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）：尽管有潜在的治愈性治疗，但大多数转移性肉瘤患者因随后的疾病复发而死亡。成人肉瘤患者复发转移性疾病完全切除后或儿童肉瘤患者联合治疗后的1年无病生存率和3年总生存率低于20%。鉴于这些患者的临床结果不佳，迫切需要开发旨在消除微转移疾病的有效辅助治疗。神经节苷脂GM 2、GD 2和GD 3代表肉瘤上三种最普遍的细胞表面抗原，并且神经节苷脂已被证明是癌症免疫控制的有效靶点，特别是在佐剂环境中。在辅助试验中，主要靶点是单个循环肿瘤细胞或微转移，这些细胞或微转移在所有已知残留肿瘤治疗后可能会持续很长时间。由针对GM 2、GD 2和GD 3的三价疫苗诱导的抗体理想地适用于根除游离肿瘤细胞和微转移。如果可以诱导足够滴度的抗体对抗这些抗原，使得它们从血液中消除这些肿瘤细胞并根除微转移，那么我们治疗肉瘤患者的方法将发生显著变化。MSKCC是唯一一个证明能够在患者中持续诱导抗这些神经节苷脂抗体的中心。疫苗的每种单独组分的安全性和免疫原性已经在患者中得到证实。如果要测试疫苗接种对肉瘤临床病程的影响，则需要进行随机双盲临床试验。随着三价神经节苷脂疫苗在MSKCC的开发和生产，我们现在可以评估该疫苗对肉瘤患者无病生存和总生存的影响。该提案的主要目的是确定在通过单一或多模式治疗使疾病消失的转移性肉瘤患者中，三价神经节苷脂-KLH结合疫苗加免疫佐剂QS-DG（QS-21的合成版本）治疗后的中位无病生存期或3年生存期是否高于单独使用QS-DG治疗。2年内将累积140例患者。这项随机、双盲试验中的所有患者将在1年内接受8次疫苗接种，并将在MSKCC接受随访。次要目的是1）评价该方案在该患者人群中的毒性，2）分析接种患者的血清学应答，以确认疫苗随时间的稳定性，3）将针对单个神经节苷脂的抗体应答与临床病程和复发中表达的抗原相关联。公共卫生关系：本文提出的双盲、随机临床试验将测试诱导针对3种丰富表达的肉瘤抗原的抗体的三价KLH结合疫苗是否可以预防循环肉瘤细胞的生长和微转移。如果可以诱导足够滴度的抗体对抗这些抗原，使得它们从血液中消除这些肿瘤细胞并根除微转移，那么我们治疗肉瘤患者的方法将发生显著变化。新转移的建立将不再是可能的，因此积极的局部治疗包括手术和放射治疗可能导致长期控制或潜在治愈甚至转移性肉瘤。