Understanding Methotrexate Dosing, Pharmacokinetics, and Toxicities for Burkitt Lymphoma in Malawi

摘要 本申请表是关于Fogarty国际中心K01国际研究科学家发展奖的申请 对于北卡罗来纳大学的儿科血液学家和肿瘤学家凯瑟琳·韦斯特摩兰博士来说 (北卡罗来纳大学)。该奖项将基于位于马拉维利隆圭的北卡罗来纳大学长期的临床研究合作， 韦斯特摩兰博士之前曾在那里生活和工作，担任临床和研究员。威斯特摩兰博士 正处于她研究生涯的形成阶段，目标是将自己确立为独立的全球卫生组织 儿童、青少年和青壮年癌症临床试验(AYA)领域的研究员。这个 该提案专门针对Burkitt淋巴瘤(BL)，这是儿童和Aya中最常见的癌症 与资源丰富的环境相比，生存状况令人沮丧的SSA。通知未来大型建筑的设计 在整个SSA中优化BL治疗Aya的地区性临床试验，Westmoland博士建议 进行指导研究，将实施甲氨蝶呤剂量递增试点临床试验，以确定 国际白血病治疗方案(目标1)中这种关键药物的最大耐受量；开发一种 甲氨蝶呤的群体药代动力学模型(目标2)；并翻译、验证和实施患者- 马拉维的报告结果(PRO)工具，用于更全面的毒性评估(目标3)。这 该奖项还将为Westmoland博士提供必要的支持，以实现以下职业生涯 发展目标：1)在SSA获得临床试验设计和实施方面的正式培训；2)推进 在临床药理学方面的培训；3)学习定性和定量的方法来翻译和应用PRO SSA的研究措施；4)获得生物统计学方面的高级技能；5)发展Aya肿瘤学方面的专业知识 在SSA中；以及6)提高赠款撰写和科学陈述的技能。为了实现这些目标，Dr。 Westmoland组建了一支非常有成就的核心导师团队，由以下人员组成：她的主要 马拉维导师，医学博士，公共卫生硕士，全球肿瘤学和癌症临床/翻译研究专家 在SSA；她在美国的主要导师，丹尼尔·冈萨雷斯，药学博士，儿科人口的领导者 药物动力学；以及她的核心导师布莱斯·里夫博士，一位专业方法学的国际专家。全 是由NIH资助的调查人员，他们有指导初级教员走向独立的记录。这个 该提案中概述的拟议研究和职业发展计划将加快Westmoland博士的 全球儿科肿瘤学研究生涯，并为未来R01申请领导多中心奠定基础 跨SSA优化BL治疗Aya的临床试验。

ABSTRACT This application is for a Fogarty International Center K01 International Research Scientist Development Award for Dr. Katherine Westmoreland, MD, a pediatric hematologist-oncologist at the University of North Carolina (UNC). The award will be based at the longstanding UNC clinical research collaboration in Lilongwe, Malawi, where Dr. Westmoreland has previously lived and worked as a clinical and research fellow. Dr. Westmoreland is in the formative stages of her research career and aims to establish herself as an independent global health investigator in the area of cancer clinical trials for children and adolescents and young adults (AYA). The proposal is specifically focused on Burkitt Lymphoma (BL), the commonest cancer among children and AYA in SSA for which survival is dismal compared to resource-rich settings. To inform the design of future large-scale regional clinical trials to optimize BL treatment for AYA throughout SSA, Dr. Westmoreland proposes to conduct mentored research that will implement a methotrexate dose escalation pilot clinical trial to determine the maximum tolerated dose for this key medicine in international BL treatment protocols (Aim 1); develop a population pharmacokinetic model for methotrexate (Aim 2); and translate, validate, and implement a patient- reported outcomes (PRO) instrument in Malawi for a more comprehensive toxicity assessment (Aim 3). This award will also provide Dr. Westmoreland with support necessary to achieve the following career development goals: 1) obtain formal training in clinical trial design and implementation in SSA; 2) advance her training in clinical pharmacology; 3) learn qualitative and quantitative methods to translate and apply PRO measures for research in SSA; 4) acquire advanced skills in biostatistics; 5) develop expertise in AYA oncology in SSA; and 6) improve grant writing and scientific presentation skills. To achieve these goals Dr. Westmoreland has assembled a highly accomplished core mentorship team comprised of: her primary Malawi mentor, Satish Gopal, MD, MPH, an expert in global oncology and cancer clinical/translational research in SSA; her primary United States mentor, Daniel Gonzalez, PharmD, PhD, a leader in pediatric population pharmacokinetics; and her core mentor Bryce Reeve, PhD, an international expert in PRO methodology. All are NIH-funded investigators with a track record of mentoring junior faculty toward independence. The proposed research and career development plans outlined in this proposal will accelerate Dr. Westmoreland’s global pediatric oncology research career, and form the basis for a future R01 application to lead a multicenter clinical trial to optimize BL treatment for AYA across SSA.