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Phase II clinical trial of pantoprazole and docetaxel for men with metastatic castration-resistant prostate cancer

Ian Tannock

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Canadian Institutes of Health Research (CIHR)
Men with metastatic prostate cancer commonly have tumours that have spread to lymph nodes and to their bones, and they frequently experience symptoms of tiredness and pain. Initial treatment is hormonal, with drugs that decrease the level and/or activity of male hormones such as testosterone that stimulate growth of most types of prostate cancer. Unfortunately men become resistant to hormonal therapy, and the standard treatment for most men is then chemotherapy with docetaxel (also known as Taxotere) given by vein every 3 weeks, together with daily oral prednisone. This treatment leads to a PSA response (a fall in level of serum PSA by >50%) in about half of the men, and it can also improve pain and quality of life. The treatment was found in a large randomised clinical trial (chaired by the current PI) to improve the average duration of survival as compared to an older type of chemotherapy. Several other clinical trials have tried to improve on these results by giving docetaxel and prednisone with other drugs (largely molecular targeted agents), but these trials have been negative. We have evidence from the laboratory that the commonly used anti-ulcer drug pantoprazole, when given in high doses by vein just before docetaxel, markedly increases the effects of docetaxel delay the re-growth of tumours grown from human tumour cell lines in immune-deficient mice, with minimal increase in toxicity. We have shown also that pantoprazole increases markers of drug activity in such tumours, and that it inhibits the process of autophagy, which is a survival mechanism for stressed cancer cells. Here we propose to evaluate this combination in a clinical trial for men with metastatic prostate cancer, who would normally receive treatment with docetaxel and prednisone alone. We will also investigate the correlation of PSA response (the primary outcome measure in our proposed clinical trial) with the levels of autophagy in the tumours of men that are treated.

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