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）是一种由APC（腺瘤性结肠息肉病）基因种系突变引起的常染色体显性遗传病。FAP的特征是多发性同步和异时性结直肠腺瘤，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）信号促进考克斯-2表达和随后的肠肿瘤的发展。在最近的一项双盲、安慰剂对照、随机试验（NCT 01187901）中，与安慰剂相比，非甾体抗炎药（NSAID）舒林酸与EGFR抑制剂厄洛替尼联合使用，可有效降低FAP受试者的总息肉负担和数量。这种效果在治疗6个月后是显著的，并且在经典和减毒FAP参与者中均观察到。然而，不良事件发生率很高。最值得注意的是治疗组87%的参与者出现痤疮样皮疹，39%的参与者出现口腔粘膜炎。在试验期间，54%的接受治疗的患者在研究期间的某个时间点减少了舒林酸剂量。有11例患者因胃肠道出血、丙氨酸转氨酶水平升高、血压升高、眼痛或视力变化和扁桃体炎而暂时停用研究药物。尽管所有受试者开始试验时均服用固定标准剂量的2种研究药物，但由于不耐受而进行的剂量调整导致剂量范围变化。尽管如此，在所使用的厄洛替尼剂量范围内观察到引起息肉消退的相同功效，表明厄洛替尼剂量可以降低，同时保持功效。虽然舒林酸的剂量是基于先前的研究，但厄洛替尼的剂量是根据癌症治疗和肺癌化疗试验估计的。这项研究的其他局限性包括：没有长期随访数据，舒林酸和厄洛替尼效果的持久性未知，对任何一种药物产生耐药性的可能性，以及患者最终是否接受更少的监督内窥镜检查/手术或发展更少的癌症的问题。此外，舒林酸和厄洛替尼均可能分别与罕见和严重的不良反应相关，如心脏毒性和间质性肺病。因此，需要进行剂量范围研究，以确定舒林酸和厄洛替尼的较低和/或较低频率给药是否可以减少这些不良反应，但保留疗效。 大鼠结肠息肉病（Pirc）模型比ApcMin/+和FAP和CRC的其他Apc突变小鼠模型具有显著优势，因为其相对高的结肠肿瘤负荷，以及适合于预防研究的寿命，所述预防研究需要评估预防功效和毒性以及在长期暴露于化学预防剂之后产生抗性。此外，Pirc模型模拟FAP患者中的肿瘤分布;大鼠发展小肠和结肠肿瘤，后者可以通过定期内窥镜检查在单个Pirc大鼠中追踪，而无需处死动物。该模型允许评估化学预防剂对小肠和结肠肿瘤类型的影响，这些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。然而，两种药物（舒林酸和厄洛替尼）联合使用的毒性可能不允许在预防环境中进行必要的长期治疗。使用小肠和结肠癌的Pirc模型，本研究的总体目标是确定舒林酸和厄洛替尼组合方案的最佳给药和/或时间表，其将表现出较低的毒性，同时保持预防肿瘤发展的功效。次要目标是评估与结肠肿瘤相比，药物对小肠肿瘤的疗效，并开发药物疗效的临床相关生物标志物。