Expedited Expansion Cohort Clinical Trial for Relapsed/Refractory 'no-option' Non-Hodgkin's Lymphoma/Leukemia Patients

摘要 非霍奇金淋巴瘤（NHL）是美国第七大常见癌症，在77,240人中， 65岁以上每年确诊。在大约50%的病例中，疾病通常在两年内复发或复发 在一些患者中，疾病对额外治疗是难治性的（难治性/复发性，R/R）。 这些患者的挽救治疗包括更强的化疗鸡尾酒或最近的细胞治疗或化疗。 造血细胞移植挽救性化疗的四年生存率约为40%， 对于ASCT。自体嵌合抗原受体T（CarT）细胞产品在免疫治疗中引发了很高的应答率。 临床试验和现实世界的使用某些类型的R/R NHL。然而，这些疗法对于高达 46%在2周至8.5个月内复发，即使有阴性微小残留病（MRD）;他们是 与显著的毒性相关，并且仅限于在认可的治疗中心施用。 AVM生物技术公司的FDA批准的试验NCT 04329728目前正在进行中。这项临床试验包括一种剂量- AVM 0703的递增研究和一项在无选择患者中进行的关键性适应性设计扩展队列研究 至少1种既往治疗方案失败的淋巴系统恶性肿瘤，不符合任何其他获批治疗的资格， 以及因疾病进展而需要治疗的患者。目前，希望之城，加州大学洛杉矶分校，诺顿癌症研究所， 莱文癌症研究所和德克萨斯大学西南分校正在积极招募患者。伊利诺伊癌症 伊利诺斯州护理大学和爱荷华州大学的霍尔顿综合癌症中心正在启动。 印第安纳州大学梅尔文和布伦西蒙综合癌症中心，新墨西哥州大学 综合癌症中心，CHI健康圣弗朗西斯医院，降临健康亨德森维尔，莫菲特癌症 中心和MD安德森癌症中心将参与扩展队列阶段。迄今为止接受给药的患者， 在同情使用和入组剂量递增队列中，证明AVM 0703与 由于没有安全性问题，在该“终末期无选择”患者人群中使用其他研究药物， 研究中心报告称，患者感觉良好，恢复食欲和精力，并记录了持久的反应。 该提案要求为适应性设计扩展队列研究提供资金。一旦扩展阶段剂量 已确定（根据迄今为止的入组、安全性和缓解情况，预计2021年11月）患者将 入组5个NHL子适应症特异性队列，每组需要约18例患者才能观察到显著的 总体响应率。适应性设计扩展研究提供了一种更快的方法，将药物带给没有选择的患者 该扩展研究专门设计用于满足FDA的上市申请指南。 未来，AVM 0703将在临床试验中与早期治疗方案联合进行研究，以确定 AVM 0703与标准治疗在提高完全缓解率、减少复发 率，并可能减少患者所需的治疗周期总数。这可以大大 通过减少副作用、减少医疗费用和减少长期毒性来改善急性生活质量。

ABSTRACT Non-Hodgkin’s Lymphoma (NHL) is the 7th most common cancer in the U.S., with over half of the 77,240 people diagnosed annually over age 65. In about 50% of cases, disease recurs or relapses, typically within two years of initial treatment, and in some patients disease is refractory to additional treatment (Refractory/Relapsed, R/R). Salvage therapy in these patients consists of stronger chemotherapy cocktails or more recently, cell therapy or hematopoietic cell transplantation. Four-year survival rates are about 40% with salvage chemotherapy and 60% for ASCT. Autologous Chimeric Antigen Receptor T (CarT) cell products have triggered great response rates in clinical trials and real-world use for some types of R/R NHL. However, the therapies are not curative with up to 46% relapsing within 2 weeks to 8.5 months even with negative minimal residual disease (MRD); they are associated with significant toxicities and are restricted to administration at accredited treatment centers. AVM Biotechnology’s FDA-approved trial, NCT04329728, is currently ongoing. This clinical trial includes a dose- escalation study of AVM0703 and a pivotal adaptive-design expansion cohort study in no-option patients with lymphoid malignancies who failed at least 1 prior regimen, who do not qualify for any other approved therapy, and who need treatment due to progressive disease. Currently City of Hope, UCLA, Norton Cancer Institute, Levine Cancer Institute, and University of Texas Southwestern are actively enrolling patients. Illinois Cancer Care University of Illinois and Holden Comprehensive Cancer Center at University of Iowa are being activated. Indiana University Melvin and Bren Simon Comprehensive Cancer Center, University of New Mexico Comprehensive Cancer Center, CHI Health St. Francis Hospital, Advent Health Hendersonville, Moffitt Cancer Center and MD Anderson Cancer Center will participate in the expansion cohort phase. Patients dosed to date, in compassionate use and in enrolled dose-escalation cohorts, demonstrate that AVM0703 is distinguished from other investigative drugs in this ‘terminal no-option’ patient population by its absence of safety concerns, and the sites report that their patients feel great, regain appetite and energy, and durable response has been recorded. This proposal requests funding for the adaptive design expansion cohort study. Once the expansion phase dose has been determined (projected for Nov 2021 based on enrollment, safety and response to date) patients will be enrolled in 5 NHL sub-indication specific cohorts, requiring about 18 patients per arm to be able to see significant overall response rates. Adaptive design expansion studies offer a faster way to bring drugs to no-option patients and this expansion study has been specifically designed to meet FDA guidance for a marketing application. In the future AVM0703 will be studied in clinical trials in combination with earlier lines of therapy to determine the potential synergy of AVM0703 with standard of care to enhance complete response rate, reduce relapse rates, and potentially reduce the total number of therapeutic cycles patients require. This could significantly improve acute quality of life by reducing side-effects, reduce medical expenses and reduce long term toxicities.