Table 3.

Clinical trials combining immunotherapy and radiotherapy in localized urinary bladder cancer

Study	Phase	Status/estimated Enrollment	Eligibility	Intervention	Details	Outcomes measured
Immunotherapy with concurrent chemoradiation following TURBT (TMT)
NCT03775265 (SWOG/NRG-1806)	III	Recruiting 475	T2–T4a MIBC	Randomizing patients to chemoRT vs chemoRT and concurrent atezolizumab	Daily 3DCRT or IMRT over 7 weeks with concurrent chemotherapy (gemcitabine, cisplatin or 5FU/mytomycinc) at physician’s discretion Atezolizumab on day 1 of chemo and q3 weeks × 6 months	Primary: BI-EFS Secondary: OS, modified BI-EFS, biopsy, CR duration, PFS, MFS, CSS, QoL
NCT04241185 (MK-3475–992/KEYNOTE-992)	III	Recruiting 636 patients	T2–T4 N0M0 MIBC	Randomizing patients to pembrolizumab with CRT or CRT alone	Pembrolizumab q6 weeks + CRT at investigator’s choice RT: 64 Gy/32 to bladder only, 64 Gy/32 to bladder + pelvis or 55 Gy/25 fractions to bladder only Chemo: cisplatin, gemcitabine, 5FU, mytomycin-C	Primary: BI-EFS Secondary: OS, MFS, time to cystectomy, time to occurrence of NMIBC, AEs rate, tolerability, QoL and function outcomes
NCT02621151	II	Recruiting 54 patients	T2–T4a N0M0 MIBC	Pembrolizumab, gemcitabine, and hypofractionated RT	Lead-in single dose pembrolizumab then TURBT EBRT: 52 Gy/20 fractions + concurrent gemcitabine and pembrolizumab q3 weeks starting on day 1 of RT	Primary: 2 year BI-DFS Secondary: AEs, CR, OS, MFS
NCT03617913	II	Active, not recruiting 27 patients	T2–T4a N0M0 MIBC	Avelumab, RT and mitomycin-C/5FU or cisplatin chemotherapy	Avelumab q2 weeks × 10 cycles maximum, ChemoRT to start 29 days after avelumab	Primary: CR Secondary: AES, patient reported outcomes, PFS, RFS
NCT02662062 (PCR-MIB)	II	Recruiting 30 patients	T2–T4a N0M0 MIBC	Pembrolizumab, cisplatin and RT	RT: 64 Gy/32 fractions over 6 weeks with cisplatin given concurrently weekly Pembrolizumab given concurrently with RT q3 weeks	Primary: grade 3–4 AEs Secondary: best response, rate metastases, salvage cystectomy
NCT03620435	II	Closed 25 patients	T2–T4 N0M0 MIBC	Concurrent atezolizumab with gemcitabine and RT after TURBT (TMT)	Atezolizumab 1200 mg IV q3 weeks concurrently with TMT and adjuvant for up to one year IMRT: 50 Gy/20 fractions over 4 weeks Gemcitabine: 100 mg/m2 q week × 4 weeks	Primary: DLT in stage 1, safety (grade ≥ 3 iRAEs or TRAEs) Secondary: OS, CR, QoL
NCT03844256 (CRMI)	I/II	Recruiting 50 patients	T2–T4a N0–1, M0 MIBC	Nivolumab or nivolumab and ipilimumab with mytomycin-C/capecitabine concurrent chemoRT	RT: 40 Gy in 20 fractions with mytomycin-C/capecitabine Nivolumab q4 weeks vs nivolumab + ipilimumab q3 weeks	Primary: AEs, DLT, DFS, DFS rate Secondary: OS, OS rate, RR
NCT04216290 (INSPIRE)	I	Not yet recruiting 114 patients	Any T, N1–2, M0 MIBC	ChemoRT vs chemoRT + durvalumab	RT over 6–8 weeks Durvalumab and chemotherapy 4 days before or after RT start	Primary: clinical CR Secondary: MFS, BI-EFS, CSS, OS, PFS, CR duration, salvage cystecotmy rate, AEs
Combined immunotherapy and RT in the neoadjuvant setting
NCT03529890 (RACE-IT)	II	Recruiting 33 patients	cT3–4N0/ + MIBC	Neoadjuvant nivolumab with RT before radical cystectomy	Nivolumab q2 weeks, starting one week before RT RT: 45 Gy/5 fractions with 5, 4 Gy/3 boost Radical cystectomy with PLND at week 11–15	Primary: completion rate Secondary: AEs, DFS, OS, ORR, pCR, R0/R1/R2 rates
Combined immunotherapy and radiotherapy for patients ineligible for or refusing chemotherapy
NCT03421652 (NUTRA)	II	Recruiting 34 patients	T2–T4b N0/ + , M0 MIBC	Concurrent nivolumab and RT followed by nivolumab monotherapy	Nivolumab q2 weeks for up to 6 months RT to start on day 3, RT over 32–35 fractions on weeks 1, 3, 5, 7 and 9	Primary: PFS Secondary: AEs, ORR, MFS, OS, QoL, PD-1/PD-L1 expression, cytokines profile
NCT03747419	II	Recruiting 24 patients	T2–T4, N0M0 MIBC	Concurrent avelumab and RT	Avelumab q2 weeks with 6 doses with concurrent RT fractionation regimen at discretion of radiation oncologist	Primary: clinical CRR Secondary: OS, PFS, MFS, LRR, QoL
NCT03702179 (IMMUNO PRESERVE)	II	Recruiting 32 patients	Patients with localized MIBC treated with bladder preservation intent	Durvalumab + tremelimumab with concurrent RT	TURBT followed by durvalumab + tremelimumab q4 weeks for 3 cycles RT 2 weeks after initiation of IO and concurrently: 64–66 Gy to the bladder and 46 Gy to the pelvis	Primary: pathological response (≤ cT1) Secondary: bladder preservation rate, salvage cystectomy, BI-EFS, DFS, OS, AEs
NCT02891161 (DUART)	I/II	Active, not recruiting 42 patients	T2–4 N0–2, M0 MIBC	Concurrent durvalumab and RT followed by durvalumab monotherapy	Durvalumab × 2 doses q4 weeks concurrent with RT 64.8 Gy/36 fractions daily Adjuvant durvalumab to start 3–4 weeks post concurrent durvalumab and RT	Primary: DLT, PFS, disease control rate Secondary: CR, OS, PD-L1 expression
Adjuvant immunotherapy after TMT in patients ineligible for or refusing cystectomy
NCT03697850 (GETUG-35 BladderSpar)	II	Suspended due to the Covid-19 pandemic 77 patients	pT2–T3, MIBC	Adjuvant atezolizumab after TURBT and ChemoRT	Atezolizumab q3 weeks for 12 months beginning 30 days (± 5 days) after TURBT and chemoRT	Primary: DFS Secondary: LC, DFS, OS, AEs, QoL
NCT03171025 (NEXT)	II	Recruiting 28 patients	pT2–4a, N0/ + , M0 or T1N + MIBC	Adjuvant nivolumab after TURBT and ChemoRT	Nivolumab q4 weeks until disease recurrence or unacceptable toxicity for a maximum of 12 treatments	Primary: 2-year FFS Secondary: FFSIB, AEs, QoL, LC, distant FFS, OS
NCT03768570 (BL13)	II	Recruiting 238 patients	T2–T4a N0M0 MIBC	Randomizing patients treated with TMT to adjuvant durvalumab or surveillance	Bladder only: 64–66 Gy in 32–33 fractions; 50–55 Gy in 20 fractions using IMRT Pelvis and bladder: 45–46 Gy to pelvic nodes + 17–20 Gy bladder boost in 33–35 fractions Durvalumab w4 weeks for 12 months	Primary: DFS Secondary: RR, LRC, patters of recurrence, OS, BI-DFS, MFS, AEs, QoL, cost effectiveness

TMT trimodal therapy, TURBT transurethral resection of the bladder tumor, RT radiotherapy, chemoRT chemoradiotherapy, IO immunotherapy, PLND pelvic lymph node disseaction, MIBC muscle-invasive bladder cancer, RCC renal cell carcinoma, EBRT external beam radiotherapy, 3DCRT 3D conformal radiotherapy, IGRT image-guided radiotherapy, IMRT intensity modulated radiotherapy, SBRT stereotactic body radiotherapy, MTD maximum tolerated dose, AEs adverse events, irAEs immune related adverse events, TRAEs treatment-related adverse events, ORR overall response rate, CRR clinical response rate, PFS progression-free survival, OS overall survival, DFS disease-free survival, RFS recurrence-free survival, MFS metastasis-free survival, RR recurrence rate, LRC locoregional control, BI-EFS Bladder intact event-free survival, QoL quality of life