Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC)

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC)

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.

Study Overview

• Status: Terminated
• Conditions: Bladder Cancer; Urothelial Carcinoma
• Intervention / Treatment: Drug: Atezolizumab; Drug: Enfortumab Vedotin; Drug: Niraparib; Drug: Tiragolumab; Drug: Sacituzumab Govitecan; Drug: Tocilizumab; Drug: Cisplatin; Drug: Gemcitabine; Drug: Magrolimab (Hu5F9-G4)

• Study Type: Interventional
• Enrollment (Actual): 272
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Caen, France, 14076
    • Centre François Baclesse
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Montpellier, France, 34298
    • Institut Régional du Cancer Montpellier
  • Toulouse, France, 31052
    • Institut Claudius Regaud
• Greece
  • Athens, Greece, 12462
    • Attiko Hospital University of Athens
  • Athens, Greece, 151 25
    • Athens Medical Center
• South Korea
  • Seoul, South Korea, 03080
    • Seoul National University Hospital
  • Seoul, South Korea, 05505
    • Asan Medical Center
  • Seoul, South Korea, 120-749
    • Severance Hospital
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial
  • Barcelona, Spain, 08035
    • Vall d?Hebron Institute of Oncology (VHIO), Barcelona
  • Barcelona, Spain, 08908
    • Institut Catala d Oncologia Hospitalet
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Madrid, Spain, 28033
    • MD Anderson Cancer Center
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz.
  • Madrid, Spain, 28050
    • START Madrid. Centro Integral Oncologico Clara Campal
  • Madrid, Spain, 28041
    • Hospital Univ 12 de Octubre
  • Madrid, Spain, 28009
    • Hospital General Universitario Gregorio Mara
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • LA Coruna
    • Santiago de Compostela, LA Coruna, Spain, 15706
      • Complejo Hospitalario Universitario de Santiago (CHUS)
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Clinica Universitaria de Navarra
• Taiwan
  • Kaohsiung City, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
• United Kingdom
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90024
      • UCLA Department of Medicine
    • San Francisco, California, United States, 94115
      • UCSF Comprehensive Cancer Ctr
    • Stanford, California, United States, 94305-5820
      • Stanford Cancer Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40241
      • Norton Cancer Institute
  • New York
    • Commack, New York, United States, 11725
      • Memorial Sloan-Kettering Cancer Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106-1716
      • University Hospitals Cleveland Medical Center
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 exclusion criteria might apply

Exclusion for MIBC Cohorts:

• Prior treatment with systemic immunostimulatory agents prior to the initiation of study treatment
• Eligibility only for the control arm
• Prior allogeneic stem cell or solid organ transplantation
• 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, with the following exceptions: Patients who received acute, low-dose, systemic immunosuppressant medications, or a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after Medical Monitor approval has been obtained. Patients who received mineralocorticoids, corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• Severe infection within 4 weeks prior to initiation of study treatment
• Pregnancy or breastfeeding, or intention of becoming pregnant during the study
• Also includes all the mUC exclusion criteria

Additional Exclusion Criteria for Atezo+Tira and Atezo (Atezolizumab) +Tira+Cis (Cisplatin)+Gem (Gemcitabine) in the MIBC Cohorts:

- Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening.

Additional Exclusion Criteria for the Cisplatin-Eligible MIBC Cohort:

• Patients who decline neoadjuvant cisplatin-based chemotherapy or in whom neoadjuvant cisplatin-based therapy is not appropriate.
• Impaired renal function.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

16

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atezolizumab for mUC Cohort (Stage 1); Participants will receive atezolizumab until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.
Experimental: Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 1); Participants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Enfortumab 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.
Experimental: Atezolizumab + Niraparib for mUC Cohort (Stage 1); Participants will receive atezolizumab and Niraparib (Nira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Niraparib; Niraparib will be administered at a dose of 200 mg once daily (QD) by mouth.
Experimental: Atezolizumab + Tiragolumab for mUC Cohort (Stage 1); Participants will receive atezolizumab and Tiragolumab (Tira) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Tiragolumab; Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21-day cycle.
Experimental: Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 1); Participants will receive atezolizumab and Sacituzumab Govitecan (SG) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Sacituzumab 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.
Experimental: Atezolizumab + Tocilizumab for mUC Cohort (Stage 1); Participants will receive atezolizumab and Tocilizumab (TCZ) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Tocilizumab; 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.
Experimental: Atezolizumab + RO7122290 for mUC Cohort (Stage 1); Participants will receive atezolizumab and RO7122290 until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.
Experimental: Atezolizumab + Enfortumab Vedotin for mUC Cohort (Stage 2); Participants will receive atezolizumab and Enfortumab Vedotin (EV) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Enfortumab 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.
Experimental: Atezolizumab + Sacituzumab Govitecan for mUC Cohort (Stage 2); Participants will receive atezolizumab and Sacituzumab Govitecan (SG) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Sacituzumab 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.
Experimental: Atezolizumab + Magrolimab for mUC Cohort (Stage 1); Participants will receive atezolizumab and magrolimab (Hu5F9-G4) until unacceptable toxicity or loss of clinical benefit, as determined by the investigator after an integrated assessment of radiographic and biochemical data, local biopsy results (if available), and clinical status. Enrollment is closed.	Drug: Atezolizumab; 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.; Drug: Magrolimab (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.
Active Comparator: Atezolizumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 1; Participants will receive Atezolizumab for 3 cycles pre-surgery and 14 cycles post-surgery.	Drug: Atezolizumab; 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.
Experimental: Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 1 PD-L1+ Arm 2; Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.	Drug: Atezolizumab; 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.; Drug: Tiragolumab; Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21-day cycle.
Active Comparator: Atezolizumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 1; Participants will receive Atezolizumab for 3 cycles pre-surgery and 14 cycles post-surgery.	Drug: Atezolizumab; 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.
Experimental: Atezolizumab + Tiragolumab for Cisplatin-ineligible MIBC Cohort 2 PD-L1- Arm 2; Participants will receive Atezolizumab and Tiragolumab (Tira) for 3 cycles pre-surgery and 14 cycles post-surgery.	Drug: Atezolizumab; 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.; Drug: Tiragolumab; Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21-day cycle.
Active Comparator: Cisplatin-eligible MIBC Cohort 3 Arm 1; Participants will receive 3 cycles of Atezolizumab, Cisplatin, and Gemcitabine pre-surgery and 14 cycles of Atezolizumab only post-surgery.	Drug: Atezolizumab; 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.; Drug: Cisplatin; 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.; Drug: Gemcitabine; 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.
Experimental: Cisplatin-eligible MIBC Cohort 3 Arm 2; Participants will receive Atezolizumab, Tiragolumab (Tira), Cisplatin and Gemcitabine for 3 cycles pre-surgery and 14 cycles of Atezolizumab and Tiragolumab (Tira) post-surgery.	Drug: Atezolizumab; 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.; Drug: Tiragolumab; Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21-day cycle.; Drug: Cisplatin; 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.; Drug: Gemcitabine; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1 mUC Cohorts: Objective Response Rate (ORR)	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.	Up to 61.5 months
MIBC Cohorts: Pathological Complete Response (pCR)	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.	Up to 17.8 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1 mUC Cohorts: Progression-free Survival (PFS) After Randomization	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.	From randomization to PD or death from any cause, whichever occurred first (up to 62 months)
Stage 1 mUC Cohorts: Overall Survival (OS) After Randomization	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.	From randomization to death from any cause (up to 69.1 months)
Stage 1 mUC Cohorts: OS Rate 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.	At Month 12
Stage 1 mUC Cohorts: Duration of Response (DOR)	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.	From first occurrence of a documented OR to PD or death from any cause, whichever occurred first (up to 61.5 months)
Stage 1 mUC Cohorts: Disease Control Rate (DCR)	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.	Up to 61.5 months
Stages 1 and 2 mUC Cohorts: Number of Participants With Adverse Events (AEs)	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 1: Up to 62.1 months; Stage 2: Up to 18.3 months
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	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.	Up to approximately 18.3 months
MIBC Cohorts: Landmark Recurrence-free Survival (RFS) Rate	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.	At Months 12, 18, and 24
MIBC Cohorts: Landmark Event-free Survival (EFS) Rate	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.	At Months 12, 18, and 24
MIBC Cohorts: Landmark OS Rate	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.	At Months 12, 18, and 24
MIBC Cohorts: Number of Participants With AEs	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.	Up to 17.8 months

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Collaborators: Gilead Sciences, Inc., GlaxoSmithKline plc, Seattle Genetics and Astellas

Publications and helpful links

General Publications

• Drakaki A, Powles T, Bamias A, Martin-Liberal J, Shin SJ, Friedlander T, Tosi D, Park C, Gomez-Roca C, Joly Lobbedez F, Castellano D, Morales-Barrera R, Moreno-Candilejo I, Flechon A, Yuen K, Rishipathak D, DuPree K, Young F, Michielin F, Shemesh CS, Steinberg EE, Williams P, Lee JL. Atezolizumab plus Magrolimab, Niraparib, or Tocilizumab versus Atezolizumab Monotherapy in Platinum-Refractory Metastatic Urothelial Carcinoma: A Phase Ib/II Open-Label, Multicenter, Randomized Umbrella Study (MORPHEUS Urothelial Carcinoma). Clin Cancer Res. 2023 Nov 1;29(21):4373-4384. doi: 10.1158/1078-0432.CCR-23-0798.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2019
• Primary Completion (Actual): October 8, 2025
• Study Completion (Actual): December 22, 2025

Study Registration Dates

• First Submitted: March 8, 2019
• First Submitted That Met QC Criteria: March 8, 2019
• First Posted (Actual): March 11, 2019

Study Record Updates

• Last Update Posted (Actual): August 3, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Urologic Neoplasms; Carcinoma; Urinary Bladder Diseases; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Platinum Compounds; Gemcitabine; Cisplatin; tocilizumab; niraparib; atezolizumab; enfortumab vedotin; Tiragolumab; sacituzumab govitecan; magrolimab
• Other Study ID Numbers: WO39613

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No