This study aims to find a safe and effective dose of the experimental oral vaccine VXM01 targeting the human VEGFR-2 for use during further investigation in a phase II clinical trial. Despite years of failure, a first active immune therapy, Dendreon’s Provenge, was efficacious in prostate cancer, and as a consequence has been approved by the FDA [25
]. Several more tumor vaccines are now in the midst or entering late-stage development [26
]. However, all these approaches are targeting so-called tumor-associated antigens (TAA). For example, vaccines targeting MUC-1 (stimuvax) and the TAA Mage-A3 are currently under development in phase III clinical trials [27
VXM01 represents a novel strategy by targeting not a tumor cell-resident antigen, but a tumor stroma-resident antigen, overexpressed by non-malignant endothelial cells of the tumor neovasculature. A Japanese group has recently published a phase I study, implementing a single VEGFR-2-derived peptide administered in weekly intervals via
the subcutaneous route of administration, thus following a similar approach, but restricting it to a certain HLA type [29
By targeting genetically stable and easily accessible endothelial cells, this product aims to overcome limitations encountered previously by vaccines targeting tumor cells directly, such as to tumor-cell heterogeneity, MHC-loss, immunosupression on a cellular level and tumor encapsulation as well as physiological barriers such as the blood brain barrier. Furthermore, since the therapeutic target is independent of the tumor type, the vaccine may potentially be active against a variety of different solid malignancies. The product represents a patient-independent, “off-the-shelf” oral vaccine, which can be stored and distributed to the clinical sites for use. While anti-angiogenic therapy, either via
small molecules or via
antibodies, has already been proven to be effective, our approach differs significantly by activating the patient’s own immune system against tumor neovasculature and is as such potentially creating a T-cell memory effect that provides long-term efficacy. Studies with bevacizumab in colon and ovarian cancer suggest that continued anti-angiogenic pressure is required to maintain beneficial treatment effects in the long term [30
Should adverse events occur that resemble hypersensitivity reactions mediated by histamine, leukotrienes, or cytokines, treatment options for fever, anaphylaxis, blood pressure instability, bronchospasm, and dyspnoea are available. Treatment options in case of unwanted T-cell derived autoaggression are derived from standard treatment schemes in acute and chronic graft vs. host disease applied after stem cell transplantation. Cyclosporin and glucocorticoids are proposed as treatment options.
In the unlikely case of systemic Salmonella typhi
Ty21a type infection, appropriate antibiotic therapy with fluoroquinolones including ciprofloxacin or ofloxacin is recommended [33
]. Bacterial infections of the gastrointestinal tract are to be treated with rifaximin.
For this phase I trial (advanced or stage IV pancreatic cancer patients) a patient population with dismal prognosis and the relatively gentle standard of care with regard to immunosuppression was chosen. Co-regimes of gemcitabine with tumor vaccination have even been reported to be synergistic [34
]. In addition, specific T-cell activation can be measured in this patient setting and may give an early indication of potential effectiveness of the vaccine VXM01. By including a placebo control in the present trial, we will gain further knowledge on specific safety issues related to the active vaccine vs. the background treatment. In addition, the pooled placebo patients will serve as a sound comparator in order to assess specific immune activation and other signs of clinical efficacy. If and when moving into phase II, a different patient entity with a longer life expectancy can be envisaged depending on the observed safety profile. Such studies will also include tumor types that have shown to be more susceptible to anti-angiogenic treatment.
We recognize the limitations inherent with a single center study and hope to partially address any bias by the introduction of the blinded placebo patients and an independent unblinded DSMB, which is without direct patient access. Further, the lack of a clear expectation as to what constitutes a sufficient positive immune reaction may be viewed as problematic. However, the read-out allows for a proof of a successful specific immune reaction. We have set predefined thresholds as to the positivity of our immunological assays. As to how far this can be correlated with dose and/or patient’s response remains to be seen.