Randomized Phase II Study of QS-DG +/- Trivalent Ganglioside Vaccine in Stage IV

QS-DG /- IV 期三价神经节苷脂疫苗的随机 II 期研究

• 批准号: 7534750
• 负责人: Richard Carvajal
• 金额: $ 42.69万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534750
• 关键词: Adjuvant; Adjuvant Study; Adjuvant Therapy; Adult; Aftercare; Antibodies; Antibody Formation; Antigens; Blood; Cancer Control; Carrier Proteins; Cells; Childhood; Clinical; Clinical Trials; Combined Modality Therapy; Conjugate Vaccines; Development; Disease; Disease-Free Survival; Double-Blind Method; Excision; G(M2) Ganglioside; Gangliosides; Immune Targeting; Immunologic Adjuvants; Individual; Keyhole Limpet Hemocyanin; Lactones; Local Therapy; Memorial Sloan-Kettering Cancer Center; Metastatic/Recurrent Disease; Micrometastasis; Modality; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Phase II Clinical Trials; Population; Positioning Attribute; Production; Public Health; Radiation therapy; Randomized; Randomized Clinical Trials; Recurrence; Recurrent disease; Residual Tumors; Safety; Serological; Specimen; Staging; Surface Antigens; Survival Rate; Testing; Time; Toxic effect; Treatment Protocols; Vaccinated; Vaccination; Vaccines; chemotherapy; immunogenicity; killings; neoplastic cell; prevent; response; sarcoma; tumor

DESCRIPTION (provided by applicant): Despite potentially curative therapies, the majority of patients with treated metastatic sarcoma die as a result of subsequent disease relapse. The one-year disease-free survival rates and overall survival at 3 years following complete resection of recurrent metastatic disease in adult sarcoma patients or following combination therapy in pediatric sarcoma patients is less than 20%. Given the poor clinical outcome of these patients, the development of effective adjuvant therapy aimed at eliminating micrometastatic disease is desperately needed. The gangliosides GM2, GD2 and GD3 represent the three most prevalent cell surface antigens on sarcomas, and gangliosides have been shown to be effective targets for immune control of cancer, especially in the adjuvant setting. In adjuvant trials, the primary targets are individual circulating tumor cells or micrometastases which may persist for long periods after treatment of all known residual tumor. Antibodies induced by a trivalent vaccine against GM2, GD2 and GD3 are ideally suited for eradication of free tumor cells and micrometastases. If antibodies of sufficient titer can be induced against these antigens such that they eliminate these tumor cells from the blood and eradicate micrometastases, our approach to treating the sarcoma patient would be dramatically changed. MSKCC is the only center that has demonstrated the ability to consistently induce antibodies against these gangliosides in patients. Safety and immunogenicity of each individual component of the vaccine has already been demonstrated in patients. If the impact of vaccination on the clinical course of sarcoma is to be tested, a randomized, double-blind clinical trial is required. With the development and production of this trivalent ganglioside vaccine at MSKCC, we are now in a position to evaluate the impact of this vaccine in sarcoma patients on disease free and overall survival. The primary aim of this proposal is to determine whether the median disease-free survival or survival at 3 years after treatment with a trivalent ganglioside-KLH conjugate vaccine plus immunological adjuvant QS-DG (a synthetic version of QS-21) is greater compared to treatment with QS-DG alone in patients with metastatic sarcoma rendered disease free by single- or multi-modality therapy. 140 patients will be accrued over 2 years. All patients in this randomized, double blind trial will receive 8 vaccinations over 1 year and will be followed at MSKCC. Secondary aims are 1) to evaluate the toxicity of this regimen in this patient population, 2) to analyze the serological response in vaccinated patients to confirm vaccine stability over time, and 3) to correlate antibody response against the individual gangliosides with clinical course and antigens expressed in recurrences. PUBLIC HEALTH RELEVANCE: The double blind, randomized clinical trial proposed here will test whether a trivalent KLH conjugate vaccine that induces antibodies against 3 abundantly expressed sarcoma antigens can prevent outgrowth of circulating sarcoma cells and micrometastases. If antibodies of sufficient titer can be induced against these antigens such that they eliminate these tumor cells from the blood and eradicate micrometastases, our approach to treating the sarcoma patient would be dramatically changed. The establishment of new metastases would no longer be possible, so aggressive local therapies including surgery and radiation therapy might result in long-term control or potential cure of even metastatic sarcoma.

描述（由申请人提供）：尽管有潜在的治疗疗法，但大多数患有转移性肉瘤的患者由于随后的疾病复发而死亡。成人肉瘤患者的复发转移性疾病或在小儿肉瘤患者的联合疗法后，无病的一年生存率和3年的总生存率在3年中的总生存率小于20％。考虑到这些患者的临床结果不佳，迫切需要旨在消除微转移疾病的有效辅助治疗的发展。神经节GM2，GD2和GD3代表了肉瘤上三种最普遍的细胞表面抗原，而神经节剂已证明是对癌症免疫控制的有效靶标，尤其是在辅助环境中。在辅助试验中，主要目标是单个循环肿瘤细胞或微转移酶，在治疗所有已知残留肿瘤后可能会长时间持续存在。由三价疫苗诱导的针对GM2，GD2和GD3诱导的抗体非常适合根除自由肿瘤细胞和微转移酶。如果可以针对这些抗原诱导足够滴答的抗体，从而使它们从血液中消除这些肿瘤细胞并消除微转移，那么我们治疗肉瘤患者的方法将发生巨大变化。 MSKCC是唯一证明能够持续诱导患者中神经节苷脂抗体的能力的中心。患者已经证明了疫苗的每个组件的安全性和免疫原性。如果要测试疫苗接种对肉瘤临床过程的影响，则需要进行随机的双盲临床试验。随着MSKCC的这种三价神经苷疫苗的开发和生产，我们现在可以评估该疫苗对肉瘤患者无疾病和整体生存的影响。该提议的主要目的是确定用三价神经节神经节疫苗和免疫学辅助QS-DG（QS-21的合成版本的合成版本）与单独的QS-DG治疗相比，单独的sarmoma施用疾病单独使用QS-DG治疗的单独使用或多M型M型，是否较大的QS-DG（QS-21的合成版本的合成版本）是更大的。 140名患者将在2年内产生。这项随机，双盲试验中的所有患者将在1年内接受8次接种疫苗，并在MSKCC进行。次要目的是1）评估该治疗方案对该患者人群的毒性，2）分析接种疫苗的患者的血清学反应，以确认疫苗的稳定性，而3）将针对单个神经毒剂的抗体反应与复发中表达的临床病程和抗原相关联。公共卫生相关性：此处提出的双盲，随机临床试验将测试三价KLH偶联疫苗，该疫苗诱导针对3种丰富表达的肉瘤抗原的抗体是否可以防止循环肉瘤细胞和微分离酶的生长。如果可以针对这些抗原诱导足够滴答的抗体，从而使它们从血液中消除这些肿瘤细胞并消除微转移，那么我们治疗肉瘤患者的方法将发生巨大变化。建立新的转移不再是可能的，因此包括手术和放射疗法在内的积极的局部疗法可能会导致长期控制或潜在的转移性肉瘤治愈。