New direction needed for PC research

The current focus on individualised care in many different cancer indications has left pancreatic cancer (PC) behind. Patients diagnosed with this disease live no longer today than those diagnosed two decades ago, despite numerous amounts of clinical trials. Whilst there have been great advances in other cancers, with patients benefiting from targeted drugs such as Gleevec (imatinib) and Herceptin (trastuzumab), PC still remains aggressive as ever.

Published in the 26th October online edition of the Journal of Clinical Oncology (10.1200/JCO.2009.21.9022), an expert panel convened by the National Cancer Institute has issued a consensus report that discusses many aspects of developing and testing treatments in this disease, and charts a course for the next five years. The authors of the report have stressed that the recommendations be strongly considered in any clinical trial being planned for PC.

A recommendation is to design pilot studies that test potential treatments in smaller groups before proceeding to larger trials, which have previously yielded disappointing results. Decisions about which molecular targets and potential drugs to pursue will be made based on scientific evidence that will include preclinical and animal studies that better represent PC in humans.

As the report notes, a better understanding of the complex signalling pathways in pancreatic tumours and the role of the local tumour environment are needed. More sophisticated modelling systems and repositories of high-quality biological samples that can be shared among preclinical researchers are also essential. Published in the same issue the Journal of Clinical Oncology (10.1200/JCO.2009.24.2446), a study provides an example of the kinds of trials many in the field hope to avoid in the future. As has been the pattern for these studies, patients saw little or no benefit from the experimental treatment, in this case, a combination of gemcitabine and capecitabine, as compared with gemcitabine alone.

Scientists involved in clinical trials for PC are aware of the limited success, and have already begun to adopt new ideas about developing and testing treatments. Dr Philip A Philip, the report's senior author, commented: "we have to be more thoughtful and innovative in bringing forward new targeted therapies and treatment combinations." The hope is that the new strategy will ensure that resources and patient time are spent on the most promising treatments.

Separately, in findings that could help researchers focus their drug-development efforts, Massachusetts Institute of Technology cancer biologists have identified a subpopulation of cells that can give rise to PC. In mouse models, they also found that tumours can form in other, more mature pancreatic cell types, but only when they are injured or inflamed, suggesting that PC can arise from different types of cells depending on the circumstances. In future studies, the MIT researchers plan to use their mouse models to follow the molecular events that take place during PC development, and identify potential targets for drug treatments and protein markers for early diagnosis. These new mouse models could also help researchers test potential PC treatments.

Alice Rossiter - Cancer Drug News Editor

Pharmexa pins hopes on Telovac

Pharmexa has decided to stop further patient enrolment in its PrimoVax Phase III trial of GV1001 for pancreatic cancer (PC) after a preliminary analysis showed no survival benefit for the vaccine. The decision does not affect the company's other Phase III trial, Telovac, which is currently recruiting patients at sites in the UK.

PrimoVax was designed to investigate the use of GV1001, a peptide vaccine targeting telomerase, administered before chemotherapy in 520 patients with non-resectable PC. The study had enrolled approximately 360 subjects and was being conducted at 77 hospitals in ten European countries, as well as Australia and the US. The trial had a primary endpoint of survival, while secondary endpoints included time-to-progression and safety.

The patients in the PrimoVax trial were randomly divided into two equally sized groups: half received standard treatment with gemcitabine and half received GV1001. If the condition of the patients in the second group deteriorated, treatment with gemcitabine was added. Preliminary data based on the deaths of 174 patients showed that the survival was no better in the GV1001 group compared to the group that received gemcitabine treatment. The final conclusions with respect to survival and all secondary endpoints must await the further follow-up of patients and full analyses of the data.

The PrimoVax trial was designed as a continuation of a previous Phase I/II study with GV1001, which showed that monotherapy treatment with the vaccine significantly prolonged patient survival, compared to the effect previously seen with gemcitabine. However the Phase III results suggest that the vaccine is not best utilised in this setting.

According to Pharmexa's Chief Executive Officer, Jakob Schmidt: "It has been an open question from the start whether GV1001 should be administered before chemotherapy, as in the PrimoVax trial, or during or after chemotherapy as in the Telovac trial. We now know that giving it first does not improve overall survival in non-resectable PC patients. The focus going forward will be to show that GV1001 has a role in combination with chemotherapy and we have therefore decided to continue our support of the Telovac trial."

In contrast to the PrimoVax study, Telovac is investigating combination gemcitabine and capecitabine therapy with concurrent and sequential chemo-immunotherapy using GV1001 in patients with locally-advanced or metastatic PC. It is hoped that these two different treatment schedules will provide information as to the best time to administer the vaccine. In addition, Pharmexa is not wholly shouldering the responsibility for the trial. The study is being supported by the UK National Cancer Research Institute (NCRI) and the Pancreas Cancer Sub-Group of the NCRI, and is funded by Cancer Research UK through the Liverpool Cancer Trials Unit. Pharmexa pays for vaccine for the study and a part of the costs related to monitoring and data collection.

Early immunomonitoring data in the Telovac trial has demonstrated the immunostimulation of the vaccine, supporting the choice of scheduling and confirming the notion that immune therapies will be maximally effective when combined with treatments that cause apoptosis, such as chemotherapy. Pharmexa will be hoping that this is the case, now that its eggs concerning GV1001 are firmly in one basket.

Matthew Dennis - Editor, Cancer Drug News