MULTIPLE DOSE STUDY OF SAFETY OF ABT 627

内皮素（ET）是一种旁分泌/自分泌因子，通过受体介导的途径调节血管舒缩张力、细胞增殖、激素产生和伤害感受。ETA受体负责细胞和病理生理效应。在这两种受体中，阻断ETA可能抑制肿瘤进展，并可能调节与转移相关的疼痛。一项新的ETA选择性受体拮抗剂ABT-627在难治性腺癌患者中的一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、肿瘤标志物的变化和疼痛评分的变化。ABT-627每天一次，持续28天，然后休息7天，如果有临床益处的证据，继续服用。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）被纳入7个剂量水平（10 - 75mg/天，37.5 mg/bid）。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%）。没有发现严重的血液、心血管、肝脏或肾脏毒性。在第1天和第28天进行药代动力学取样，发现血浆浓度迅速上升并呈双指数下降（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适度增加，提示肽从受体中移位。治疗28天后PSA/CEA的下降出现在10/15（66% -范围5% - 48%）。到目前为止，有2/6的有症状的男性在视觉模拟量表上疼痛下降了0.5分，麻醉药物的使用也减少了。没有注意到可测量的反应。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例患者继续研究长达8个月以上。ABT-627耐受性良好。早期肿瘤标志物的改变和疼痛的改善是令人鼓舞的。前列腺癌的二期试验正在进行中。

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.