INTRODUCTION: PKC412 (formally CGP41251) selectively inhibits protein kinase C (PKC) isoforms and has been shown to be cytotoxic to malignant cells in vitro. We have undertaken a single centre, open-label, multi-dose, exploratory Phase II clinical trial of PKC412 in patients with CLL and low grade NHL. METHODS: Thirteen CLL patients and eight stage IV NHL patients were treated at three oral dose levels of 25, 150 and 225 mg/day for 14 days. RESULTS: There was a median decrease of 29.4% in the lymphocyte count in 11 out of 18 patients with circulating disease following treatment. Two NHL patients without circulating disease showed loss of immunophenotypic evidence of marrow disease and a third showed an improvement in blood counts and transfusion requirements. Adverse events were mostly gastrointestinal (16 patients) requiring little or no intervention. In nine patients there was an asymptomatic rise in serum amylase and/or transaminases. Asymptomatic hyperglycemia was also observed in eight patients. All returned to normal following cessation of treatment. In 14 out of 20 patients total PKC activity measured in peripheral blood and/or bone marrow lymphocytes was reduced during treatment to a mean of 54% of pre-treatment level. CONCLUSION: PKC412 is safe, well tolerated and reduces the tumor load in chronic B-cell malignancies. Inhibition of PKC offers a novel approach to the chemotherapy of B-cell malignancies.
INTRODUCTION: PKC412 (formally CGP41251) selectively inhibits protein kinase C (PKC) isoforms and has been shown to be cytotoxic to malignant cells in vitro. We have undertaken a single centre, open-label, multi-dose, exploratory Phase II clinical trial of PKC412 in patients with CLL and low grade NHL. METHODS: Thirteen CLLpatients and eight stage IV NHLpatients were treated at three oral dose levels of 25, 150 and 225 mg/day for 14 days. RESULTS: There was a median decrease of 29.4% in the lymphocyte count in 11 out of 18 patients with circulating disease following treatment. Two NHLpatients without circulating disease showed loss of immunophenotypic evidence of marrow disease and a third showed an improvement in blood counts and transfusion requirements. Adverse events were mostly gastrointestinal (16 patients) requiring little or no intervention. In nine patients there was an asymptomatic rise in serum amylase and/or transaminases. Asymptomatic hyperglycemia was also observed in eight patients. All returned to normal following cessation of treatment. In 14 out of 20 patients total PKC activity measured in peripheral blood and/or bone marrow lymphocytes was reduced during treatment to a mean of 54% of pre-treatment level. CONCLUSION: PKC412 is safe, well tolerated and reduces the tumor load in chronic B-cell malignancies. Inhibition of PKC offers a novel approach to the chemotherapy of B-cell malignancies.
Authors: Barbara Marengo; Chiara De Ciucis; Roberta Ricciarelli; Maria A Pronzato; Umberto M Marinari; Cinzia Domenicotti Journal: Cancers (Basel) Date: 2011-02-01 Impact factor: 6.639