PHASE I TRIAL OF I. P. OVB3-PE IN OVARIAN CANCER PATIENTS

I.P. OVB3-PE 在卵巢癌患者中的 I 期试验

• 批准号: 3896349
• 负责人: J W SMITH
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3896349
• 关键词: antiantibody; antitumor antibody; biological response modifiers; exotoxins; human subject; human therapy evaluation; human tissue; immunoconjugates; immunomodulators; immunotoxicity; injection /infusion; monoclonal antibody; neoplasm /cancer immunotherapy; neurotoxins; ovary neoplasms; peritoneal cavity; tumor antigens

OVB3-PE is an immunoconjugate comprised of a IgG2b murine monoclonal antibody that recognizes an antigen on the surface of all human ovarian cancers and pseudomonas exotoxin joined by means of a thioether bond. Pseudomonas exotoxin is a bacterial toxin that kills cells by inhibiting protein synthesis. This immunotoxin was shown to kill human ovarian cancer cells in vitro. Studies of this immunotoxin in mice with the OVCAR 3 ascites tumor demonstrated that mice receiving the immunotoxin had a significantly prolonged survival. We conducted a Phase I study of the OVB3-PE immunotoxin given as multiple intraperitoneal infusions in patients with refractory ovarian carcinoma involving the peritoneal cavity in order to determine the toxicity of treatment, to determine serum and intraperitoneal levels of OVB3-PE, to determine the types of host anti-- immunotoxin antibodies that might develop, and to assess any antitumor activity of the immunotoxin. Seventeen patients were entered onto this nonrandomized, Phase I multi-dose escalation study. Patients were entered from several different cooperating institutions. The BRMP entered 3 patients - one at the 2 mcg/kg dose level and 2 at the 10 mcg/kg dose level. One of our 3 patients sustained grade 3 pain and neurological toxicity after treatment with 10 mcg/kg. Similar but not identical grade 3 neurological toxicity was also observed in another patient treated at the Medicine Branch, NCI and as a result, no further dose escalations occurred beyond 10 mcg/kg. Despite intensive investigation, the mechanism for the neurotoxicity in these patients has not been elucidated. The protocol- has been amended to treat 4 more groups of patients all at 5 mcg/k-g b-ut with the number of doses increasing from 3 to 8, all administered within 12 days. Patients will begin treatment on the revised schedule starting in July 1989.

OVB 3-PE是由IgG 2b鼠单克隆抗体组成的免疫缀合物， 一种识别所有人类卵巢表面抗原的抗体 癌症和假单胞菌外毒素通过硫醚键连接。 假单胞菌外毒素是一种细菌毒素，通过抑制 蛋白质合成。这种免疫毒素被证明可以杀死人类卵巢癌 体外细胞用OVCAR 3在小鼠中研究该免疫毒素 腹水肿瘤表明，接受免疫毒素的小鼠具有 显著延长生存期。我们进行了一项I期研究， OVB 3-PE免疫毒素在患者中多次腹腔内输注 难治性卵巢癌累及腹膜腔， 以确定治疗的毒性，以确定血清和 腹腔内OVB 3-PE水平，以确定宿主抗- 免疫毒素抗体可能发展，并评估任何抗肿瘤 免疫毒素的活性。17名患者参加了这次会议。 非随机、I期多次剂量递增研究。患者入选 来自不同的合作机构。BRMP输入3 患者-2 mcg/kg剂量水平1例，10 mcg/kg剂量水平2例 水平我们的3名患者中有一名持续3级疼痛和神经系统疾病 10 mcg/kg处理后的毒性。相似但不完全相同3级 在另一名接受治疗的患者中也观察到神经毒性， 医学分支，NCI，因此，未发生进一步剂量递增 超过10 mcg/kg。尽管深入调查， 这些患者的神经毒性尚未阐明。该协议-具有 修改为治疗另外4组患者，均为5 mcg/k-g b-ut， 给药次数从3次增加到8次，均在12次给药内 天患者将按照修订后的时间表开始治疗， 一九八九年七月。