Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma

被引：143

作者：

Cloughesy, Timothy F. ^{[1
,2
]}

Landolfi, Joseph ^{[3
]}

Hogan, Daniel J. ^{[4
]}

Bloomfield, Stephen ^{[3
]}

Carter, Bob ^{[5
]}

Chen, Clark C. ^{[5
]}

Elder, J. Bradley ^{[6
]}

Kalkanis, Steven N. ^{[7
]}

Kesari, Santosh ^{[5
,13
]}

Lai, Albert ^{[1
,2
]}

Lee, Ian Y. ^{[7
]}

Liau, Linda M. ^{[1
,2
]}

Mikkelsen, Tom ^{[7
,14
]}

Nghiemphu, Phioanh Leia ^{[1
,2
]}

Piccioni, David ^{[5
]}

Walbert, Tobias ^{[7
]}

Chu, Alice ^{[4
]}

Das, Asha ^{[4
]}

Diago, Oscar R. ^{[4
]}

Gammon, Dawn ^{[4
]}

Gruber, Harry E. ^{[4
]}

Hanna, Michelle ^{[8
,9
]}

Jolly, Douglas J. ^{[4
]}

Kasahara, Noriyuki ^{[10
,11
]}

McCarthy, David ^{[8
]}

Mitchell, Leah ^{[4
]}

Ostertag, Derek ^{[4
]}

Robbins, Joan M. ^{[4
]}

Rodriguez-Aguirre, Maria ^{[4
]}

Vogelbaum, Michael A. ^{[12
]}

机构：

[1] Univ Calif Los Angeles, Dept Neurooncol, 710 Westwood Plaza, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Neurosurg, 710 Westwood Plaza, Los Angeles, CA 90095 USA

[3] John F Kennedy Med Ctr, New Jersey Neurosci Inst, 65 James St, Edison, NJ 08820 USA

[4] John F Kennedy Med Ctr, New Jersey Neurosci Inst, 65 James St, Edison, NJ 08820 USA

[5] Univ Calif San Diego, Moores Canc Ctr, Dept Neurosci, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA

[6] Ohio State Univ, Wexner Med Ctr, 410 West 10th Ave, Columbus, OH 43210 USA

[7] Henry Ford Hosp, 2799 West Grand Blvd, Detroit, MI 48202 USA

[8] Ribomed Biotechnol Inc, 3030 Bunker Hill St, San Diego, CA 92109 USA

[9] Univ Arizona, Ctr Canc, 1515 North Campbell Ave, Tucson, AZ 85724 USA

[10] Univ Miami, Miller Sch Med, Dept Cell Biol, Miami, FL 33136 USA

[11] Univ Miami, Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL 33136 USA

[12] Cleveland Clin Fdn, 9500 Euclid Ave, Cleveland, OH 44195 USA

[13] John Wayne Canc Inst, 2200 Santa Monica Blvd, Santa Monica, CA 90404 USA

[14] Ontario Brain Inst, 438 Univ Ave,Suite 1618, Toronto, ON M5G 2K8, Canada

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2016年 / 8卷 / 341期

关键词：

RETROVIRAL REPLICATING VECTOR; III RANDOMIZED-TRIAL; CYTOSINE DEAMINASE; TOCA; 511; GENE; GLIOBLASTOMA; 5-FLUOROURACIL; TEMOZOLOMIDE; LOMUSTINE; MGMT;

D O I：

10.1126/scitranslmed.aad9784

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Toca 511 (vocimagene amiretrorepvec) is an investigational nonlytic, retroviral replicating vector (RRV) that delivers a yeast cytosine deaminase, which converts subsequently administered courses of the investigational prodrug Toca FC (extended-release 5-fluorocytosine) into the antimetabolite 5-fluorouracil. Forty-five subjects with recurrent or progressive high-grade glioma were treated. The end points of this phase 1, open-label, ascending dose, multicenter trial included safety, efficacy, and molecular profiling; survival was compared to a matching subgroup from an external control. Overall survival for recurrent high-grade glioma was 13.6 months (95% confidence interval, 10.8 to 20.0) and was statistically improved relative to an external control (hazard ratio, 0.45; P = 0.003). Tumor samples from subjects surviving more than 52 weeks after Toca 511 delivery disproportionately displayed a survival-related mRNA expression signature, identifying a potential molecular signature that may correlate with treatment-related survival rather than being prognostic. Toca 511 and Toca FC show excellent tolerability, with RRV persisting in the tumor and RRV control systemically. The favorable assessment of Toca 511 and Toca FC supports confirmation in a randomized phase 2/3 trial (NCT02414165).

引用

页数：11

共 44 条

[1] Prognostic impact of MGMT promoter methylation and MGMT and CD133 expression in colorectal adenocarcinoma [J].

Antonio Oliver, Jaime ;

Ortiz, Raul ;

Melguizo, Consolacion ;

Juan Alvarez, Pablo ;

Gomez-Millan, Jaime ;

Prados, Jose .

BMC CANCER, 2014, 14

[2] Phase III Randomized Trial Comparing the Efficacy of Cediranib As Monotherapy, and in Combination With Lomustine, Versus Lomustine Alone in Patients With Recurrent Glioblastoma [J].

Batchelor, Tracy T. ;

Mulholland, Paul ;

Neyns, Bart ;

Nabors, L. Burt ;

Campone, Mario ;

Wick, Antje ;

Mason, Warren ;

Mikkelsen, Tom ;

Phuphanich, Surasak ;

Ashby, Lynn S. ;

DeGroot, John ;

Gattamaneni, Rao ;

Cher, Lawrence ;

Rosenthal, Mark ;

Payer, Franz ;

Juergensmeier, Juliane M. ;

Jain, Rakesh K. ;

Sorensen, A. Gregory ;

Xu, John ;

Liu, Qi ;

van den Bent, Martin .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (26) :3212-3218

[3] The Somatic Genomic Landscape of Glioblastoma [J].

Brennan, Cameron W. ;

Verhaak, Roel G. W. ;

McKenna, Aaron ;

Campos, Benito ;

Noushmehr, Houtan ;

Salama, Sofie R. ;

Zheng, Siyuan ;

Chakravarty, Debyani ;

Sanborn, J. Zachary ;

Berman, Samuel H. ;

Beroukhim, Rameen ;

Bernard, Brady ;

Wu, Chang-Jiun ;

Genovese, Giannicola ;

Shmulevich, Ilya ;

Barnholtz-Sloan, Jill ;

Zou, Lihua ;

Vegesna, Rahulsimham ;

Shukla, Sachet A. ;

Ciriello, Giovanni ;

Yung, W. K. ;

Zhang, Wei ;

Sougnez, Carrie ;

Mikkelsen, Tom ;

Aldape, Kenneth ;

Bigner, Darell D. ;

Van Meir, Erwin G. ;

Prados, Michael ;

Sloan, Andrew ;

Black, Keith L. ;

Eschbacher, Jennifer ;

Finocchiaro, Gaetano ;

Friedman, William ;

Andrews, David W. ;

Guha, Abhijit ;

Iacocca, Mary ;

O'Neill, Brian P. ;

Foltz, Greg ;

Myers, Jerome ;

Weisenberger, Daniel J. ;

Penny, Robert ;

Kucherlapati, Raju ;

Perou, Charles M. ;

Hayes, D. Neil ;

Gibbs, Richard ;

Marra, Marco ;

Mills, Gordon B. ;

Lander, Eric ;

Spellman, Paul ;

Wilson, Richard .

CELL, 2013, 155 (02) :462-477

[4]

Chamberlain Marc C, 2006, Neurosurg Focus, V20, pE19, DOI 10.3171/foc.2006.20.4.12

[5]

Chinot OL, 2014, NEW ENGL J MED, V370, P709, DOI 10.1056/NEJMoa1308345

[6] Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma? [J].

Clarke, Jennifer L. ;

Ennis, Michele M. ;

Yung, W. K. Alfred ;

Chang, Susan M. ;

Wen, Patrick Y. ;

Cloughesy, Timothy F. ;

DeAngelis, Lisa M. ;

Robins, H. Ian ;

Lieberman, Frank S. ;

Fine, Howard A. ;

Abrey, Lauren ;

Gilbert, Mark R. ;

Mehta, Minesh ;

Kuhn, John G. ;

Aldape, Kenneth D. ;

Lamborn, Kathleen R. ;

Prados, Michael D. .

NEURO-ONCOLOGY, 2011, 13 (10) :1118-1124

[7] The Proneural Molecular Signature Is Enriched in Oligodendrogliomas and Predicts Improved Survival among Diffuse Gliomas [J].

Cooper, Lee A. D. ;

Gutman, David A. ;

Long, Qi ;

Johnson, Brent A. ;

Cholleti, Sharath R. ;

Kurc, Tahsin ;

Saltz, Joel H. ;

Brat, Daniel J. ;

Moreno, Carlos S. .

PLOS ONE, 2010, 5 (09) :1-9

[8] Beyond oncolytic virotherapy: Replication-competent retrovirus vectors for selective and stable transduction of tumors [J].

Dalba, C ;

Klatzmann, D ;

Logg, CR ;

Kasahara, N .

CURRENT GENE THERAPY, 2005, 5 (06) :655-667

[9] Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents [J].

Esteller, M ;

Garcia-Foncillas, J ;

Andion, E ;

Goodman, SN ;

Hidalgo, OF ;

Vanaclocha, V ;

Baylin, SB ;

Herman, JG .

NEW ENGLAND JOURNAL OF MEDICINE, 2000, 343 (19) :1350-1354

[10] 5-Fluorouracil can cross brain-blood barrier and cause encephalopathy: should we expect the same from capecitabine? A case report on capecitabine-induced central neurotoxicity progressing to coma [J].

Formica, V ;

Leary, A ;

Cunningham, D ;

Chua, YJ .

CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2006, 58 (02) :276-278

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