A phase-1 trial of intraperitoneal 5-fluorouracil and oxaliplatin in patients with colorectal cancer and unresectable peritoneal metastasis.

腹腔注射 5-氟尿嘧啶和奥沙利铂治疗结直肠癌和不可切除的腹膜转移患者的 1 期试验。

基本信息

  • 批准号:
    10722263
  • 负责人:
  • 金额:
    $ 33.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-12 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

SUMMARY Patients with colorectal cancer (CRC) and peritoneal metastases (PM) have significantly worse outcomes than metastases to other sites like the lungs or liver. In patients with a limited volume of disease based on an intraoperatively calculated peritoneal carcinomatosis index (PCI) of less than 20, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) may provide a survival benefit. Unfortunately, only a minority of patients are candidates for CRS+HIPEC, and even in patients that undergo CRS + HIPEC, there is almost universal cancer recurrence. There is a critical need for novel therapeutic strategies, including regional delivery of anti-tumor agents in patients with CRC PM. Although 5-fluorouracil (5FU) and oxaliplatin forms the foundation of intravenous (IV) systemic therapy for patients with metastatic CRC, poor penetration and efficacy of IV chemotherapy in the peritoneum leads to much poorer outcomes. In animal models, chemotherapies such as 5FU have higher intra-tumoral concentrations and longer half-lives when administered directly to the peritoneal cavity compared to IV administration, making intraperitoneal (IP) chemotherapy an attractive treatment modality. While small pilot studies of IP 5FU from the 1980s and 90s showed promising efficacy, no systematic trials have been conducted to assess the feasibility of IP chemotherapy in patients with CRC and unresectable PM, and none using the modern chemotherapy combination of 5-FU + oxaliplatin. Furthermore, there have been no studies on the effects of IP 5FU+oxaliplatin on stimulating an anti-tumor immune response. To address these knowledge gaps, we have designed a phase-1 dose-escalation trial of 5FU and oxaliplatin administered IP in patients with CRC and PM not eligible for CRS+HIPEC due to PCI > 20. This trial will use the Bayesian optimal interval design (BOIN) to determine the maximally tolerated dose (MTD), with 6 additional patients treated at the MTD for additional safety, response, and correlative analyses. Patients will undergo a diagnostic laparoscopy with tumor biopsy at baseline and again after 4 cycles of IP chemotherapy. PCI is calculated intraoperatively at each diagnostic laparoscopy. Imaging as per SOC will be performed every 2 cycles, and response assessed by RECIST 1.1. Markers for tumor response and immune phenotype will be analyzed by spectral flow cytometry on tumor and blood samples. Our central hypothesis is that IP 5FU+oxaliplatin will be safe, lead to direct cytotoxicity, and stimulate anti-tumor immune responses due to immunogenic cell death. Additionally, local administration of chemotherapy may avoid the systemic immunosuppressive effects of systemic chemotherapy. If successful, this research will form the foundation of larger efficacy trials to optimize IP chemotherapy alone or in combination with immune-modulating agents, and ultimately, offers the potential to improve outcomes for a population of patients with poor survival, limited treatment options, and significant morbidity using affordable and widely available chemotherapy agents.
摘要 结直肠癌(CRC)和腹膜转移(PM)患者的预后明显差于 转移到其他部位,如肺或肝脏。在疾病数量有限的患者中,基于 术中计算腹膜癌指数(PCI)<20,细胞减少术(CRS) 采用高温腹膜内化疗灌流(HIPEC)可提供生存益处。不幸的是,只有 少数患者是CRS+HIPEC的候选患者,即使在接受CRS+HIPEC的患者中,也有 几乎是癌症复发的普遍现象。迫切需要新的治疗策略,包括 结直肠癌PM患者抗肿瘤药物的区域性给药 尽管5-氟尿嘧啶(5FU)和奥沙利铂构成了静脉(IV)系统治疗的基础 转移性结直肠癌患者,腹膜穿透性差和静脉化疗疗效差导致 结果要糟糕得多。在动物模型中,像5FU这样的化疗药物具有更高的肿瘤内 与静脉给药相比,直接给药时的血药浓度和半衰期更长 给药,使腹膜腔内化疗成为一种有吸引力的治疗方式。虽然是小飞行员 20世纪80年代和90年代对IP 5FU的研究显示出良好的疗效,尚未进行系统试验 对结直肠癌和不能切除的PM患者进行IP化疗的可行性评估,而没有 采用5-FU+奥沙利铂的现代化疗方案。此外,目前还没有研究 Ip 5FU+奥沙利铂刺激抗肿瘤免疫反应的研究 为了解决这些知识差距,我们设计了一项5FU和奥沙利铂的1期剂量递增试验 对因PCI&GT;20不符合CRS+HIPEC标准的结直肠癌和PM患者进行IP治疗。本试验将使用 确定最大耐受剂量(MTD)的贝叶斯最优区间设计(Boin),另外6个 在MTD接受治疗的患者进行额外的安全性、反应性和相关性分析。患者将接受一项 诊断性腹腔镜术,肿瘤活检于基线,IP化疗4个周期后复查。PCIIS 在每次诊断性腹腔镜术中计算。按照SOC进行成像将每隔2个月执行一次 周期,以及由RECIST 1.1评估的反应。肿瘤反应和免疫表型的标志物将是 用流式细胞仪对肿瘤和血液标本进行光谱分析。我们的中心假设是IP 5FU+奥沙利铂将是安全的,导致直接的细胞毒性,并刺激抗肿瘤免疫反应 免疫原性细胞死亡。此外,局部给药可避免全身性 全身化疗的免疫抑制作用。如果成功,这项研究将为 更大的疗效试验,以优化IP化疗单独或与免疫调节剂联合使用,以及 最终,它有可能改善存活率较低、有限的患者群体的预后 使用负担得起且随处可得的化疗药物,可提供多种治疗方案和显著的发病率。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Alex C. Kim其他文献

Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent: Final Results from a Phase II Study.
使用 pH 敏感成像剂 Pegsitacinine 检测细胞减灭手术后残留的腹膜转移瘤:II 期研究的最终结果。
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Patrick L. Wagner;Edward A. Levine;Alex C. Kim;Perry Shen;N. Fleming;S. Westin;Laurel K Berry;G. Karakousis;J. Tanyi;Madeline T Olson;Brian Madajewski;Brian Ostrander;Kartik Krishnan;Charles M. Balch;David L. Bartlett
  • 通讯作者:
    David L. Bartlett
ASO Visual Abstract: Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent—Final Results from a Phase 2 Study
  • DOI:
    10.1245/s10434-024-15307-8
  • 发表时间:
    2024-05-09
  • 期刊:
  • 影响因子:
    3.500
  • 作者:
    Patrick Wagner;Edward A. Levine;Alex C. Kim;Perry Shen;Nicole D. Fleming;Shannon N. Westin;Laurel K. Berry;Giorgos C. Karakousis;Janos L. Tanyi;Madeline T. Olson;Brian Madajewski;Brian Ostrander;Kartik Krishnan;Charles M. Balch;David L. Bartlett
  • 通讯作者:
    David L. Bartlett
ASO Visual Abstract: Disparities in␣Care Access to␣Liver-Directed Therapy Among Medicare Beneficiaries with␣Colorectal Cancer Liver Metastasis
  • DOI:
    10.1245/s10434-022-12652-4
  • 发表时间:
    2022-10-11
  • 期刊:
  • 影响因子:
    3.500
  • 作者:
    Christopher T. Aquina;Zachary J. Brown;Joal D. Beane;Aslam Ejaz;Jordan M. Cloyd;Allan Tsung;Mohamed O. Adam;Timothy M. Pawlik;Alex C. Kim
  • 通讯作者:
    Alex C. Kim
Defining Colorectal Cancer Cells on a Single Cell Level Reveals LGR5+ Proliferative Stem Cell Expression in Peritoneal Metastasis
  • DOI:
    10.1245/s10434-024-15783-y
  • 发表时间:
    2024-07-16
  • 期刊:
  • 影响因子:
    3.500
  • 作者:
    Kevin Nee;Linzi Hosohama;Wilson Alobuia;Alex C. Kim;Maheswari Senthil;Oliver S. Eng
  • 通讯作者:
    Oliver S. Eng

Alex C. Kim的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.64万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了