Phase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer

2006 ◽  
Vol 24 (25) ◽  
pp. 4092-4099 ◽  
Author(s):  
Michael A. Carducci ◽  
Luna Musib ◽  
Merrill S. Kies ◽  
Roberto Pili ◽  
Mylene Truong ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phase I ◽  
Advanced Cancer ◽  
Phase Ii ◽  
Dose Escalation ◽  
Stable Disease ◽  
Recommended Dose ◽  
Once Daily ◽  
Kinase C

Purpose This phase I study was conducted to determine the recommended dose of enzastaurin, an oral protein kinase C beta (PKCβ) inhibitor, for phase II trials. Secondary objectives were maximum-tolerated dose (MTD), pharmacokinetics (PK), toxicity, and response. Patients and Methods Patients at least 18 years of age with advanced cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 lower received enzastaurin orally once daily at a starting dose of 20 mg. Dose escalation proceeded using a modified Simon design. Results All 47 patients enrolled (mean age, 58 years) received at least one dose of enzastaurin, with a median of two cycles (range, one to 17 cycles). Prevalent malignancies were lung (n = 10) and head and neck cancers (n = 9). Although no MTD was identified up to 700 mg/d, 525 mg was chosen as the recommended dose, and 12 additional patients were accrued at that level. Three dose-limiting toxicities (QTc changes) occurred: one at the 700-mg dose (patient discontinued), and two in the expansion cohort at the 525-mg dose. Total analytes (enzastaurin and its metabolites) exposure increased with increasing doses up to 240 mg, and appeared to plateau at 525 and 700 mg. Grade 1 chromaturia, fatigue, and other GI toxicities were the most common, while no clinically significant grade 3/4 toxicities occurred. Two deaths, unrelated to enzastaurin, occurred. Twenty-one patients (45%) achieved stable disease (SD) for two to 16 cycles. Conclusion On the basis of plasma exposures and safety data, enzastaurin 525 mg once daily is the recommended phase II dose. Enzastaurin is well tolerated up to 700 mg/d. Evidence of early activity was seen with significant stable disease.

Expression, regulation, and function of P2X4purinergic receptor in human cervical epithelial cells

2002 ◽  
Vol 282 (1) ◽  
pp. C84-C93 ◽  
Author(s):  
George I. Gorodeski
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Epithelial Cells ◽  
Vitamin A ◽  
Phase I ◽  
Phase Ii ◽  
Calcium Influx ◽  
Receptor Mrna ◽  
Kinase C ◽  
Junctional Resistance

Micromolar concentrations of ATP stimulate biphasic change in transepithelial conductance across CaSki cultures on filters, an acute transient increase ( phase I response; triggered by P2Y2receptor and mediated by calcium mobilization-dependent cell volume decrease) followed by a slower decrease in permeability ( phase II response). Phase II response is mediated by augmented calcium influx and protein kinase C-dependent increase in tight junctional resistance. The objective of the study was to determine the role of P2X4receptor as a mediator of phase II response. Human cervical epithelial cells express P2X4receptor mRNA (1.4-, 2.2-, and 4.4-kb isoforms by Northern blot analysis) and P2X4protein. Depletion of vitamin A reversibly downregulated P2X4receptor mRNA and protein and ATP-induced calcium influx. Depletion of vitamin A abrogated phase II response, and the effect could be partially reversed only with retinoic acid receptor (RAR)-selective retinoids but not retinoid X receptor (RXR) agonists. Depletion of vitamin A also abrogated protein kinase C increase in tight junctional resistance, and the effect could not be reversed with retinoids. Depletion of vitamin A also abrogated phase I increase in permeability and reversibly downregulated P2Y2receptor mRNA and ATP-induced calcium mobilization. However, in contrast to phase II response, both RAR and RXR agonists could fully reverse those effects. These results suggest that phase IIresponse is mediated by a P2X4receptor mechanism.

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral Protein Kinase C β-Inhibitor Enzastaurin in Combination with Gemcitabine and Cisplatin in Patients with Advanced Cancer

2007 ◽  
Vol 13 (15) ◽  
pp. 4474-4481 ◽  
Author(s):  
Jeany M. Rademaker-Lakhai ◽  
Laurens V. Beerepoot ◽  
Niven Mehra ◽  
Sandra A. Radema ◽  
Rianne van Maanen ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phase I ◽  
Advanced Cancer ◽  
Kinase C ◽  
Pharmacodynamic Study ◽  
Gemcitabine And Cisplatin

Phase I dose-escalation study of the protein kinase C (PKC) inhibitor AEB071 in patients with metastatic uveal melanoma.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 9030-9030 ◽  
Author(s):  
Sophie Piperno-Neumann ◽  
Ellen Kapiteijn ◽  
James M. G. Larkin ◽  
Richard D. Carvajal ◽  
Jason J. Luke ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phase I ◽  
Uveal Melanoma ◽  
Dose Escalation ◽  
Dose Escalation Study ◽  
Pkc Inhibitor ◽  
Kinase C

A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3594-3594 ◽  
Author(s):  
S. K. Chia ◽  
K. N. Chi ◽  
C. Kollmannsberger ◽  
K. Paton ◽  
K. Bhagat ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Stable Disease ◽  
Dose Schedule ◽  
Recommended Dose ◽  
High Dose ◽  
Weekly Schedule ◽  
Advanced Stage ◽  
Minor Response ◽  
Daily Dose

3594 Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median Cmax, Tmax and AUC0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose. No significant financial relationships to disclose.

Phase I Trial of the Cyclin-Dependent Kinase Inhibitor and Protein Kinase C Inhibitor 7-Hydroxystaurosporine in Combination With Fluorouracil in Patients With Advanced Solid Tumors

2005 ◽  
Vol 23 (9) ◽  
pp. 1875-1884 ◽  
Author(s):  
Jeremy Kortmansky ◽  
Manish A. Shah ◽  
Andreas Kaubisch ◽  
Amanda Weyerbacher ◽  
Sandy Yi ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phase I ◽  
Peripheral Blood Mononuclear Cells ◽  
Mononuclear Cells ◽  
Cyclin Dependent Kinase ◽  
Peripheral Blood Mononuclear ◽  
Kinase C ◽  
Blood Mononuclear Cells ◽  
Protein Kinase C Inhibitor

Purpose Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. Patients and Methods FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m2 over 72 hours in cycle 1 and 67.5 mg/m2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. Results We escalated the weekly FU dose to 2,600 mg/m2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. Conclusion The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m2.

scholarly journals A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C ?, administered as a 21-day infusion to patients with advanced ovarian carcinoma

Cancer ◽  
2004 ◽  
Vol 100 (2) ◽  
pp. 321-326 ◽  
Author(s):  
Ranjana Advani ◽  
Prema Peethambaram ◽  
Bert L. Lum ◽  
George A. Fisher ◽  
Lynn Hartmann ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ovarian Carcinoma ◽  
Phase Ii ◽  
Antisense Oligonucleotide ◽  
Phase Ii Trial ◽  
Advanced Ovarian Carcinoma ◽  
Kinase C
Sign in / Sign up

Export Citation Format

Share Document