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作为血管舒缩张力、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。 一项在难治性腺癌患者中进行的新型ETA选择性受体拮抗剂ABT-627的I期剂量递增试验评价了治疗后的安全性、药代动力学、肿瘤缓解、肿瘤标志物变化和疼痛评分变化。 ABT-627每天给药一次，持续28天，然后停药7天，如果有临床获益的证据，则继续给药。 在7个剂量水平（10 - 75 mg/天和37.5 mg/bid）下入组了29例患者（15例前列腺、8例结肠、2例乳腺、2例肾脏、1例胰腺、1例肺）。 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%）。 未观察到重度血液学、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升高，并呈双指数下降（半衰期约为22小时）。 在整个研究范围内，剂量标准化AUC呈线性。 所有剂量水平的免疫反应性ET血浆浓度均适度增加，表明肽从受体中置换。 治疗28天后，10/15例患者的PSA/CEA下降（66% -范围5% - 48%）。 到目前为止，在分析的（2/6）有症状的男性中，可见视觉模拟量表上疼痛下降> 2，麻醉剂使用减少。 尚未注意到可衡量的反应。 11名患者在最初的28天后继续治疗，疾病相关症状稳定或改善。 3例患者继续参加研究长达8个月以上。 ABT-627耐受性良好。 早期肿瘤标志物的变化和疼痛的改善是令人鼓舞的。 前列腺癌的II期试验正在进行中。