Statement of Translational RelevanceSurvival rates for patients with glioblastoma (GBM) are abysmal, with median overall survival of approximately 15 months. Immunotherapy of GBM is a promising area of investigation, although challenges around identification of novel and immunogenic target antigens exist. IMA950 is a GBM specific vaccine comprising 11 tumor-associated peptides (TUMAPs) developed to address this challenge. We have performed a phase 1 safety and immunogenicity study in newly diagnosed GBM patients using IMA950 plus GM-CSF alongside standard of care chemo-radiotherapy. Our results demonstrate that IMA950 is well tolerated with 90% of patients having a CD8+ T-cell immune response to at least one TUMAP, with 50% responding to two or more TUMAPs. No effect of pre-treatment regulatory T-cell levels on IMA950 immunogenicity was found and steroids did not appear to affect immune responses to the TUMAPs. This data provides evidence to support further development and optimization of IMA950 together with other immunotherapies for GBM. were multi-TUMAP responders, with no important differences between cohorts. No effect of pre-treatment Treg levels on IMA950 immunogenicity was observed and steroids did not affect TUMAP responses. PFS was 74% at 6 months and 31% at 9 months. CONCLUSION: IMA950 plus GM-CSF was well tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded.Further development of IMA950 is encouraged.

Purpose: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents.Experimental Design: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors.Results: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m 2 , then expanded cohorts to 15.4 mg/m 2 in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drugrelated dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m 2 or higher. Conclusions:The maximum tolerated dose was 8.5 mg/m 2 but escalation to 14 mg/m 2 was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m 2 and maximum tumor perfusion reductions were seen at doses of 11 mg/m 2 or higher, the recommended phase II dose is from 11 to 14 mg/m 2 .

Background:OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1–3 h and secondary tumour cell necrosis between 6 and 72 h.Methods:To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24 h, day 8 and day 15).Results:OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%).Conclusion:These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503.