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7大最常见的癌症，在77240人中占一半以上 65岁以上每年确诊一次。在大约50%的病例中，疾病会复发或复发，通常在两年内 在一些患者中，疾病对额外的治疗(难治/复发，R/R)难以治愈。 这些患者的抢救治疗包括更强的化疗鸡尾酒或最近的细胞疗法或 造血细胞移植。挽救化疗的四年生存率约为40%，而挽救化疗的四年生存率约为60%。 用于ASCT。自体嵌合抗原受体T(CART)细胞产品在 某些类型的R/R非霍奇金淋巴瘤的临床试验和实际应用。然而，这种疗法并不能治愈 46%的人在2周至8.5个月内复发，即使是最小残留病(MRD)阴性；他们 与重大毒性有关，并仅限于在经认证的治疗中心给药。 AVM Biotech的FDA批准的试验NCT04329728目前正在进行中。这项临床试验包括一种剂量- AVM0703的升级研究和一项关键的适应性设计扩展队列研究 淋巴系统恶性肿瘤，之前至少有一次化疗失败，没有资格接受任何其他批准的治疗， 以及因进展性疾病而需要治疗的人。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。伊利诺伊州癌症 伊利诺伊大学的CARE大学和爱荷华大学的霍尔顿综合癌症中心正在启动。 新墨西哥大学印第安纳大学梅尔文和布伦·西蒙综合癌症中心 综合癌症中心，中华健康圣弗朗西斯医院，先锋健康亨德森维尔，莫菲特癌症 中心和MD安德森癌症中心将参与扩大队列阶段。到目前为止已经服药的患者， 在同情使用和登记剂量递增队列中，证明AVM0703区别于 其他研究药物由于其安全性问题，在这一“末期无选择”的患者群体中，以及 网站报告说，他们的患者感觉很好，恢复了食欲和精力，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。一旦膨胀阶段的剂量 已确定(根据登记人数、安全性和到目前为止的反应预计2021年11月)患者将 登记在5个NHL亚适应症特定队列中，要求每支手臂大约18名患者能够看到显著的 总体回复率。适应性设计扩展研究提供了一种将药物更快地带给非选择患者的方法 这项扩展研究是专门为满足FDA的营销应用指南而设计的。 在未来，AVM0703将在临床试验中结合早期的治疗路线进行研究，以确定 AVM0703与标准护理方案在提高完全缓解率、减少复发方面的潜在协同作用 降低了死亡率，并可能减少患者所需的治疗周期。这可能会显著地 通过减少副作用、减少医疗费用和减少长期毒性来提高急性生活质量。

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.