Irinotecan in Combination with Celecoxib: A phase I Stu*

描述（由申请人提供）：腹泻和中性粒细胞减少症是与临床活性化疗药物相关的常见且通常是剂量限制性的毒性，包括伊立替康，这是本提案的重点药物。尽管伊立替康/FU/LV被认为是治疗晚期结直肠癌患者的标准疗法，但大量接受治疗的患者仍存在临床耐药，并且i /IV级腹泻（约30%）和中性粒细胞减少症（约15%）很常见。这些毒性损害了反应者和无反应者的生活质量。因此，迫切需要确定和评估可能对现有药物治疗的患者的治疗选择性和生活质量产生积极影响的方法。在我们实验室进行的研究表明，大鼠给予伊立替康最大耐受剂量的两倍（200 mg/kg/d × 3），在伊立替康治疗7天内死亡率为100%。相比之下，当相同剂量的伊立替康与环氧化酶（COX-2）抑制剂塞来昔布（30 mg/kg）联合使用时，100%存活，无明显腹泻。此外，在患有晚期结直肠肿瘤（3gm）的大鼠中，伊立替康没有产生显著的肿瘤反应，而与塞来昔布联合产生75%的总反应率（50% PR和25% CR）。研究正在继续证实这一发现在其他药物和其他携带可移植人类肿瘤的啮齿动物中的普遍性，并描绘其潜在机制。这些临床前数据清楚地证明了塞来昔布改善伊立替康的治疗指标，并为拟议的I期临床试验设计提供了基础，并进行了平行的实验室研究。基本假设：1)塞来昔布选择性地保护正常组织；2)塞来昔布下调正常组织中COX-2，选择性恢复细胞增殖，改善伊立替康毒性；3)塞来昔布在不改变伊立替康活性代谢物SN-38与非活性SN-38葡萄糖醛酸盐比值的情况下，可以防止伊立替康诱导的毒性。具体目的是：1)确定伊立替康联合塞来昔布400mg PO BID的最大耐受剂量。2)评估每周伊立替康联合塞来昔布400mg PO BID患者伊立替康致腹泻的发生率3)获得伊立替康单药或伊立替康联合塞来昔布患者治疗前和治疗后以下生物学相关指标的评价：a) COX-2表达；B)组织病理学评估，重点是粘膜损伤和炎症；c)肠黏膜凋亡；4)评价塞来昔布对伊立替康及其代谢物药动学参数的影响。一个由科学家、医学肿瘤学家和病理学家组成的合作小组已经到位，以确保拟议的研究将有效地进行。如果我们成功地实现了拟议计划的目标，这种方法的推广可以在其他药物和其他恶性肿瘤中进行测试，在II期临床试验中评估对治疗结果的影响。

DESCRIPTION (provided by applicant): Diarrhea and neutropenia are common and often dose-limiting toxicities associated with clinically active chemotherapeutic agents, including irinotecan, the drug of focus in this proposal. Although irinotecan/FU/LV is considered a standard therapy in the treatment of patients with advanced colorectal cancer, a significant number of treated patients remain clinically resistant and grade Ill/IV diarrhea (approximately 30%) and neutropenia (approximately 15%) are common. These toxicities compromise the quality of life of responders and non-responders alike. Thus, there is a critical and pressing need to identify and evaluate approaches that could impact positively on the therapeutic selectivity and quality of life of patients treated with existing drugs. Studies carried out in our laboratory demonstrated that administration of double the maximum tolerated dose of irinotecan (200 mg/kg/d x 3) in rats yielded 100% lethality within 7 days of treatment with irinotecan. In contrast, when the same dose of irinotecan was combined with celecoxib, a cyclooxygenase (COX-2) inhibitor (30 mg/kg), 100% survived with no significant diarrhea. Furthermore, in rats bearing advanced ward colorectal tumor (3 gm), irinotecan yielded no significant tumor responses, while the combination with celecoxib yielded an overall response rate of 75% (50% PR and 25% CR). Studies are continuing to confirm the generalizability of this finding with other drugs and in other rodents bearing transplantable human tumors and to delineate the underlying mechanisms. These data preclinically provide a clear demonstration of improved therapeutic index of irinotecan by celecoxib and provide the basis for the design of the proposed phase I clinical trial with parallel laboratory investigations. The underlying hypotheses: 1) celecoxib protects selectively normal tissues; 2) down regulation of COX-2 by celecoxib in normal tissues results in selective restoration of the proliferation and amelioration of irinotecan toxicity; and 3) celecoxib protects against irinotecan-induced toxicity without altering the active irinotecan metabolite SN-38 to the inactive SN-38 glucuronide ratio. The specific aims are: 1) determine the maximum tolerated dose of irinotecan combined with celecoxib 400 mg PO BID. 2) assess the incidence of irinotecan-induced diarrhea in patients receiving weekly irinotecan in combination with celecoxib at 400 mg PO BID 3) Obtain pre-treatment and post-treatment evaluation of the following biological correlates in patients receiving irinotecan single agent or a combination of irinotecan and celecoxib: a) COX-2 expression; b) histopathologic evaluation with focus on mucosal damage and inflammation; and c) intestinal mucosal apoptosis; and 4) Evaluate the effect of celecoxib on the pharmacokinetic parameters of irinotecan and its metabolites. A collaborative team of scientists, medical oncologists, and pathologists is in place to assure that the proposed studies will be carried out efficiently. If we are successful in fulfilling the objectives of the proposed plan, the generalization of this approach can be tested with other drugs and other malignancies where impact on therapeutic outcome can be evaluated in phase II clinical trials.