Phase I dose escalation and pharmacokinetic study of oral enzastaurin (LY317615) in advanced solid tumors

Cancer Science

Volumn 101, Issue 10, 2010, Pages 2193-2199

  Mukohara, Toru ^a,c   Nagai, Shunji ^a   Koshiji, Minori ^b   Yoshizawa, Kenichi ^b   Minami, Hironobu ^a,c  

^a NATIONAL CANCER CENTER HOSPITAL EAST   (Japan)

^b ELI LILLY AND COMPANY   (United States)

^c KOBE UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ALBUMIN; ENZASTAURIN; FLUORODEOXYGLUCOSE F 18; LSN 2406799; LY 326020; LY 485912; PROTEIN KINASE C; UNCLASSIFIED DRUG; INDOLE DERIVATIVE; PROTEIN KINASE INHIBITOR;

ABNORMAL FECES; ADULT; ADVANCED CANCER; AGED; ALBUMIN BLOOD LEVEL; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; ARTICLE; BILE DUCT CARCINOMA; BLADDER CANCER; BRAIN TUMOR; BREAST CANCER; CANCER GROWTH; CANCER OF UNKNOWN PRIMARY SITE; CHROMATURIA; CLINICAL ARTICLE; CLINICAL TRIAL; DISEASE SEVERITY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; FATIGUE; FEMALE; GASTROINTESTINAL STROMAL TUMOR; HEMATURIA; HUMAN; HUMAN TISSUE; JAPANESE; KIDNEY CANCER; LARGE INTESTINE CANCER; LEIOMYOSARCOMA; LIPOSARCOMA; LUNG NON SMALL CELL CANCER; LYMPHOCYTE COUNT; LYMPHOCYTOPENIA; MALE; MALIGNANT NEOPLASM OF RETROMOLAR AREA; MALIGNANT NEOPLASM OF URACHUS; MALIGNANT NEOPLASTIC DISEASE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MESOTHELIOMA; MULTIPLE CYCLE TREATMENT; PHASE 1 CLINICAL TRIAL; PLEURA MESOTHELIOMA; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; QT PROLONGATION; RASH; RECOMMENDED DRUG DOSE; RECTUM CANCER; SIDE EFFECT; SOLID TUMOR; SOMNOLENCE; STOMACH CANCER; THYROID TUMOR; TIME TO MAXIMUM PLASMA CONCENTRATION; TREATMENT DURATION; TREATMENT RESPONSE; URINARY TRACT DISEASE; DRUG EFFECTS; ELECTROCARDIOGRAPHY; MIDDLE AGED; NEOPLASMS; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; ADULT; AGED; ELECTROCARDIOGRAPHY; FEMALE; HUMANS; INDOLES; MALE; MAXIMUM TOLERATED DOSE; MIDDLE AGED; NEOPLASMS; PROTEIN KINASE INHIBITORS;

EID: 77957026074     PISSN: 13479032     EISSN: 13497006     Source Type: Journal    
DOI: 10.1111/j.1349-7006.2010.01677.x     Document Type: Article

References (15)

1. Graff JR, McNulty AM, Hanna KR. The protein kinase Cß-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 2005, 65:7462-9.
2. Clark AS, West KA, Blumberg PM, Dennis PA. Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCdelta promotes cellular survival and chemotherapeutic resistence. Cancer Res 2003, 63:780-6.
3. Shipp MA, Ross KN, Tamayo P. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med 2002, 8:68-74.
4. McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist 2000, 5(Suppl 1):3-10.
5. Balendran A, Hare GR, Kieloch A, Williams MR, Alessi DR. Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett 2000, 484:217-23.
6. Partovian C, Simons M. Regulation of protein kinase B/Akt activity and Ser473 phosphorylation by protein kinase Calpha in endothelial cells. Cell Signal 2004, 16:951-7.
7. Wu E, Aguiar R, Savage K. PKCbeta: a rational therapeutic target in diffuse large B-cell lymphoma. Blood 2002, 100:202a.
8. Rossi RM, Henn AD, Conkling R. The PKCbeta selective inhibitor, enzastaurin (LY317615), inhibits growth of human lymphoma cells. Blood 2005, 106:427a.
9. Liu Y, Su W, Thompson EA, Leitges M, Murray NR, Fields AP. Protein kinase CbetaII regulates its own expression in rat intestinal epithelial cells and the colonic epithelium in vivo. J Biol Chem 2004, 279:45556-63.
10. Keyes K, Cox K, Treadway P. An in vitro tumor model: analysis of angiogenic factor expression after chemotherapy. Cancer Res 2002, 62:5597-602.
11. Carducci MA, Musib L, Kies MS. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 2006, 24:4092-9.
12. Welch PA, Sinha VP, Cleverly AL, Darstein C, Flanagan SD, Musib LC. Safety, tolerability, QTc evaluation, and pharmacokinetics of single and multiple doses of enzastaurin HCl (LY317615), a protein kinase C-beta inhibitor, in healthy subjects. J Clin Pharmacol 2007, 47:1138-51.
13. Therasse P, Arbuck SG, Eisenhauer EA. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000, 92:205-16.
14. Strevel EL, Ing DJ, Siu LL. Molecularly targeted oncology therapeutics and prolongation of the QT interval. J Clin Oncol 2007, 25:3362-33671.
15. Robertson MJ, Kahl BS, Vose JM. Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2007, 25:1741-6.