Clinical Trial

. 2023 Jun;83(6):486-494.

doi: 10.1016/j.eururo.2023.01.017. Epub 2023 Jan 28.

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

Noah M Hahn¹, Michael A O'Donnell², Jason A Efstathiou³, Marianna Zahurak⁴, Gary L Rosner⁴, Jeff Smith⁵, Max R Kates⁶, Trinity J Bivalacqua⁷, Phuoc T Tran⁸, Daniel Y Song⁹, Alex S Baras¹⁰, Andres Matoso¹⁰, Woonyoung Choi⁶, Kellie N Smith¹¹, Drew M Pardoll¹¹, Luigi Marchionni¹², Bridget McGuire⁶, Mary Grace Phelan⁶, Burles A Johnson 3rd⁶, Tanya O'Neal⁴, David J McConkey⁶, Tracy L Rose¹³, Marc Bjurlin¹⁴, Emerson A Lim¹⁵, Charles G Drake¹⁶, James M McKiernan¹⁷, Israel Deutsch¹⁸, Christopher B Anderson¹⁷, Donald L Lamm¹⁹, Daniel M Geynisman²⁰, Elizabeth R Plimack²⁰, Mark A Hallman²¹, Eric M Horwitz²¹, Essel Al-Saleem²², David Y T Chen²³, Richard E Greenberg²³, Alexander Kutikov²³, Gordon Guo²⁴, Timothy A Masterson²⁵, Nabil Adra²⁶, Hristos Z Kaimakliotis²⁵

Affiliations

¹ 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.
² University of Iowa Carver College of Medicine, Iowa City, IA, USA.
³ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
⁴ Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
⁵ Hoosier Cancer Research Network, Indianapolis, IN, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Urology, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Spectrum Health Medical Group, Grand Rapids, MI, USA.
¹⁶ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Janssen Research and Development, Springhouse, PA, USA.
¹⁷ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Urology, Columbia University, New York, NY, USA.
¹⁸ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Radiation Oncology, Columbia University, New York, NY, USA.
¹⁹ BCG Oncology, Phoenix, AZ, USA.
²⁰ Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²¹ Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²² Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²³ Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²⁴ Department of Radiation Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
²⁵ Department of Urology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
²⁶ Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

PMID: 36717286
PMCID: PMC10192088
DOI: 10.1016/j.eururo.2023.01.017

Clinical Trial

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

Noah M Hahn et al. Eur Urol. 2023 Jun.

. 2023 Jun;83(6):486-494.

doi: 10.1016/j.eururo.2023.01.017. Epub 2023 Jan 28.

Authors

Affiliations

¹ 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.
² University of Iowa Carver College of Medicine, Iowa City, IA, USA.
³ Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
⁴ Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
⁵ Hoosier Cancer Research Network, Indianapolis, IN, USA.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA; Department of Urology, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Spectrum Health Medical Group, Grand Rapids, MI, USA.
¹⁶ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Janssen Research and Development, Springhouse, PA, USA.
¹⁷ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Urology, Columbia University, New York, NY, USA.
¹⁸ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA; Department of Radiation Oncology, Columbia University, New York, NY, USA.
¹⁹ BCG Oncology, Phoenix, AZ, USA.
²⁰ Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²¹ Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²² Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²³ Department of Urology, Fox Chase Cancer Center, Philadelphia, PA, USA.
²⁴ Department of Radiation Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA; University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
²⁵ Department of Urology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
²⁶ Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA.

PMID: 36717286
PMCID: PMC10192088
DOI: 10.1016/j.eururo.2023.01.017

Abstract

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.

Keywords: Bacillus Calmette-Guerin; Bacillus Calmette-Guerin unresponsive; Bladder cancer; Clinical trial; Durvalumab; Non–muscle invasive; PD-L1; Radiation; Urothelial carcinoma.

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Conflict of interest statement

Financial disclosures: Noah M. Hahn certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Noah Hahn discloses consulting compensation from AstraZeneca, Merck, Genentech, GlaxoSmithKline, Ferring, Champions Oncology, Health Advances, Keyquest Health, Guidepoint Global, Seattle Genetics, Mirati, Incyte, TransMed, CicloMed, Janssen, Pfizer, Boehringer Ingelheim, EMD Serono, Verity Pharmaceuticals, and Astellas Pharma; research support to the institution from HTG Molecular Diagnostics, AstraZeneca, Bristol Myers-Squibb, Genentech, Seattle Genetics, Pieris, Inovio, Principia Biopharm, and Incyte; and speaker honoraria from Creative Educational Concepts and Large Urology Group Practice Association. Michael O’Donnell discloses consulting compensation from Fidia, Merck, Photocure, Theralase, Urogen, and Vaxiion. Jason Efstathiou discloses consulting and advisory board compensation from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Pfizer, Progencis, Merck, Roviant Pharma, Myovant Sciences, Janssen, and Bayer Healthcare. Max Kates discloses consulting compensation from Genesis Biotech, Janssen, Pacific Edge, and FerGene. Phuoc Tran discloses research funding from Astellas Pharm, Bayer Healthcare, and RefleXion Medial Inc.; personal fees for consulting from RefleXion, Janssen-Taris Biomedical, Myovant, and AstraZeneca outside the submitted work; and has a patent 9114158—Compounds and methods of use in ablative radiotherapy, licensed to Natsar Pharm. Andres Matoso discloses consulting compensation from PathAI. Burles A. Johnson III discloses consulting compensation from Seattle Genetics. Burles A. Johnson III, Noah Hahn, and David McConkey are coauthors on a provisional US patent for an immunebased biomarker to predict response to immunotherapy in patients with advanced bladder cancer. Tracy Rose receives research funding from GeneCentric Therapeutics, Genentech/Hoffman-La Roche, Bristol-Myers Squibb, and Merck. Charles G. Drake is a paid employee of Janssen, Inc. Elizabeth Plimack discloses consulting compensation from Astellas, AstraZeneca, Aveo, Bristol Myers-Squibb, Calithera, EMD Serono, Exelexis, Flatiron, Genentech, IMV, Janssen, MEI, Merck, Natera, Pfizer, Regeneron, and Seattle Genetics; research support to the institution from Astellas, Bristol MyersSquibb, Genentech, and Merck; and speaker honoraria from ACHL, Bioascend, Cancer Therapy Advisor, Clinical Care Options, Creative Educational Solutions, CUA, ASCO Genitourinary Cancers Symposium, JADPRO Bladder, Medscape, NCCN, OncLive, Platform Q, Peak Medicals Gmbh, PER, Research to Practice, Spire Learning, Springer, Total CME, and the University of Hawaii. Nabil Adra discloses consulting compensation from Merck, Exelixis, Bristol Myers-Squibb, Sanofi-Aventis, and Aveo, and research support to the institution from Genentech, Exelixis, Merck, and Bristol Myers-Squibb.

Figures

**Fig. 1 –**
Study CONSORT diagram. BCG = bacillus Calmette-Guerin; CT = computed tomography; EBRT = external beam radiation therapy; TURBT = transurethral resection of bladder tumor. ^a One patient who required BCG dose reduction due to BCG supply shortage was included in the safety and response evaluations, but replaced with an additional patient to ensure that 12 patients were evaluable for dose limiting toxicity.

See this image and copyright information in PMC

Comment in

ADAPT and Improvise: Overcoming Bacillus Calmette-Guérin Unresponsiveness in Non-muscle-invasive Bladder Cancer.
Maitre P, Sangar V, Choudhury A. Maitre P, et al. Eur Urol. 2023 Jun;83(6):495-496. doi: 10.1016/j.eururo.2023.02.018. Epub 2023 Mar 9. Eur Urol. 2023. PMID: 36898871 No abstract available.

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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

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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

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