Clinical TrialA randomised phase II trial of a trivalent ganglioside vaccine targeting GM2, GD2 and GD3 combined with immunological adjuvant OPT-821 versus OPT-821 alone in metastatic sarcoma patients rendered disease-free by surgery☆
Introduction
Sarcomas are a heterogenous group of mesenchymal malignancies representing less than 1% of adult cancers [1]. The prognosis of patients with metastatic sarcoma is poor, with a median overall survival (OS) of approximately 20 months from the time of metastasis in a recent study [2], although prognosis is often histology-specific [3]. The most frequent site of distant metastasis is the lung, followed by soft tissue, retroperitoneum and other distant sites [4]. Large retrospective studies have suggested that patients who undergo complete resection of distant metastases may have a higher survival rate than those with unresectable metastatic disease [5,6]. Nevertheless, more than 50% of patients recur after pulmonary metastasectomy with an expected 5-year survival rate of 34% [7].
Anti-cancer vaccination targeting tumour-associated antigens is an attractive strategy to activate the adaptive immune system and eliminate minimal residual disease [8]. Gangliosides are a subclass of glycosphingolipids linked to sialic acids that are anchored to the cell membrane. They are often expressed in a range of sarcoma subtypes and are often immunogenic, triggering anti-ganglioside antibodies that are readily measurable in the peripheral blood [[9], [10], [11]]. Eliciting an immune response to multiple gangliosides may lead to greater anti-neoplastic activity compared to a monovalent vaccination strategy [12]. Further, conjugation of a ganglioside vaccine to keyhole limpet haemocyanin (KLH) induces a more potent T cell and antibody response [13,14].
This randomised phase II study was designed to evaluate the hypothesis that administration of a trivalent vaccine targeting the GM2, GD2 and GD3 gangliosides, in addition to the novel immunological adjuvant OPT-821, would improve survival in patients with metastatic sarcoma rendered disease-free by surgery compared to treatment with OPT-821 alone. OPT-821 is a potent immunological adjuvant derived from the soapbark tree Quillaja saponaria that was found to be safe and immunogenic in the pre-clinical and clinical settings [15]. As subcutaneous injection of OPT-821 consistently induces local induration and erythema when administered alone or in combination, it was required in the control arm to maintain double-blind status.
Section snippets
Methods
This was a Phase II, randomised, double-blind, multi-centre study of a trivalent ganglioside vaccine plus the immunological adjuvant OPT-821 versus OPT-821 alone for patients with metastatic sarcoma who were rendered disease-free (NCT01141491). The study was completed according to the Declaration of Helsinki and the international standards of Good Clinical Practice. The independent ethics committee or institutional review board of each participating study centre approved the protocol and all
Patient characteristics
Between June 2010 and December 2012, a total of 136 patients were randomised on this study, 68 to each treatment arm. Patient characteristics (Table 1) were generally well balanced between randomisation arms. Most study patients were <65 years of age (83.8% in the vaccine arm and 75% in the OPT-821 monotherapy arm). Approximately half of patients had a recent disease-free interval of <12 months and had received prior radiation therapy or chemotherapy. Most patients on the vaccine and adjuvant
Discussion
To our knowledge, this randomised, double-blind, controlled trial is the largest vaccine trial of its kind in sarcoma patients. The study did not meet its primary end-point. No significant difference in RFS was seen between patients who received a trivalent KLH-conjugated ganglioside vaccine administered with the adjuvant OPT-821 compared to patients who received OPT-821 alone. There was a lack of efficacy in the vaccine arm above and beyond the control despite measurable and durable serologic
Author contribution
Evan Rosenbaum: Data curation, Formal analysis, Writing – original draft. Rashmi Chugh: Investigation. Christopher W. Ryan: Investigation, Writing – review and editing. Mark Agulnik: Investigation, Writing – review and editing. Mohammed M. Milhem: Investigation. Suzanne George: Investigation. Robin L. Jones: Investigation, Writing – review and editing. Bartosz Chmielowski: Investigation. Brian Andrew Van Tine: Investigation, Writing – review and editing. Hussein Tawbi: Investigation. Anthony D.
Conflict of interest statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Robin Jones: MSD, GSK (grants/research support); Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma, Pharmamar, Springworks, SynOx, Tracon, UptoDate (consultation fees). Brian Van Tine: Pfizer, Merck, Tracon, GSK (research grants);
Funding
MabVax Therapeutics provided funding for this study.
Acknowledgements
The authors would like to recognize the patients and their families for participating in this research study and the Memorial Sloan Kettering Cancer Center Clinical Grade Production (CGP) Facility for Vaccine Production, which was partially supported by NCI Cancer Center Support grant P30 CA008748.
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Prior Presentations: ASCO 2013, ASCO 2014