A novel treatment approach for low grade lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C.
BACKGROUND
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.


CONCLUSIONS
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.
Department of Haematology, The Royal Free & University College School of Medicine, Royal Free Campus, University College, London, UK. Andres.Virchis@barnet-chase-tr.nhs.uk
Andres
A
Virchis
Kanagasabai
K
Ganeshaguru
Steve
S
Hart
Dylan
D
Jones
Linda
L
Fletcher
Faith
F
Wright
Ranmohan
R
Wickremasinghe
Anthony
A
Man
Katalin
K
Csermak
Thomas
T
Meyer
Doriano
D
Fabbro
Kate
K
Champain
Alan
A
Yap
H Grant
HG
Prentice
Atul
A
Mehta
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D019311:Staurosporine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity
D000970:Antineoplastic Agents; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin