CLINICAL STUDIES OF CHEMOTHERAPY PLUS RECEPTOR BLOCKADE

化疗加受体阻断的临床研究

• 批准号: 6237505
• 负责人: JOHN MENDELSOHN
• 金额: $ 8.19万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-05 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6237505
• 关键词: antineoplastics; antireceptor antibody; biopsy; breast neoplasms; clinical trials; combination cancer therapy; cooperative study; dosage; doxorubicin; drug administration rate /duration; drug adverse effect; drug screening /evaluation; epidermal growth factor; female; growth factor receptors; human subject; human therapy evaluation; hybrid antibody; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; paclitaxel; pharmacokinetics; receptor expression

This proposal, the Clinical Program of a Breast Cancer Treatment Group, requests funding through a Cooperative Agreement with the National Cancer Institute. We have produced monoclonal antibodies (MAbs), against the EGF receptor (EGFR), that block activation of receptor tyrosine kinase and inhibit the growth of tumors expressing the receptor. We consider these MAbs to be pharmacologic antagonists of receptor mediated signal transduction pathways, although they also may have the capacity to activate immune antitumor mechanisms. In a series of experiments in vivo we have observed that combined treatments with anti-EGFR MAbs plus either doxorubicin or paclitaxel have a major antitumor effect, resulting in the disappearance of well-established tumor xenografts that cannot be eradicated by any other known therapy. Human clinical trials with murine anti-EGFR MAbs, conducted by our group, have shown that the administration of single doses of the mMAbs is safe and that we can achieve plasma levels of the muMAbs sufficient to saturate receptors. Based on these pre-clinical and clinical data we plan to conduct a series of Phase I and II clinical trials with the human:murine chimeric version of MAb 225 (HC MAb 225). Our goal is to determine the safety, feasibility, and noncomparative efficacy of multiple doses of MAb and of chemotherapy plus MAb in the treatment of patients with metastatic breast cancers expressing high levels of EGFR. The description of efficacy will be based on experience with patients who have received no prior chemotherapy for their advanced disease. Simultaneously, we will obtain pharmacokinetic data and tissue biopsies to study potential mechanisms of action. Should these clinical trials demonstrate the safety, feasibility, and reasonable activity of these treatments, we plan to design prospective, randomized trials of chemotherapy with and without MAb, in order to determine the comparative efficacy of the combination. Such randomized comparisons cannot proceed in the absence of the research proposed in this application.

该提案是乳腺癌治疗组的临床计划， 通过与国家癌症的合作协议要求资助 研究所。 我们已经产生了单克隆抗体（mAb） EGF受体（EGFR），阻断受体酪氨酸激酶的激活 并抑制表达受体的肿瘤的生长。 我们考虑 这些mAb是受体介导的信号的药理拮抗剂 转导途径，尽管它们也可能有能力 激活免疫抗肿瘤机制。 在一系列体内实验中 我们已经观察到与抗EGFR mabs以及两者合并处理 阿霉素或紫杉醇具有主要的抗肿瘤作用，导致 不可能的肿瘤异种移植物的消失 被任何其他已知疗法消除。 鼠类临床试验 由我们小组进行的反EGFR mABS已表明 给予单剂量的MMAB是安全的，我们可以 达到足以使受体饱和的血浆水平。 基于这些临床前和临床数据，我们计划进行一系列 与人类的第一阶段和II临床试验：鼠嵌合版 MAB 225（HC MAB 225）。 我们的目标是确定安全性 多剂量mab和的可行性以及不合制的功效 化学疗法加上MAB，以治疗转移性乳房患者 表达高水平EGFR的癌症。 功效的描述将 基于没有先前的患者的经验 化学疗法治疗其晚期疾病。 同时，我们将获得 药代动力学数据和组织活检以研究潜在机制 行动。 这些临床试验是否证明了安全性，可行性和 这些处理的合理活动，我们计划设计潜在的， 有或没有mAb的化学疗法的随机试验，以便 确定组合的比较功效。 这样的随机 在没有提出的研究的情况下进行比较 此应用程序。