MULTIPLE DOSE STUDY OF SAFETY OF ABT 627

ABT 627 安全性的多剂量研究

• 批准号: 6218279
• 负责人: Michael A Carducci
• 金额: $ 0.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6218279
• 关键词: adenocarcinoma; antineoplastics; clinical research; clinical trial phase I; colon neoplasms; dosage; drug administration rate /duration; drug adverse effect; drug screening /evaluation; human subject; lung neoplasms; neoplasm /cancer chemotherapy; neoplasm /cancer classification /staging; oral administration; pharmacokinetics; prostate neoplasms; renal cell carcinoma

Endothelins (ET) are paracrine/autocrine factors that act as modulators of vasomotor tone, cell proliferation, hormone production, and nociception through receptor-mediated pathways. The ETA receptor is responsible for the cellular and patho-physiologic effects. Of the two receptors, blockade of ETA may inhibit tumor progression and may modulate pain associated with metastasis. A Phase 1, dose escalation trial of a novel ETA -selective receptor-antagonist, ABT-627, in patients with refractory adenocarcinoma evaluated the safety, pharmacokinetics, tumor response, changes in tumor markers, and changes in pain scores after therapy. ABT-627 was given once a day for 28 days, followed by a 7-day break, with continuation if there was evidence of clinical benefit. Twenty-nine patients (15 prostate, 8 colon, 2 breast, 2 renal, 1 pancreas, 1 lung,) have been enrolled at 7 dose levels (10 - 75mg/day and 37.5 mg/bid). Toxicity has been minimal, with transient Grade 2 headache (35%), rhinitis (91%), mild anorexia (35%) and fatigue (35%) as the most common side effects. No severe hematologic, cardiovascular, hepatic, or renal toxicity has been noted. Pharmacokinetic sampling, on Days 1 and 28, found plasma concentrations increased rapidly and declined biexponentially (half-life of about 22 hours). Dose normalized AUC were linear throughout the range studied. Immunoreactive ET plasma concentrations increased modestly for all dose levels suggesting displacement of the peptide from the receptor. Declines in PSA/CEA after 28 days of treatment were noted in 10/15 (66% - Range 5% - 48%). Declines in pain by > 2 on the visual analog scale and decreases in narcotic use were seen in (2/6) symptomatic men analyzed so far. Measurable responses have not been noted. Eleven patients continued after the initial 28-day period with stable or improved disease-related symptoms. Three patients remained on study up to 8 + months. ABT-627 is well-tolerated. Early tumor marker changes and improvement in pain are encouraging. Phase II trials are underway in prostate cancer.

内皮素 (ET) 是旁分泌/自分泌因子，通过受体介导的途径充当血管舒缩张力、细胞增殖、激素产生和伤害感受的调节剂。 ETA 受体负责细胞和病理生理效应。 在这两种受体中，阻断 ETA 可能会抑制肿瘤进展，并可能调节与转移相关的疼痛。 一种新型 ETA 选择性受体拮抗剂 ABT-627 在难治性腺癌患者中进行的 1 期剂量递增试验评估了治疗后的安全性、药代动力学、肿瘤反应、肿瘤标志物的变化以及疼痛评分的变化。 ABT-627 每天给予一次，持续 28 天，然后休息 7 天，如果有临床获益的证据，则继续给予。 29 名患者（15 名前列腺患者、8 名结肠患者、2 名乳腺患者、2 名肾患者、1 名胰腺患者、1 名肺患者）已以 7 个剂量水平（10 - 75 mg/天和 37.5 mg/bid）入组。 毒性很小，最常见的副作用是短暂的 2 级头痛 (35%)、鼻炎 (91%)、轻度厌食 (35%) 和疲劳 (35%)。 尚未发现严重的血液、心血管、肝脏或肾脏毒性。 第 1 天和第 28 天的药代动力学采样发现血浆浓度迅速增加并呈双指数下降（半衰期约为 22 小时）。 剂量归一化 AUC 在整个研究范围内呈线性。 免疫反应性 ET 血浆浓度在所有剂量水平下均略有增加，表明肽从受体上被置换。 治疗 28 天后 10/15 观察到 PSA/CEA 下降（66% - 范围 5% - 48%）。 迄今为止，在分析的（2/6）有症状男性中，视觉模拟量表上的疼痛下降> 2，并且麻醉剂使用减少。 尚未注意到可衡量的反应。 11 名患者在最初 28 天的治疗后继续治疗，疾病相关症状稳定或改善。 三名患者继续研究长达 8 个多月。 ABT-627 具有良好的耐受性。 早期肿瘤标志物的变化和疼痛的改善令人鼓舞。 前列腺癌的 II 期试验正在进行中。