Following its fourth interim review of the TRIST (TroVax Renal Immunotherapy Survival Trial) study, the independent Data Safety Monitoring Board (DSMB) has advised that TroVax administered according to the protocol will not meet the predefined primary efficacy endpoint. The Phase III study is investigating the vaccine in locally-advanced or metastatic clear cell renal carcinoma (RCC) and has a primary endpoint of overall survival in the TroVax-treated versus the placebo group. TroVax is Oxford BioMedica's (OBM) novel therapeutic cancer vaccine, which is being developed in collaboration with sanofi-aventis.
The DSMB has recommended that the study continues because there is important scientific merit and more to be learned by additional follow-up of all patients, but further vaccinations are discontinued; OBM has implemented the recommendation. In addition, the company intends to amend the statistical plan of the study to determine whether patient outcome is dependent on the number of TroVax doses administered. The news hit the former’s share price hard, as its stock fell from a close of 18.5p on 10th July, to open at 7p on 11th July, before closing the day at 7.5p, a 59 per cent drop.
The companies will discuss the proposed TRIST protocol amendments with regulatory authorities. With these amendments, a focus of the ongoing TRIST study will be to explore the number of doses that provide optimal benefit. In particular, it may be that the optimal benefit-to-risk ratio is delivered without the requirement for as many vaccinations as specified in the original TRIST study protocol. It is unlikely that the TRIST study alone will support registration of TroVax in RCC, although the trial may ultimately demonstrate a survival advantage for TroVax, and the results may form part of a regulatory submission alongside an additional confirmatory trial.
The randomised, placebo-controlled TRIST study was initiated in November 2006 and completed recruitment of 733 patients in March 2008 at more than 100 sites in the US, EU and Eastern Europe. It is designed to evaluate TroVax in combination with standard-of-care in locally-advanced or metastatic clear cell RCC. The original trial protocol, which was the subject of a Special Protocol Assessment by the FDA, allowed for patients to receive up to 13 immunisations over 73 weeks.
TroVax targets the tumour antigen 5T4, which is broadly distributed throughout a wide range of solid tumours. The product consists of a modified vaccinia Ankara vector, which delivers the gene for 5T4 and stimulates a patient's body to produce an anti-5T4 immune response. This immune response destroys tumour cells carrying the 5T4 antigen.
OBM and sanofi-aventis will evaluate the available data and the implications on the development plan for TroVax, including the planned Phase III trials in colorectal cancer (CRC). The Oncology Clinical Trials Office, part of the Clinical Pharmacology Department of the University of Oxford, has stated that the DSMB's recommendations in relation to the TRIST study "does not impact on our enthusiasm to progress the QUASAR V TroVax study" in adjuvant CRC. But it remains to be seen what the companies' stance on future trials is.
Matthew Dennis - Editor, Cancer Drug News
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