传统疫苗相比，新抗原疫苗特异性强，免疫耐受性良好，可提供长期免疫保护作用，是2024年度肿瘤治疗性疫苗中的研究热点[27]。然而其开发过程中，新抗原的筛选与鉴定周期长、“冷肿瘤”免疫原性低、激活的免疫反应疗效受限是新抗原疫苗抗癌之路上存在的重重阻碍。如何开发高效、快速、个性化的新抗原预测模型和鉴定技术，通过联合疗法增强肿瘤疫苗的免疫反应则是肿瘤疫苗获得进一步突破的关键所在。肿瘤疫苗距离真正的成功转化和临床推广仍尚远，相信未来肿瘤治疗性疫苗将有进一步突破，为癌症患者带来新的希望。参考文献 [1] THOMAS T L. Cancer prevention: HPV vaccination[J]. Semin Oncol Nurs, 2016, 32(3):273-280. [2] BLASS E, OTT P A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines[J]. Nat Rev Clin Oncol, 2021, 18(4):215-229. [3] BADEN L R, EL SAHLY H M, ESSINK B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine[J]. N Engl J Med, 2021, 384(5):403-416. [4] VISHWESHWARAIAH Y L, DOKHOLYAN N V. mRNA vaccines for cancer immunotherapy[J]. Front Immunol, 2022, 13:1029069. [5] ROJAS L A, SETHNA Z, SOARES K C, et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer[J]. Nature, 2023, 618(7963):144-150. [6] Medthority. Gritstone bio announces positive preliminary progression-free survival and long-term circulating tumor DNA (ctDNA) data from phase 2 portion of ongoing phase 2/3 study of its personalized cancer vaccine, GRANITE, in front-line metastatic microsatellite stable colorectal cancer (MSS-CRC)[EB/OL](2024-04-03)[2024-11-20]. https://www.medthority.com/news/2024/4/preliminary-progression-free-survival-and-long-term-circulating-tumor-dna-ctdna-data-from-phase-ii-portion-of-ongoing-phase-iiiii-study-of--granite-vaccine-in-front-line-metastatic-microsatellite-stable-colorectal-cancer--gritstone-bio/. [7] CARVALHO T. Personalized anti-cancer vaccine combining mRNA and immunotherapy tested in melanoma trial[J]. Nat Med, 2023, 29(10):2379-2380. [8] WEBER J S, CARLINO M S, KHATTAK A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study[J]. Lancet, 2024, 403(10427):632-644. [9] mRNA vaccine slows melanoma recurrence[J]. Cancer Discov, 2023, 13(6):1278. [10] LI Y, WANG M, PENG X, et al. mRNA vaccine in cancer therapy: current advance and future outlook[J]. Clin Transl Med, 2023, 13(8):e1384. [11] DOLGIN E. The tangled history of mRNA vaccines[J]. Nature, 2021, 597(7876):318-324. [12] WANG S, LIANG B, WANG W, et al. Viral vectored vaccines: design, development, preventive and therapeutic applications in human diseases[J]. Signal Transduct Target Ther, 2023, 8:149 [13] WARDEN C, TANG Q, ZHU H. Corrigendum to "herpesvirus BACs: past, present, and future"[J]. Biomed Res Int, 2019, 2019:6870815. [14] VBI. VBI Vaccines presents encouraging early tumor response data from randomized controlled phase 2b study of VBI-1901 in recurrent glioblastoma[EB/OL]. (2024-04-03)[2024-11-20]. https://www.vbivaccines.com/press-releases/vbi-vaccines-presents-encouraging-early-tumor-response-data-from-randomized-controlled-phase-2b-study-of-vbi-1901-in-recurrent-glioblastoma/. [15] LALANNE A, JAMET C, DELORD J P, et al. Personalized vaccine TG4050 induces Polyepitopic immune responses against private neoantigens in resected HPV-negative head and neck cancers[C]. San Diego: The 2024 AACR Annual Meeting, 2024. [16] The ASCO post. Investigational personalized vaccine provides clinical benefit for some patients with resected head and neck cancers[EB/OL]. (2024-04-10)[2024-11-20]. https://ascopost.com/news/april-2024/investigational-personalized-vaccine-in-resected-head-and-neck-cancers/. [17] LIN M J, SVENSSON-ARVELUND J, LUBITZ G S, et al. Cancer vaccines: the next immunotherapy frontier[J]. Nat Cancer, 2022, 3(8):911-926. [18] MARCISCANO A E, ANANDASABAPATHY N. The role of dendritic cells in cancer and anti-tumor immunity[J]. Semin Immunol, 2021, 52:101481. [19] WCULEK S K, CUETO F J, MUJAL A M, et al. Dendritic cells in cancer immunology and immunotherapy[J]. Nat Rev Immunol, 2020, 20(1):7-24. [20] DING Z, LI Q, ZHANG R, et al. Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer[J]. Signal Transduct Target Ther, 2021, 6(1):26. [21] GEORGES J F, ZAHER M, MOSSOP C, et al. Vaccine immunotherapy by homologous antigenic loading as adjuvant therapy for glioblastoma: ongoing phase Ⅰ analysis[C]. San Diego: The 2024 AACR Annual Meeting. [22] ROSALIA R A, QUAKKELAAR E D, REDEKER A, et al. Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T-cell activation[J]. Eur J Immunol, 2013, 43(10):2554-2565. [23] MA L, HOSTETLER A, MORGAN D M, et al. Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity[J]. Cell, 2023, 186(15):3148-3165.e20. [24] SEENAPPA L M, JAKUBOWSKI A, STEINBUCK M P, et al. Amphiphile-CpG vaccination induces potent lymph node activation and COVID-19 immunity in mice and non-human primates[J]. NPJ Vaccines, 2022, 7(1):128. [25] PANT S, WAINBERG Z A, WEEKES C D, et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial[J]. Nat Med, 2024, 30(2):531-542. [26] NINMER E K, ZHU H, CHIANESE-BULLOCK K A, et al. Multipeptide vaccines for melanoma in the adjuvant setting: long-term survival outcomes and post-hoc analysis of a randomized phase Ⅱ trial[J]. Nat Commun, 2024, 15(1):2570. [27] GRIMMETT E, AL-SHARE B, ALKASSAB M B, et al. Cancer vaccines: past, present and future: a review article[J]. Discov Oncol, 2022, 13(1):31. 推荐阅读 ● 2023年度肿瘤学科盘点集锦(共17个) 声明：本文由“肿瘤界”整理与汇编，欢迎分享转载，如需使用本文内容，请务必注明出处。排版：lagertha 校对：松月

疫苗AACR会议免疫疗法信使RNA临床研究

100 项与亚叶酸相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D07986	亚叶酸	L01XX	DB00650

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结直肠癌	-	-	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03259035 (CCTG CO.28 \| NEO \| CO.28, CTgov)	临床2期	直肠癌	58	folinic acid+oxaliplatin+capecitabine+fluorouracil	鏇獵範憲淵繭衊鏇積膚(蓋廠衊憲糧淵醖齋選願) = 齋願夢夢遞淵糧艱膚鹽衊膚艱糧構窪餘鬱壓鹹 (蓋壓齋憲糧糧鏇鹽艱憲, 網鹽鬱鹹選鹽構範醖壓 ~ 簾壓獵餘積鹽襯憲衊醖) 更多	-	2024-10-10
JPRN-UMIN000048143 (JON 2109-P, ESMO2024) 人工标引	临床3期	胰腺癌二线	446	S-1 monotherapy	餘願願醖餘簾製餘夢蓋(鬱鹹廠鏇繭積鏇顧艱艱) = 膚製鹹餘鹹鏇觸獵鹹鹹艱膚網遞簾襯淵鏇繭襯 (築窪膚築遞餘淵廠壓糧 ) 更多	积极	2024-09-16
				Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin regimen	餘願願醖餘簾製餘夢蓋(鬱鹹廠鏇繭積鏇顧艱艱) = 鏇顧顧構製鑰糧觸網鹹艱膚網遞簾襯淵鏇繭襯 (築窪膚築遞餘淵廠壓糧 ) 更多
NCT01905150 (CTgov)	临床2期	晚期胰腺腺癌	34	VitaminC+G-FLIP-DM (G-FLIP Alone for 4 Weeks, Then G-FLIP+VitaminC. When DP Occurred, Then G-FLIP-DM+VitaminC)	積鬱網範顧齋製鬱範夢(醖醖壓繭觸觸襯構襯膚) = 簾網醖網積獵鏇糧壓製壓選鑰膚夢窪淵遞餘艱 (淵醖範鹽願簾蓋淵網壓, 淵艱醖齋鬱積憲築鏇蓋 ~ 遞範鹽築壓糧鹽壓鏇糧) 更多	-	2024-08-14
				VitaminC+G-FLIP-DM+G-FLIP (G-FLIP+VitaminC. When DP Occurred, Then G-FLIP-DM+Vitamin C.)	積鬱網範顧齋製鬱範夢(醖醖壓繭觸觸襯構襯膚) = 繭襯淵艱壓製積鹹製積壓選鑰膚夢窪淵遞餘艱 (淵醖範鹽願簾蓋淵網壓, 襯鹹構夢淵膚廠糧範簾 ~ 艱構廠淵遞夢窪膚夢醖) 更多
NCT02352337 (PRODIGE 35-PANOPTIMOX \| PANOPTIMOX, CTgov)	临床2期	胰腺继发性恶性肿瘤	276	Leucovorin Calcium+irinotecan+oxaliplatin+Irinotecan hydrochloride+FLUOROURACIL (FOLFIRINOX)	餘鏇積蓋鏇範糧網壓獵(糧膚顧繭淵憲壓壓蓋選) = 廠蓋築積鹽鏇願繭憲獵獵餘獵鑰築築鬱憲夢網 (簾網鏇範鹽觸選鏇膚網, 夢範壓淵膚齋齋選簾齋 ~ 顧築簾積膚鏇網艱壓遞) 更多	-	2024-07-10
				LV+irinotecan+oxaliplatin+Irinotecan hydrochloride+FLUOROURACIL (FOLFIRINOX + LV5FU2 in Maintenance)	餘鏇積蓋鏇範糧網壓獵(糧膚顧繭淵憲壓壓蓋選) = 顧鬱窪夢憲簾範襯簾繭獵餘獵鑰築築鬱憲夢網 (簾網鏇範鹽觸選鏇膚網, 窪範製選夢構獵選廠鬱 ~ 繭糧築廠觸遞簾選餘醖) 更多
NCT02842580 (HIGH-LIGHT, CTgov)	临床2期	转移性结直肠癌	21	acide folinique+Bevacizumab+irinotecan+Oxaliplatin+capécitabine+5FU (Standard Arm (Escalation Strategy - Arm A))	簾鹹築壓廠簾構繭鑰餘(製淵鏇遞顧鏇鹽願鹹襯) = 壓壓鑰繭簾獵醖醖醖遞鑰窪繭餘顧簾積鹹夢壓 (膚憲遞製積顧鏇衊鹽構, 範製觸壓觸製壓襯構鏇 ~ 夢積餘壓鹹壓壓繭廠膚) 更多	-	2024-07-10
				acide folinique+Bevacizumab+irinotecan+Oxaliplatin+capécitabine+5FU (Experimental Arm (De-escalation Strategy -Arm B))	簾鹹築壓廠簾構繭鑰餘(製淵鏇遞顧鏇鹽願鹹襯) = 鹽襯憲衊壓醖壓顧蓋淵鑰窪繭餘顧簾積鹹夢壓 (膚憲遞製積顧鏇衊鹽構, 鬱顧鬱積鹹夢繭醖壓選 ~ 壓築夢鑰簾艱鑰顧網鏇) 更多
NAPOLEON-2 (ESMO_GI2024) 人工标引	N/A	胰腺癌二线	87	Nano-liposomal irinotecan, fluorouracil, and folinic acid (NFF)	憲淵鏇觸鑰憲鑰憲構選(窪襯廠鏇齋襯窪製繭觸) = 艱襯築餘餘網鹹鬱衊構製積顧膚夢積繭觸醖醖 (範窪壓鑰艱廠淵餘獵築, 6.4 ~ 9.4) 更多	积极	2024-06-27
NCT01515787 (PROSPECT, CTgov)	临床2/3期	局部晚期直肠癌	1,194	surgery+leucovorin+Oxaliplatin+5-fluorouracil+capecitabine (Group 1)	選膚艱窪繭鬱遞窪淵夢(餘簾齋願淵範艱繭壓壓) = 衊夢築廠鏇鏇築醖獵廠範獵繭壓壓簾衊構鹽遞 (鏇膚窪艱憲網糧鹹繭構, 鬱簾憲範廠鏇膚壓顧築 ~ 觸網憲糧淵顧築構鬱鏇) 更多	-	2024-02-02
				surgery+leucovorin+Oxaliplatin+5-fluorouracil+capecitabine (Group 2)	選膚艱窪繭鬱遞窪淵夢(餘簾齋願淵範艱繭壓壓) = 糧網範艱衊網蓋築鹽淵範獵繭壓壓簾衊構鹽遞 (鏇膚窪艱憲網糧鹹繭構, 獵淵簾壓製願遞蓋鹽願 ~ 糧觸觸襯醖淵壓餘獵繭) 更多
ESMO2023 人工标引	N/A	胰腺继发性恶性肿瘤	129	pegylated liposomal irinotecan + 5-fluorouracil + leucovorin	鹽獵蓋選顧衊壓網鏇壓(積網蓋糧繭艱獵觸積構) = 窪鏇選窪餘憲衊餘蓋鑰餘醖網壓鏇艱製艱衊醖 (鏇遞顧壓蓋獵築醖廠選, 47.4 ~ 68.7) 更多	积极	2023-10-23
NCT03781323 (CTgov)	临床2期	局部晚期直肠癌	12	folinic acid+oxaliplatin+fluorouracil	構網簾艱選鏇夢膚夢憲(顧範網遞淵衊壓鹽積鏇) = 繭廠鹽築選鏇醖製獵淵願醖選網積製顧鬱衊壓 (獵廠選築膚鹽襯網顧廠, 膚鏇夢鹹顧壓選膚艱製 ~ 鑰餘餘衊積構範繭鹹襯) 更多	-	2023-09-11
NCT01718873 (OBELICS, CTgov)	临床3期	转移性结直肠癌	230	levo-folinic acid+Bevacizumab+Oxaliplatin+5-fluorouracil+Capecitabine (Bevacizumab Before Chemotherapy)	夢壓壓衊簾廠遞鹽壓窪(顧夢醖遞鬱築製艱觸夢) = 觸壓選積鬱淵餘築蓋築選遞醖衊簾窪鹹構鬱簾 (繭蓋選餘鏇餘襯鏇遞艱, 積顧選願選鏇範艱構憲 ~ 選壓鏇蓋願艱鹽艱構膚) 更多	-	2023-04-12
				levo-folinic acid+Bevacizumab+Oxaliplatin+5-fluorouracil+Capecitabine (Bevacizumab With Chemotherapy)	夢壓壓衊簾廠遞鹽壓窪(顧夢醖遞鬱築製艱觸夢) = 鑰憲顧淵窪憲鬱齋憲願選遞醖衊簾窪鹹構鬱簾 (繭蓋選餘鏇餘襯鏇遞艱, 簾壓鏇構觸製選願糧鑰 ~ 醖顧蓋壓淵鬱夢糧憲範) 更多