Phase i study of enzastaurin and bevacizumab in patients with advanced cancer: Safety, efficacy and pharmacokinetics

Investigational New Drugs

Volumn 31, Issue 3, 2013, Pages 653-660

  Nwankwo, Nwabundo ^a   Zhang, Zhe ^a   Wang, Ting ^a   Collins, Connie ^a   Resta, Lee ^a   Ermisch, Sabine ^b   Day, Jeannette ^c   Decker, Rodney ^b   Kornberg, Lori ^c   Nicol, Steven ^b   Thornton, Donald ^b   Armstrong, Deborah K ^a   Carducci, Michael A ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b ELI LILLY AND COMPANY   (United States)

^c SYNEOS HEALTH   (United States)

Author keywords

Advanced cancer; Bevacizumab; Enzastaurin; Ovarian cancer; Phase I

Indexed keywords

BEVACIZUMAB; ENZASTAURIN; LY 326020; UNCLASSIFIED DRUG; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; GLYCOGEN SYNTHASE KINASE 3; GLYCOGEN SYNTHASE KINASE 3 BETA; INDOLE DERIVATIVE; MONOCLONAL ANTIBODY; PROTEIN KINASE INHIBITOR;

ABDOMINAL DISTENSION; ADULT; ADVANCED CANCER; AGED; ANOREXIA; ARTICLE; BLEEDING; BLOATING; BRAIN HEMORRHAGE; CANCER COMBINATION CHEMOTHERAPY; CANCER GROWTH; COHORT ANALYSIS; CONSTIPATION; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DIARRHEA; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG FATALITY; DRUG RESPONSE; DRUG SAFETY; DRUG SUBSTITUTION; FAILURE TO THRIVE; FATIGUE; FECES COLOR; FEMALE; FISTULA; GASTROINTESTINAL SYMPTOM; GENITAL SYSTEM DISEASE; GENITAL TRACT FISTULA; HEART INFARCTION; HEART VENTRICLE TACHYCARDIA; HUMAN; LOADING DRUG DOSE; LUNG EMBOLISM; LUNG HEMORRHAGE; MAJOR CLINICAL STUDY; MALE; MULTIPLE CYCLE TREATMENT; NAUSEA; OVARY CANCER; PAIN; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; SIDE EFFECT; THROMBOSIS; UPPER RESPIRATORY TRACT HEMORRHAGE; URINE COLOR; VOMITING; BLOOD; CLINICAL TRIAL; MIDDLE AGED; NEOPLASMS; TREATMENT OUTCOME; VERY ELDERLY; YOUNG ADULT;

ADULT; AGED; AGED, 80 AND OVER; ANGIOGENESIS INHIBITORS; ANTIBODIES, MONOCLONAL, HUMANIZED; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; FEMALE; GLYCOGEN SYNTHASE KINASE 3; HUMANS; INDOLES; MALE; MIDDLE AGED; NEOPLASMS; PROTEIN KINASE INHIBITORS; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84879106474     PISSN: 01676997     EISSN: 15730646     Source Type: Journal    
DOI: 10.1007/s10637-012-9850-6     Document Type: Article

References (19)

1. Faul MM, Gillig JR, Jirousek MR, et al. (2003) Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCbeta. Bioorg Med Chem Lett 13:1857-1859
2. Graff JR, McNulty AM, Hanna KR, et al. (2005) The protein kinase Cbeta-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 65:7462-7469
3. Keyes KA, Mann L, Sherman M, et al. (2004) LY317615 decreases plasma VEGF levels in human tumor xenograft-bearing mice. Cancer Chemother Pharmacol 53:133-140
4. Ferrara N, Hillan KJ, Gerber HP, et al. (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3:391-400
5. Carducci MA, Musib L, Kies MS, et al. (2006) Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase C beta inhibitor, in patients with advanced cancer. J Clin Oncol 24:4092-4099
6. Hanauske A-R, Lahn M, Musib LC, Weigang-Kohler K, et al. (2009) Phase 1b safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer. Ann Oncol 20:1565-1575
7. Kreisl TN, Kim L, Moore K, et al. (2009) A phase I trial of enzastaurin in patients with recurrent gliomas. Clin Cancer Res 15:3617-3623
8. Rademaker-Lakhai JM, Beerepoot LV, Mehra N, et al. (2007) Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer. Clin Cancer Res 13:4474-4481
9. Camidge DR, Gail ES, Gore L, et al. (2008) A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors. Anticancer Drugs 19:77-84
10. Burger RA, Sill MW, Monk BJ, et al. (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25:5165-5171
11. Therasse P, Arbuck SG, Eisenhauer EA, et al. (2000) 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 92:205-216
12. Gordon MS, Cunningham D (2005) Managing patients treated with bevacizumab combination therapy. Oncology 69(Suppl 3):25-33
13. Gordon MS, Margolin K, Talpaz M, et al. (2001) Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19:843-850
14. Wu JY, Wu XN, Ding L, et al. (2010) Phase I safety and pharmacokinetic study of bevacizumab in Chinese patients with advanced cancer. Chin Med J (Engl) 123:901-906
15. Shih T, Lindley C (2006) Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28:1779-1802
16. Moustakas A, Iwamoto FM, Kreisl TN, et al. (2010) Phase II trial of enzastaurin (Enz) with bevacizumab (BV) in adults with recurrent glioblastoma (GBM). J Clin Oncol 28(suppl): Abstract e12511
17. Cannistra SA, Matulonis UA, Penson RT, et al. (2007) Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180-5186
18. Usha L, Sill MW, Darcy KM, et al. (2011) A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol Oncol 121:455-461
19. Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339-345