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A phase I study of an MVA vaccine targeting p53 in cancer.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Despite chemotherapy, survival for most patients with metastatic gastrointestinal cancer is <2 years. These dismal statistics reflect lack of effective therapy. We are conducting a first-in-human trial of modified vaccinia Ankara (MVA), an attenuated viral vaccine that targets wild-type (wt) p53. This approach applies to the majority of p53-involved tumors, since the bulk of the p53 sequence is identical, except for individual point mutations. Our phase I study evaluates the safety and tolerability of the vaccine. Methods: Patients with metastatic colon, gastric and pancreas cancer that failed standard treatment were eligible for vaccination if >10% of the cells stained strongly positive for p53. A standard 3+3 design was employed and patients were accrued to either the 108 pfu or 5.6 x 108pfu dose levels. A total of 3 injections were given, each spaced apart by 3 weeks and patients were evaluated for dose limiting toxicities. Results: Three patients were accrued to the 108 pfu dose level; 2 patients with colon cancer and 1 patient with pancreatic cancer. There were no dose limiting toxicities and the injection was well tolerated and only local irritation at the injection site was seen. The dose was escalated to 5.6 x 108 pfu; 3 patients were accrued, 1 with colon cancer and 2 with pancreatic cancer. There were no dose limiting toxicities observed in the 3 patients. Grade 2 toxicities that were at least possibly related to the vaccine include injection site reaction and fatigue seen in one patient each. One patient with pancreatic cancer had stable disease on CT after completion of the 3 injections. This dose level is being expanded to accrue an additional 6 patients to evaluate safety and immunogenicity using cytokine flow cytometry to characterize p53-specific CD4+ and CD8+ T cell response. Of the cell-surface markers employed, PD1 showed extraordinary strong expression prior to vaccine injection. All patients had a humoral response to the MVA backbone. Conclusions: Our MVA p53 vaccine is well tolerated with minimal grade 1-2 toxicities. The highest dose tested is 5.6 x 108 pfu and additional patients are being accrued to evaluate immunogenicity. Since many cancers have mutant p53, this is an attractive target and may potentially be used with many other cancers. Clinical trial information: NCT01191684.
Abstracts by V. M. Chung:
SWOG S1115: Randomized phase II clinical trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC-749607) versus mFOLFOX in patients withmetastatic pancreatic cancer after prior chemotherapy.Meeting: 2013 ASCO Annual Meeting | Abstract No: TPS4145
Phase I trial of gene-mediated cytotoxic immunotherapy in combination with chemoradiation for locally advanced pancreatic cancer.Meeting: 2011 Gastrointestinal Cancers Symposium | Abstract No: 195