OPTIMIZATION OF DOSING REGIMENS OF SULINDAC IN COMBINATION WITH ERLOTINIB FOR SMALL INTESTINAL AND COLON CANCER PREVENTION

优化舒林酸联合埃洛替尼预防小肠癌和结肠癌的给药方案

• 批准号: 10020546
• 负责人: POWELL BROWN
• 金额: $ 85.43万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2022-01-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020546
• 关键词: APC gene; Adenomatous Polyposis Coli; Adverse effects; Adverse event; Alanine Transaminase; Animals; ApcMin/+ mice; Attenuated; Biological Markers; Blood Pressure; Cardiotoxicity; Chemopreventive Agent; Chemotherapy-Oncologic Procedure; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Adenoma; Colorectal Cancer; Data; Development; Dominant Genetic Conditions; Dose; Double-Blind Method; Endoscopy; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Exanthema; Exhibits; Exposure to; Gastrointestinal Hemorrhage; Genetic Diseases; Germ-Line Mutation; Goals; Individual; Interstitial Lung Diseases; Intestinal Cancer; Intestinal Neoplasms; Longevity; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Modification; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; PTGS2 gene; Participant; Patients; Periodicity; Pharmaceutical Preparations; Placebos; Polyps; Prevention; Preventive; Rattus; Receptor Signaling; Regimen; Resistance; Resistance development; Risk; Schedule; Sulindac; Tonsillitis; Toxic effect; Transcription Alteration; Tumor Burden; Vision; base; cancer therapy; clinically relevant; colon cancer prevention; in vivo; mutant mouse model; ocular pain; oral mucositis; pharmacodynamic biomarker; polyposis; predictive marker; prevent; randomized trial; treatment group; tumor

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic disorder caused by germline mutations in the APC (adenomatous polyposis coli) gene. FAP is characterized by multiple synchronous and metachronous colorectal adenomas with a 70% to 100% risk of developing colorectal cancer (CRC). Studies have suggested that APC inactivation and epidermal growth factor receptor (EGFR) signaling promote COX-2 expression and the subsequent development of intestinal neoplasia. In a recent double-blind, placebo-controlled, randomized trial (NCT01187901), a non-steroidal anti-inflammatory drug (NSAID), sulindac, in combination with an EGFR inhibitor, erlotinib, effectively reduced the total polyp burden and number in participants with FAP compared with placebo. This effect was significant after 6 months of therapy and was observed in both classic and attenuated FAP participants. However, there was a high rate of adverse events. The most notable were an acneiform rash in 87% of participants and oral mucositis in 39% of participants in the treatment group. During the trial, 54% of patients taking treatment had sulindac-dose reduction at some point during the study. There were 11 patients for whom study drugs were temporarily discontinued due to concern for gastrointestinal bleeding, elevated alanine aminotransferase level, elevated blood pressure, ocular pain or change in vision, and tonsillitis. Though all participants started the trial taking fixed standard doses of the 2 study medications, dose modifications due to intolerance led to a range of doses. Nonetheless, equal efficacy in causing polyp regression was observed across the resulting range of erlotinib doses used, suggesting the erlotinib dose could be lowered while maintaining efficacy. Although the dosing of sulindac was based on prior studies, the dosing of erlotinib was estimated from cancer treatment and lung cancer chemotherapy trials. Other limitations of this study include: no long-term follow-up data, unknown durability of the effect of sulindac and erlotinib, the potential to develop resistance to either drug, and the question as to whether patients ultimately undergo fewer surveillance endoscopies/surgery or develop fewer cancers. Also, both sulindac and erlotinib can be associated with rare and serious adverse effects such as cardiotoxicity and interstitial lung disease respectively. Hence dose-ranging studies are needed to determine if lower and/or less-frequent dosing of sulindac and erlotinib could diminish these adverse effects but retain efficacy. The polyposis in rat colon (Pirc) model has a significant advantage over ApcMin/+ and other Apc mutant mouse models of FAP and CRC, because of its relatively high colon tumor burden, and a lifespan suitable for prevention studies that require an assessment of preventive efficacies and toxicities as well as the development of resistance following long term exposure to chemopreventive agents. In addition, the Pirc model mimics the tumor distribution in FAP patients; the rats develop both small intestinal and colonic tumors, the latter of which can be tracked in individual Pirc rats by periodic endoscopic examinations without sacrificing animals. This model allows an assessment of the effects of chemopreventive agents on both small intestinal and colon tumor types, which have clinically exhibited different transcriptional alterations and sensitivities to agents. However, the toxicity of the two drugs (sulindac and erlotinib) in combination may not allow long term treatment necessary in a prevention setting. Using the Pirc model of small intestinal and colon cancer, the overarching goal of this study is to identify optimal dosing and/or scheduling of sulindac and erlotinib combination regimen that would exhibit lower toxicity while maintaining efficacy in preventing tumor development. A secondary goal is to assess the efficacy of the agents on small intestinal tumors compared to colonic tumors and to develop clinically relevant biomarkers of agent efficacy.

家族性腺瘤性息肉病（FAP）是由APC（腺瘤性息肉大肠杆菌）基因种系突变引起的常染色体显性遗传疾病。 FAP的特征是多个同步和高速直肠腺瘤，发生结直肠癌（CRC）的风险为70％至100％。研究表明，APC失活和表皮生长因子受体（EGFR）信号传导促进COX-2表达和随后的肠道肿瘤的发展。在最近的双盲，安慰剂对照，随机试验（NCT01187901）中，一种非甾体类抗炎药（NSAID），苏莱达克，结合了EGFR抑制剂Erlotinib，与FAP相比，EGFR抑制剂erlotinib有效降低了总polyp负担和数量。经过6个月的治疗后，这种作用很明显，并且在经典和减弱的FAP参与者中都观察到。但是，不良事件发生率很高。最值得注意的是87％的参与者中的弓形皮疹和治疗组39％的口腔粘膜炎。在试验期间，54％的接受治疗的患者在研究期间的某个时候减少了苏糖剂量。有11名患者因胃肠道出血，丙氨酸氨基转移酶水平升高，血压升高，眼部疼痛或视力变化和扁桃体炎而暂时停止研究药物。尽管所有参与者都开始接受2种研究药物的固定标准剂量的试验，但由于不耐受而导致的剂量改变导致了一系列剂量。尽管如此，在所得的厄洛替尼剂量范围内观察到引起息肉回归的同等疗效，这表明可以降低erlotinib剂量，同时保持疗效。尽管硫酸的剂量是基于先前的研究，但从癌症治疗和肺癌化学疗法试验中估算了厄洛替尼的剂量。这项研究的其他局限性包括：没有长期的随访数据，硫酸和厄洛替尼影响的未知耐用性，具有对药物抗性的潜力，以及患者最终接受监测内窥镜/手术或较少癌症的问题。同样，苏氏菌和厄洛替尼都可以分别与罕见和严重的不良反应有关，例如心脏毒性和间质性肺部疾病。因此，需要进行剂量范围的研究来确定苏氏菌和厄洛替尼的较低和/或较少剂量是否会降低这些不良反应，但保持疗效。 大鼠结肠（PIRC）模型中的息肉病比APCMIN/+和其他APC突变小鼠模型的FAP和CRC具有显着优势，因为其结肠肿瘤的负担相对较高，并且具有适合预防研究的寿命，需要评估预防效率和毒性，并在长期对化学剂进行抗药性之后的抵抗力发展，以进行化学典型的介入。此外，PIRC模型模仿了FAP患者的肿瘤分布；大鼠同时发展小肠和结肠肿瘤，后者可以通过周期性内窥镜检查而无需牺牲动物来跟踪单个PIRC大鼠。该模型允许评估化学预防剂对小肠和结肠肿瘤类型的作用，这些肠道肿瘤类型在临床上表现出不同的转录改变和对药物的敏感性。但是，两种药物（Sulindac和Erlotinib）组合的毒性可能不允许在预防环境中长期治疗。使用小肠和结肠癌的PIRC模型，这项研究的总体目标是确定Sulindac和Erlotinib组合方案的最佳剂量和/或调度，该方案将表现出较低的毒性，同时保持在预防肿瘤发展方面的功效。第二个目标是评估与结肠肿瘤相比，评估药物对小肠道肿瘤的功效，并开发与临床相关的剂疗效生物标志物。