A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

Humans Urinary Bladder / pathology BCG Vaccine / adverse effects Non-Muscle Invasive Bladder Neoplasms Administration, Intravesical Urinary Bladder Neoplasms / pathology Adjuvants, Immunologic Neoplasm Invasiveness / pathology Neoplasm Recurrence, Local / pathology
Bacillus Calmette-Guerin Bacillus Calmette-Guerin unresponsive Bladder cancer Clinical trial Durvalumab Non–muscle invasive PD-L1 Radiation Urothelial carcinoma

Journal

European urology
ISSN: 1873-7560
Titre abrégé: Eur Urol
Pays: Switzerland
ID NLM: 7512719

Informations de publication

Date de publication:
06 2023
Historique:
received: 30 07 2022
revised: 09 12 2022
accepted: 09 01 2023
pmc-release: 01 06 2024
medline: 15 5 2023
pubmed: 31 1 2023
entrez: 30 1 2023
Statut: ppublish

Résumé

Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). A multicenter phase 1 trial was conducted at community and academic sites. Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Sections du résumé

BACKGROUND
Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients.
OBJECTIVE
To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT).
DESIGN, SETTING, AND PARTICIPANTS
A multicenter phase 1 trial was conducted at community and academic sites.
INTERVENTION
Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates.
RESULTS AND LIMITATIONS
Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients.
CONCLUSIONS
D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches.
PATIENT SUMMARY
Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

Identifiants

DOI: 10.1016/j.eururo.2023.01.017 PMID: 36717286 PMC: PMC10192088
pubmed: 36717286
pii: S0302-2838(23)00025-8
doi: 10.1016/j.eururo.2023.01.017
pmc: PMC10192088
mid: NIHMS1870452
pii:
doi:

Substances chimiques

BCG Vaccine 0
durvalumab 28X28X9OKV
Adjuvants, Immunologic 0

Types de publication

Clinical Trial, Phase I Multicenter Study Journal Article Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

486-494

Subventions

Organisme : NCI NIH HHS
ID : K08 CA248967
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA006973
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA086862
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA235681
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186691
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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Auteurs

Noah M Hahn (NM)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA. Electronic address: nhahn4@jhmi.edu.

Michael A O'Donnell (MA)

University of Iowa Carver College of Medicine, Iowa City, IA, USA.

Jason A Efstathiou (JA)

Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.

Marianna Zahurak (M)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.

Gary L Rosner (GL)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.

Jeff Smith (J)

Hoosier Cancer Research Network, Indianapolis, IN, USA.

Max R Kates (MR)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.

Trinity J Bivalacqua (TJ)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Division of Urology and Urologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Phuoc T Tran (PT)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Radiation Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA.

Daniel Y Song (DY)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Radiation Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Alex S Baras (AS)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Andres Matoso (A)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Woonyoung Choi (W)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.

Kellie N Smith (KN)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Johns Hopkins Bloomberg Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.

Drew M Pardoll (DM)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Johns Hopkins Bloomberg Kimmel Institute for Cancer Immunotherapy, Baltimore, MD, USA.

Luigi Marchionni (L)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; Johns Hopkins University School of Medicine, Center for Computational Genomics, Baltimore, MD, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

Bridget McGuire (B)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.

Mary Grace Phelan (M)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.

Burles A Johnson (BA)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.

Tanya O'Neal (T)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.

David J McConkey (DJ)

Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA; The Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA; The James Buchanan Brady Urological Institute, Baltimore, MD, USA.

Tracy L Rose (TL)

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Division of Medical Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA.

Marc Bjurlin (M)

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Urology, University of North Carolina, Chapel Hill, NC, USA.

Emerson A Lim (EA)

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Spectrum Health Medical Group, Grand Rapids, MI, USA.

Charles G Drake (CG)

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Janssen Research and Development, Springhouse, PA, USA.

James M McKiernan (JM)

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Urology, Columbia University, New York, NY, USA.

Israel Deutsch (I)

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Radiation Oncology, Columbia University, New York, NY, USA.

Christopher B Anderson (CB)

Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Urology, Columbia University, New York, NY, USA.

Donald L Lamm (DL)

BCG Oncology, Phoenix, AZ, USA.

Daniel M Geynisman (DM)

Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Elizabeth R Plimack (ER)

Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Mark A Hallman (MA)

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Eric M Horwitz (EM)

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Essel Al-Saleem (E)

Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.

David Y T Chen (DYT)

Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Richard E Greenberg (RE)

Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Alexander Kutikov (A)

Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Gordon Guo (G)

Department of Radiation Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Timothy A Masterson (TA)

Department of Urology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

Nabil Adra (N)

Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

Hristos Z Kaimakliotis (HZ)

Department of Urology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Vessie urinaire › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › Mélanges complexes › Produits biologiques › Vaccins › Vaccins antibactériens › Vaccins antituberculeux › Vaccin BCG › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs de la vessie urinaire › Tumeurs de la vessie n'infiltrant pas le muscle › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Voies d'administration de substances chimiques et des médicaments › Administration par voie topique › Administration par voie vésicale › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs de la vessie urinaire › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Adjuvants immunologiques › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Invasion tumorale › A Phase 1 Trial of Durvalumab in Combination...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › A Phase 1 Trial of Durvalumab in Combination...