Arsenic Trioxide in Primary Curative APL Therapy

三氧化二砷在 APL 初级治疗中的应用

• 批准号: 6824591
• 负责人: STEVEN D GORE
• 金额: $ 55.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-12 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824591
• 关键词: acute myelogenous leukemia; anthracyclines; antineoplastics; arsenic; biomarker; blood tests; clinical research; clinical trial phase II; combination chemotherapy; drug adverse effect; etoposide; genetic transcription; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplasm /cancer relapse /recurrence; neoplasm /cancer remission /regression; neoplastic process; oncogenes; oxides; patient oriented research; polymerase chain reaction; protein quantitation /detection; technology /technique development

DESCRIPTION (provided by applicant): Despite the remarkable improvement in outcome for patients with acute promyelocytic leukemia (APL) since the incorporation of all trans-retinoic acid (ATRA), as many as 30% of patients are not cured with primary therapy. Secondary leukemias and myelodysplastic syndromes are increasingly reported following treatment according to current protocols that include three or more cycles of consolidation chemotherapy. Thus, minimizing exposure to excessive cytotoxic agents while maintaining or increasing the cure rate must represent priority goals for future developmental APL therapy. Arsenic trioxide (ATO) has demonstrated extraordinary single-agent activity against relapsed APL, inducing complete remissions in 70 - 90% of patients. The research proposed in this application investigates the incorporation of ATO into the primary curative therapy of newly diagnosed APL. A Phase II multicenter clinical trial will be performed in which ATO is substituted for etoposide during a single intensive consolidation cycle. This trial is based on a prior trial in which a single intensive consolidation appeared to yield comparable remissions to more conventional regimens which include two to three cycles of consolidation therapy, potentially minimizing short- and long-term toxicity, including secondary malignancies. The overall hypothesis is that substitution of ATO for the less active etoposide in a single cycle of consolidation chemotherapy will lead to equivalent durable remissions and cures, with less short- and long-term toxicity. To enable assessment of the success of this pilot approach in a rapid time frame, the primary endpoint of this study will be the determination of the frequency of maintenance of remissions at one year in which PML-RARalpha transcript remains undetectable above 10 E-4, the threshold which predicts relapse. This trial will utilize a novel quantitative rt-PCR technique to monitor samples of peripheral blood for adequacy of ongoing remission and evidence of early relapse. This assay will greatly ease the burden of disease monitoring for patients, who currently undergo bone marrow aspirations every three - six months. This assay will also enable determination of the log-reduction of tumor contamination attributable to this novel consolidation approach. Success of this trial will potentially be followed by the testing of regimen against more conventional and more extensive treatment for APL in a Phase III trial.

描述（由申请人提供）：尽管急性前临床白血病（APL）患者的预后有显着改善，因为所有抗激酸（ATRA）掺入，但多达30％的患者未固化一级治疗。根据当前的方案，越来越多地报道了继发性白血病和骨髓增生性综合征，包括包括三个或多个巩固化疗周期的方案。因此，在维持或提高治愈率的同时，最大程度地减少了对过多的细胞毒性剂的接触，必须代表未来发育型APL疗法的优先目标。砷三氧化物（ATO）表现出了针对复发APL的非同寻常的单药活性，从而在70-90％的患者中诱发了完全缓解。该应用程序中提出的研究调查了将ATO纳入新诊断的APL的主要治疗疗法。将进行II期多中心临床试验，其中ATO在单个密集的整合周期中代替依托泊苷。该试验基于先前的试验，在先前的试验中，单个密集型合并似乎可以对更常规的方案产生可比的恢复，其中包括两到三个巩固疗法的周期，可能会最大程度地减少短期和长期毒性，包括继发性恶性肿瘤。总体假设是，在单个合并化疗周期中，ATO代替较少活跃的依托泊苷将导致等效的持久减免和治愈，而短期和长期毒性较少。为了在快速的时间范围内评估该试验方法的成功，这项研究的主要终点将确定在一年中pml-Raralpha转录本在10 E-4上方无法检测到的一年中的恢复频率，该阈值预测了复发的阈值。该试验将利用一种新型的定量RT-PCR技术来监测外周血样本，以充分持续缓解和早期复发的证据。该测定法可以极大地减轻患者疾病监测的负担，他们目前每三个月进行一次骨髓术语。该测定还将确定归因于这种新型巩固方法的肿瘤污染的对数还原。在III期试验中，该试验的成功可能会随后对APL进行更常规和更广泛的治疗方法进行测试。