Bladder Cancer, Urothelial Carcinoma
Conditions
Brief summary
A Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with MIBC and in participants with locally advanced or metastatic Urothelial Carcinoma (UC) who have progressed during or following a platinum-containing regimen. The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, or modify the participant population (e.g., with regard to prior anti-cancer treatment or biomarker status). Participants in the mUC Cohort who experience loss of clinical benefit or unacceptable toxicity during Stage 1 may be eligible to continue treatment with a different treatment regimen for Stage 2.
Interventions
DRUGAtezolizumab
For the control, + EV, + Nira, + Tira, and + SG arms, + RO7122290, Atezolizumab will be administered intravenously (IV) at a fixed dose of 1200 mg every 3 weeks (Q3W) on Day 1 of each 21-day cycle. For the Atezo + Hu5F9-G4 and + TCZ arms, Atezo will be administered IV at a fixed dose of 840 mg every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.
DRUGEnfortumab Vedotin
Enfortumab vedotin will be administered at a dose of 1.25 mg/kg IV on Days 1 and 8 of each 21-day cycle.
DRUGNiraparib
Niraparib will be administered at a dose of 200 mg once daily (QD) by mouth.
DRUGMagrolimab (Hu5F9-G4)
Participants will receive an 1-mg/kg priming dose IV on Day 1 followed by three weekly IV doses of 30 mg/kg on Days 8, 15, and 22. During Cycle 2, participants will receive weekly IV doses of 30 mg/kg on Days 1, 8, 15, and 22. For all subsequent cycles, participants will receive 30 mg/kg on Days 1 and 15. Cycle = 28 days.
DRUGTiragolumab
Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21-day cycle.
DRUGSacituzumab Govitecan
Sacituzumab Govitecan will be administered at a dose of 10 mg/kg by IV on Day 1 and 8 of each 21-day cycle.
DRUGTocilizumab
Tocilizumab will be administered by IV infusion at a dose of 8 mg/kg every 4 weeks (Q4W) on Day 1 of each 28-day cycle.
DRUGCisplatin
Cisplatin will be administered at a dose of 70mg/m\^2 by IV on Day 1 of each cycle for Cycles 1-3 pre-surgery.
DRUGGemcitabine
Gemcitabine will be administered at a dose of 1000mg/m\^2 by IV on Days 1 and 8 of each cycle for Cycles 1-3 pre-surgery.
Sponsors
Hoffmann-La Roche
Gilead Sciences, Inc., GlaxoSmithKline plc, Seattle Genetics and Astellas
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for mUC Cohort: * Histologically documented, locally advanced or metastatic UC (also termed TCC or urothelial cell carcinoma of the urinary tract; including renal pelvis, ureters, urinary bladder, and urethra) * Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status by means of central testing * Disease progression during or following treatment with no more than one platinum-containing regimen for inoperable, locally advanced or metastatic UC or disease recurrence * ECOG Performance Status of 0 or 1 * Measurable disease (at least one target lesion) according to RECIST v1.1 * Adequate hematologic and end-organ function * Negative HIV test at screening * Negative total hepatitis B core antibody (HBcAb) test and hepatitis C virus (HCV) antibody at screening * Tumor accessible for biopsy * For women of childbearing potential: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating eggs * For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm Inclusion Criteria for MIBC Cohorts: * ECOG PS of 0 or 1 * Fit and planned-for cystectomy * Histologically documented MIBC (pT2-4, N0, M0), also termed TCC or urothelial cell carcinoma of the urinary bladder * N0 or M0 disease by CT or MRI * Adequate hematologic and end-organ function * Availability of TURBT specimen * Negative HIV, HBcAb, and HCV test at screening * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating eggs as outlined for each specific treatment arm * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as outlined for each specific treatment arm
Exclusion criteria
for mUC Cohort: * Prior treatment with a T-cell co-stimulating therapy or a CPI including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies * Prior treatment with any of the protocol-specified study treatments including treatment with poly (adenosine diphosphate \[ADP\]-ribose) polymerase (PARP) inhibitor, nectin-4 targeting agents, signal regulatory protein alpha-targeting agents, or TIGIT-targeting agents, Trop-2 targeting agents, FAP-directed therapies, 4-1BB (CD137)-directed therapies, or topoisomerase 1 inhibitors * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment * Eligibility only for the control arm * Prior allogeneic stem cell or solid organ transplantation * Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment * Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressant medication during study treatment * Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Uncontrolled tumor-related pain * Uncontrolled or symptomatic hypercalcemia * Symptomatic, untreated, or actively progressing CNS metastases * History of leptomeningeal disease * Active or history of autoimmune disease or immune deficiency * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis * History of malignancy other than UC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death * Active tuberculosis * Severe infection within 4 weeks prior to initiation of study treatment * Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment * Significant cardiovascular disease * Uncontrolled hypertension * Grade 3 or greater hemorrhage or bleeding event within 28 days prior to initiation of study treatment * Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment * Pregnancy or breastfeeding, or intention of becoming pregnant during the study * Additional drug-specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 mUC Cohorts: Objective Response Rate (ORR) | Up to 61.5 months | ORR was defined as the percentage of participants with an objective response (OR), characterized by a complete response (CR) or a partial response (PR), on 2 consecutive occasions ≥ 4 weeks apart during Stage 1, as determined by the investigator per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target and non-target lesions and normalization of tumor marker level. Additionally, any pathological lymph nodes (whether target or non-target) must have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of all target lesions, taking as reference the baseline SOD, in the absence of CR. Percentages have been rounded off. |
| MIBC Cohorts: Pathological Complete Response (pCR) | Up to 17.8 months | pCR was defined as the percentage of participants with an absence of residual invasive cancer of the complete resected specimen. Percentages have been rounded off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Stage 1 mUC Cohorts: Progression-free Survival (PFS) After Randomization | From randomization to PD or death from any cause, whichever occurred first (up to 62 months) | PFS after randomization was defined as the time from randomization to the first occurrence of disease progression (PD) or death from any cause, whichever occurred first in Stage 1, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurred first. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. PFS for participants with no documented PD or death was censored at the day of the last tumor assessment. Kaplan-Meier (K-M) method was used to estimate the median PFS. |
| Stage 1 mUC Cohorts: Overall Survival (OS) After Randomization | From randomization to death from any cause (up to 69.1 months) | OS after randomization was defined as the time from randomization to death from any cause. Data for participants who had not died were censored at the last date they were known to be alive. K-M method was used to estimate the median OS. |
| Stage 1 mUC Cohorts: OS Rate at Month 12 | At Month 12 | OS rate at Month 12 was defined as percentage of participants who did not experience death from any cause at the specified timepoint. OS was defined as the time from randomization to death from any cause. K-M method was used to estimate OS rate. Percentages have been rounded off. |
| Stage 1 mUC Cohorts: Duration of Response (DOR) | From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to 61.5 months) | DOR was defined as the time from the first occurrence of a documented OR (CR or PR) during Stage 1 to PD or death from any cause during Stage 1, whichever occurred first, as determined by the investigator according to RECIST v1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Additionally, any lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. K-M method was used to estimate the median DOR. |
| Stage 1 mUC Cohorts: Disease Control Rate (DCR) | Up to 61.5 months | DCR was defined as percentage of participants with stable disease for ≥ 18 weeks or an OR (CR or PR) during Stage 1, as determined by the investigator according to RECIST v1.1. SD was defined as neither sufficient shrinkage of target lesions to qualify for CR or PR nor sufficient increase to qualify for PD. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker level. Additionally, any lymph nodes (whether target or non-target) must have a reduction in short axis to \< 10 mm. PR was defined as at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. Percentages have been rounded off. |
| Stages 1 and 2 mUC Cohorts: Number of Participants With Adverse Events (AEs) | Stage 1: Up to 62.1 months; Stage 2: Up to 18.3 months | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
| Stage 2 mUC [Atezo + EV Cohort]: Serum Concentration of Atezolizumab at Specified Timepoints | Predose: Day 1 of Cycles 1, 2 and 4; 30 minutes postdose: Day 1 Cycle 1 | — |
| Stage 2 mUC [Atezo + EV Cohort]: Number of Participants With Anti-drug Antibodies (ADAs) to Atezolizumab | Up to approximately 18.3 months | Participants were considered to be treatment-emergent ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following atezolizumab exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 0.60 titer unit (t.u.) greater than the baseline titer result (treatment-enhanced ADA response). Participants with a positive post-baseline sample have been reported here. |
| MIBC Cohorts: Landmark Recurrence-free Survival (RFS) Rate | At Months 12, 18, and 24 | Landmark RFS was defined as the percentage of participants who were alive without disease recurrence at specified timepoints following surgery. RFS was defined as the time from Day 1 in the first cycle after surgery to the first documented recurrence of disease or death from any cause. RFS rates at the specified landmark timepoints were estimated using the K-M method. |
| MIBC Cohorts: Landmark Event-free Survival (EFS) Rate | At Months 12, 18, and 24 | Landmark EFS was defined as the percentage of participants who were alive without experiencing a predefined event at specified timepoints. EFS was defined as the time from randomization to any of the following events, whichever occurred first: PD that precludes surgery, as assessed by the investigator; local or distant disease recurrence; or death from any cause. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on study (including baseline). Additionally, the SOD must also demonstrate an absolute increase of ≥ 5 mm or unequivocal progression of existing non-target lesions. EFS rates at the specified landmark timepoints were estimated using the K-M method. |
| MIBC Cohorts: Landmark OS Rate | At Months 12, 18, and 24 | Landmark OS was defined as the percentage of participants who were alive at specified timepoints. OS was defined as the time from randomization to death from any cause. OS rates at the specified landmark timepoints were estimated using the K-M method. |
| MIBC Cohorts: Number of Participants With AEs | Up to 17.8 months | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. |
Countries
France, Greece, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
A total of 272 participants with muscle-invasive bladder cancer (MIBC) or locally advanced or metastatic urothelial carcinoma (mUC) who had progressed during or following a platinum-containing regimen took part in the study across 7 countries from 01 June 2019 to 22 December 2025.
Pre-assignment details
Results include only those cohorts that enrolled participants; planned cohorts that were never opened for enrollment are not presented.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized Stage 1 85 years and over | 2 Participants |
| Age, Customized Stage 1 Adults (18-64 years) | 4 Participants |
| Age, Customized Stage 1 From 65-84 years | 44 Participants |
| Age, Customized Stage 2 85 years and over | 1 Participants |
| Age, Customized Stage 2 Adults (18-64 years) | 8 Participants |
| Age, Customized Stage 2 From 65-84 years | 21 Participants |
| Ethnicity (NIH/OMB) Stage 1 Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Stage 1 Not Hispanic or Latino | 27 Participants |
| Ethnicity (NIH/OMB) Stage 1 Unknown or Not Reported | 0 Participants |
| Ethnicity (NIH/OMB) Stage 2 Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Stage 2 Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Stage 2 Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Stage 1 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Stage 1 Asian | 51 Participants |
| Race (NIH/OMB) Stage 1 Black or African American | 0 Participants |
| Race (NIH/OMB) Stage 1 More than one race | 0 Participants |
| Race (NIH/OMB) Stage 1 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Stage 1 Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) Stage 1 White | 8 Participants |
| Race (NIH/OMB) Stage 2 American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Stage 2 Asian | 4 Participants |
| Race (NIH/OMB) Stage 2 Black or African American | 0 Participants |
| Race (NIH/OMB) Stage 2 More than one race | 0 Participants |
| Race (NIH/OMB) Stage 2 Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Stage 2 Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) Stage 2 White | 11 Participants |
| Sex: Female, Male Stage 1 Female | 5 Participants |
| Sex: Female, Male Stage 1 Male | 37 Participants |
| Sex: Female, Male Stage 2 Female | 4 Participants |
| Sex: Female, Male Stage 2 Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 30 | 13 / 15 | 8 / 16 | 8 / 15 | 7 / 12 | 9 / 15 | 19 / 31 | 10 / 15 | 1 / 6 | 2 / 11 | 8 / 23 | 17 / 47 | 5 / 18 | 2 / 18 | 11 / 15 | 12 / 15 |
| other Total, other adverse events | 29 / 29 | 14 / 15 | 14 / 15 | 15 / 15 | 11 / 12 | 14 / 15 | 30 / 30 | 14 / 15 | 6 / 6 | 11 / 11 | 22 / 23 | 41 / 46 | 18 / 18 | 16 / 17 | 15 / 15 | 15 / 15 |
| serious Total, serious adverse events | 11 / 29 | 9 / 15 | 8 / 15 | 7 / 15 | 9 / 12 | 9 / 15 | 12 / 30 | 8 / 15 | 5 / 6 | 6 / 11 | 14 / 23 | 35 / 46 | 10 / 18 | 10 / 17 | 8 / 15 | 10 / 15 |
Outcome results
None listed