Bryostatin by Intravenous Infusion in Advanced Cancer

Georgetown University, Washington DC

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Abstract

One unique property makes angiogenesis a promising target for the chemotherapy of malignant growth: In the adult the only physiologic conditions which require endothelial cell proliferatin are wound healing and the reproductive cycle. Endothelial cell proliferation in a growing primary tumor can thus be targeted with high selelctivity. Animal studies have given the best insight into the selective tumor-induced angiogenesis in vivo. In rats bearing experimental tumors, up to 80% of endothelial cells in the tumors incorporated 3H-thymidine in vivo. Less than 5% of endothelial cells in normal tissues of the same animals showed uptake o f the radiolabel. Polypeptide grwoth factors released from tumor cells are believed to trigger host endothelial responses and induce neoangiogenesis in the progressing tumor. It has been shown in numerous studies with different approaches, that a solid tumor can not grow beyond two millimeters in diameter without recruiting new blood vessels. The clinical significance of tumor angiogenesis and its close relation to overall prognosis and metastasis has been demonstrated in a recent study in breast cancer patients. This study showed that the number of stained microvessels in a given specimen was directly proportionate to metastatic progression of the respective tumor. Furthermore, local progression from normal tissue to carcinoma in situ and finally invasive tumors was reflected in an increase in stainable microvessels. The endothelial cell proliferation in tumors is thought to be induced by polypeptide growth factors. Amongst these, heparin-binding growth factors (HBGFs) from the FGF-family have been shown to be the most efficacious endothelial stimulators in vitro as well as inducers of angiogenesis in vivo. In addition, recently shown a novel HBGF, pleiotropin (PTN) is an endothelial cell stimulating factor expressed at high levels in cell lines from human melanoma, breast cancer and prostate cancer . This gene is unrelated to the FGF-family and was originally shown to be a developmentally regulated, heparin-binding, neurite growth factor. Receptors for these growth factors mediate their effects on the cell by signalling through pathways that PKC is involved in directly or indirectly. Therefore perturbing PKC activity by treatment with Bryostatin 1 might interfere with the signals that are responsible for neo-vascularization. The objectives of the present study are to determine the dose limiting toxicities, maximum tolerated dose and pharmacokinetics of Bryostatin when administered by continuous intravenous infusion for 96 to 168 hours every 2 weeks in patients with advanced, incurable malignancies. To measure levels of the active and latent forms of MMPs in the plasma of patients receiving Bryostatin. To measure PKC alpha levels in peripheral blood lymphocytes of patients receiving Bryostatin as an indirect measure of Bryostatin activity and pharmacokinetics. To document any objective antitumor responses that occur in patients treated on this protocol. Summary of accrual. 30 patients have been accrued. The initial 5 dose levels were completed as outlined in the original trial design. At dose level 5 (24mcg/m/day over 144 hours), 6 patients were accrued secondary to dose limiting myalgias. All 6 of the patients experienced some level of toxicity, primarily fatigue, nausea, myalgias, and anorexia. Because of this, we chose to deescalate the dose to 16mcg/m/day over 144 hours. This was better tolerated in the 3 patients accrued and therefore we extended the length of the infusion to 16 mcg/m/day over 168 hours. Two of the 3 patients accrued experienced grade 3 myalgias and was therefore above the maximum tolerated dose. Blood samples from all patients were analysed for all PKC isoforms. The only isoforms which has shown consistent changes in PBLs is PKC eta. At all dose levels, there is the consistent finding in most patients of an initial up regulation of PKC eta followed by a prolonged down regulation. The effect was seen for as long as the drug is administered. Given that our initial plan was to prolong the down regulation on PKC, we reasoned that we may be able to extend the length of the infusion longer than 168 hours if we used a lower dose. Thus the f inal amendment to this study is designed to address this issue.