Skip to main content
Erschienen in: Investigational New Drugs 4/2013

01.08.2013 | PHASE II STUDIES

A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer

verfasst von: Robert Dreicer, Jorge Garcia, Brian Rini, Nicholas Vogelzang, Sandy Srinivas, Bradley Somer, Peipei Shi, Marek Kania, Derek Raghavan

Erschienen in: Investigational New Drugs | Ausgabe 4/2013

Einloggen, um Zugang zu erhalten

Summary

Purpose Enzastaurin is an oral serine/threonine kinase inhibitor that inhibits the beta isoform of protein kinase C and which may have therapeutic activity in prostate cancer. We explored the efficacy of docetaxel/prednisone with or without enzastaurin in patients with castration-resistant metastatic prostate cancer. Methods A nonrandomized safety cohort consisting of 14 patients was followed by a double-blind randomized Phase II trial. Patients received standard doses of docetaxel (75 mg/m2) with prednisone 10 mg daily with or without 500 mg/day of enzastaurin. Results There was no difference in the objective response rate between the enzastaurin and placebo arms (placebo: 7 [15.2 %]; enzastaurin: 6 [15.0 %]; P = 1.00). The median PFS was 229 days for patients in the enzastaurin arm versus 213 days for the placebo arm (P = 0.524). The 1-year overall survival rates were almost identical, with 76.7 % and 75.1 % in the enzastaurin and placebo arms, respectively. Therapy was well tolerated although the combination of enzastaurin and docetaxel was more myelosuppressive than with docetaxel alone. Conclusions The clinical activity of docetaxel/prednisone plus enzastaurin cannot be distinguished from docetaxel/prednisone alone, given the limitations of a randomized Phase II design. Although the toxicity profile was favorable for the enzastaurin-containing regimen, there is no compelling rationale to move this combination forward for the treatment of castration-resistant metastatic prostate cancer.
Literatur
1.
Zurück zum Zitat Kantoff P, Higano C, Shore N et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422PubMedCrossRef Kantoff P, Higano C, Shore N et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422PubMedCrossRef
2.
Zurück zum Zitat de Bono J, Oudard S, Ozguroglu M et al. (2010) Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). J Clin Oncol 28 (Suppl 15):abstract 4508 de Bono J, Oudard S, Ozguroglu M et al. (2010) Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). J Clin Oncol 28 (Suppl 15):abstract 4508
3.
Zurück zum Zitat de Bono J, Logothetis C, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005PubMedCrossRef de Bono J, Logothetis C, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005PubMedCrossRef
4.
Zurück zum Zitat Scher H, Fizazi K, Saad F et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187–1197PubMedCrossRef Scher H, Fizazi K, Saad F et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187–1197PubMedCrossRef
5.
Zurück zum Zitat Tannock I, de Wit R, Berry W et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512PubMedCrossRef Tannock I, de Wit R, Berry W et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512PubMedCrossRef
6.
Zurück zum Zitat Berthold D, Pond G, Roessner M et al (2008) Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life, response and survival in the TAX-327 study. Clin Cancer Res 14:2763–2767PubMedCrossRef Berthold D, Pond G, Roessner M et al (2008) Treatment of hormone-refractory prostate cancer with docetaxel or mitoxantrone: relationships between prostate-specific antigen, pain, and quality of life, response and survival in the TAX-327 study. Clin Cancer Res 14:2763–2767PubMedCrossRef
7.
Zurück zum Zitat Kelly W, Halabi S, Carducci M et al (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30:1534–1540PubMedCrossRef Kelly W, Halabi S, Carducci M et al (2012) Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 30:1534–1540PubMedCrossRef
8.
Zurück zum Zitat Scher H, Jia X, Chi K et al (2011) Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol 29:2191–2198PubMedCrossRef Scher H, Jia X, Chi K et al (2011) Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. J Clin Oncol 29:2191–2198PubMedCrossRef
9.
Zurück zum Zitat Jarvis W, Grant S (1999) Protein kinase C targeting in antineoplastic treatment strategies. Invest New Drugs 17:227–240PubMedCrossRef Jarvis W, Grant S (1999) Protein kinase C targeting in antineoplastic treatment strategies. Invest New Drugs 17:227–240PubMedCrossRef
11.
Zurück zum Zitat Graff J, McNulty A, Hanna K 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 65:7462–7469PubMedCrossRef Graff J, McNulty A, Hanna K 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 65:7462–7469PubMedCrossRef
12.
Zurück zum Zitat Dreicer R, Garcia J, Hussain M et al (2011) Oral enzastaurin in prostate cancer: a two-cohort phase II trial in patients with PSA progression in the non-metastatic castrate state and following docetaxel-based chemotherapy for castrate metastatic disease. Invest New Drugs 29:1441–1448PubMedCrossRef Dreicer R, Garcia J, Hussain M et al (2011) Oral enzastaurin in prostate cancer: a two-cohort phase II trial in patients with PSA progression in the non-metastatic castrate state and following docetaxel-based chemotherapy for castrate metastatic disease. Invest New Drugs 29:1441–1448PubMedCrossRef
13.
Zurück zum Zitat Small E, Demkow T, Gerritsen W et al. (2009) A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer. In American Society of Clinical Oncology - Genitourinary Cancers Symposium 2009, Orlando, FL:abstract 7 Small E, Demkow T, Gerritsen W et al. (2009) A phase III trial of GVAX immunotherapy for prostate cancer in combination with docetaxel versus docetaxel plus prednisone in symptomatic, castration-resistant prostate cancer. In American Society of Clinical Oncology - Genitourinary Cancers Symposium 2009, Orlando, FL:abstract 7
14.
Zurück zum Zitat Chen Y, LaCasce A (2009) Enzastaurin. Expert Opin Investig Drugs 17:939–944CrossRef Chen Y, LaCasce A (2009) Enzastaurin. Expert Opin Investig Drugs 17:939–944CrossRef
15.
Zurück zum Zitat Wick W, Puduvalli, VK Chamberlain MC, et al. Phase III Study of Enzastaurin Compared With Lomustine in the Treatment of Recurrent Intracranial Glioblastoma. J Clin Oncol 28:1168-1174 Wick W, Puduvalli, VK Chamberlain MC, et al. Phase III Study of Enzastaurin Compared With Lomustine in the Treatment of Recurrent Intracranial Glioblastoma. J Clin Oncol 28:1168-1174
16.
Zurück zum Zitat Ysebaert L, Morschhauser F (2011) Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies. Expert Opin Investig Drugs 20:1167–1174, Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignanciesPubMedCrossRef Ysebaert L, Morschhauser F (2011) Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies. Expert Opin Investig Drugs 20:1167–1174, Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignanciesPubMedCrossRef
17.
Zurück zum Zitat Galanis E, Buckner JC (2010) Enzastaurin in the Treatment of Recurrent Glioblastoma: A Promise That Did Not Materialize. J Clin Oncol 28:1097–1098PubMedCrossRef Galanis E, Buckner JC (2010) Enzastaurin in the Treatment of Recurrent Glioblastoma: A Promise That Did Not Materialize. J Clin Oncol 28:1097–1098PubMedCrossRef
Metadaten
Titel
A randomized, double-blind, placebo-controlled, Phase II study with and without enzastaurin in combination with docetaxel-based chemotherapy in patients with castration-resistant metastatic prostate cancer
verfasst von
Robert Dreicer
Jorge Garcia
Brian Rini
Nicholas Vogelzang
Sandy Srinivas
Bradley Somer
Peipei Shi
Marek Kania
Derek Raghavan
Publikationsdatum
01.08.2013
Verlag
Springer US
Erschienen in
Investigational New Drugs / Ausgabe 4/2013
Print ISSN: 0167-6997
Elektronische ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-013-9940-0

Weitere Artikel der Ausgabe 4/2013

Investigational New Drugs 4/2013 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.