Intravesical rAd–IFNa/Syn3 for patients with high-grade, bacillus calmette-guerin–refractory or relapsed non–muscle-invasive bladder cancer: A phase II randomized study

Neal D. Shore, Stephen A. Boorjian, Daniel J. Canter, Kenneth Ogan, Lawrence I. Karsh, Tracy M. Downs, Leonard G. Gomella, Ashish M. Kamat, Yair Lotan, Robert S. Svatek, Trinity Bivalacqua, Robert L. Grubb, Tracey L. Krupski, Seth P. Lerner, Michael E. Woods, Brant A. Inman, Matthew I. Milowsky, Alan Boyd, F. Peter Treasure, Gillian GregoryDavid G. Sawutz, Seppo Yla-Herttuala, Nigel R. Parker, Colin P.N. Dinney

Research output: Contribution to journalArticle

Abstract

Purpose Many patients with high-risk non–muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd–IFNa/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study (ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd–IFNa/ Syn3 (randomly assigned 1:1 to 1 3 1011 viral particles (vp)/mL or 3 3 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd–IFNa/Syn3 (1 3 1011 vp/mL, n = 21; 3 3 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd–IFNa/ Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd—IFNa/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.

Original languageEnglish (US)
Pages (from-to)3410-3416
Number of pages7
JournalJournal of Clinical Oncology
Volume35
Issue number30
DOIs
StatePublished - Oct 20 2017

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Urinary Bladder Neoplasms
Interferon-alpha
Adenoviridae
Bacillus
Mycobacterium bovis
Recurrence
Virion
Nocturia
Therapeutics
Safety
Dysuria
Patient Transfer
Survival
Urination
Cystectomy
Hematuria
Drug-Related Side Effects and Adverse Reactions
Fatigue
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Intravesical rAd–IFNa/Syn3 for patients with high-grade, bacillus calmette-guerin–refractory or relapsed non–muscle-invasive bladder cancer : A phase II randomized study. / Shore, Neal D.; Boorjian, Stephen A.; Canter, Daniel J.; Ogan, Kenneth; Karsh, Lawrence I.; Downs, Tracy M.; Gomella, Leonard G.; Kamat, Ashish M.; Lotan, Yair; Svatek, Robert S.; Bivalacqua, Trinity; Grubb, Robert L.; Krupski, Tracey L.; Lerner, Seth P.; Woods, Michael E.; Inman, Brant A.; Milowsky, Matthew I.; Boyd, Alan; Treasure, F. Peter; Gregory, Gillian; Sawutz, David G.; Yla-Herttuala, Seppo; Parker, Nigel R.; Dinney, Colin P.N.

In: Journal of Clinical Oncology, Vol. 35, No. 30, 20.10.2017, p. 3410-3416.

Research output: Contribution to journalArticle

Shore, ND, Boorjian, SA, Canter, DJ, Ogan, K, Karsh, LI, Downs, TM, Gomella, LG, Kamat, AM, Lotan, Y, Svatek, RS, Bivalacqua, T, Grubb, RL, Krupski, TL, Lerner, SP, Woods, ME, Inman, BA, Milowsky, MI, Boyd, A, Treasure, FP, Gregory, G, Sawutz, DG, Yla-Herttuala, S, Parker, NR & Dinney, CPN 2017, 'Intravesical rAd–IFNa/Syn3 for patients with high-grade, bacillus calmette-guerin–refractory or relapsed non–muscle-invasive bladder cancer: A phase II randomized study', Journal of Clinical Oncology, vol. 35, no. 30, pp. 3410-3416. https://doi.org/10.1200/JCO.2017.72.3064
Shore, Neal D. ; Boorjian, Stephen A. ; Canter, Daniel J. ; Ogan, Kenneth ; Karsh, Lawrence I. ; Downs, Tracy M. ; Gomella, Leonard G. ; Kamat, Ashish M. ; Lotan, Yair ; Svatek, Robert S. ; Bivalacqua, Trinity ; Grubb, Robert L. ; Krupski, Tracey L. ; Lerner, Seth P. ; Woods, Michael E. ; Inman, Brant A. ; Milowsky, Matthew I. ; Boyd, Alan ; Treasure, F. Peter ; Gregory, Gillian ; Sawutz, David G. ; Yla-Herttuala, Seppo ; Parker, Nigel R. ; Dinney, Colin P.N. / Intravesical rAd–IFNa/Syn3 for patients with high-grade, bacillus calmette-guerin–refractory or relapsed non–muscle-invasive bladder cancer : A phase II randomized study. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 30. pp. 3410-3416.
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title = "Intravesical rAd–IFNa/Syn3 for patients with high-grade, bacillus calmette-guerin–refractory or relapsed non–muscle-invasive bladder cancer: A phase II randomized study",
abstract = "Purpose Many patients with high-risk non–muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd–IFNa/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study (ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd–IFNa/ Syn3 (randomly assigned 1:1 to 1 3 1011 viral particles (vp)/mL or 3 3 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd–IFNa/Syn3 (1 3 1011 vp/mL, n = 21; 3 3 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0{\%}; 90{\%} CI, 22.6{\%} to 49.2{\%}) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd–IFNa/ Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40{\%}), dysuria (n = 16; 40{\%}), fatigue (n = 13; 32.5{\%}), pollakiuria (n = 11; 28{\%}), and hematuria and nocturia (n = 10 each; 25{\%}). Conclusion rAd—IFNa/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.",
author = "Shore, {Neal D.} and Boorjian, {Stephen A.} and Canter, {Daniel J.} and Kenneth Ogan and Karsh, {Lawrence I.} and Downs, {Tracy M.} and Gomella, {Leonard G.} and Kamat, {Ashish M.} and Yair Lotan and Svatek, {Robert S.} and Trinity Bivalacqua and Grubb, {Robert L.} and Krupski, {Tracey L.} and Lerner, {Seth P.} and Woods, {Michael E.} and Inman, {Brant A.} and Milowsky, {Matthew I.} and Alan Boyd and Treasure, {F. Peter} and Gillian Gregory and Sawutz, {David G.} and Seppo Yla-Herttuala and Parker, {Nigel R.} and Dinney, {Colin P.N.}",
year = "2017",
month = "10",
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doi = "10.1200/JCO.2017.72.3064",
language = "English (US)",
volume = "35",
pages = "3410--3416",
journal = "Journal of Clinical Oncology",
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}

TY - JOUR

T1 - Intravesical rAd–IFNa/Syn3 for patients with high-grade, bacillus calmette-guerin–refractory or relapsed non–muscle-invasive bladder cancer

T2 - A phase II randomized study

AU - Shore, Neal D.

AU - Boorjian, Stephen A.

AU - Canter, Daniel J.

AU - Ogan, Kenneth

AU - Karsh, Lawrence I.

AU - Downs, Tracy M.

AU - Gomella, Leonard G.

AU - Kamat, Ashish M.

AU - Lotan, Yair

AU - Svatek, Robert S.

AU - Bivalacqua, Trinity

AU - Grubb, Robert L.

AU - Krupski, Tracey L.

AU - Lerner, Seth P.

AU - Woods, Michael E.

AU - Inman, Brant A.

AU - Milowsky, Matthew I.

AU - Boyd, Alan

AU - Treasure, F. Peter

AU - Gregory, Gillian

AU - Sawutz, David G.

AU - Yla-Herttuala, Seppo

AU - Parker, Nigel R.

AU - Dinney, Colin P.N.

PY - 2017/10/20

Y1 - 2017/10/20

N2 - Purpose Many patients with high-risk non–muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd–IFNa/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study (ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd–IFNa/ Syn3 (randomly assigned 1:1 to 1 3 1011 viral particles (vp)/mL or 3 3 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd–IFNa/Syn3 (1 3 1011 vp/mL, n = 21; 3 3 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd–IFNa/ Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd—IFNa/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.

AB - Purpose Many patients with high-risk non–muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd–IFNa/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study (ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd–IFNa/ Syn3 (randomly assigned 1:1 to 1 3 1011 viral particles (vp)/mL or 3 3 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd–IFNa/Syn3 (1 3 1011 vp/mL, n = 21; 3 3 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd–IFNa/ Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd—IFNa/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.

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