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

Bladder Cancer Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03869190
• Other study ID #: WO39613
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 1, 2019
• Est. completion date: November 27, 2027

Study information

• Verified date: May 2024
• Source: Hoffmann-La Roche
• Contact: Reference Study ID Number: WO39613 https://forpatients.roche.com
• Phone: 888-662-6728 (U.S. Only)
• Email: global-roche-genentech-trials[@]gene.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 645
• Est. completion date: November 27, 2027
• Est. primary completion date: December 6, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bladder Cancer
• Carcinoma
• Carcinoma, Transitional Cell
• Urothelial Carcinoma

Intervention

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.
• 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.
• Niraparib
Niraparib will be administered at a dose of 200 mg once daily (QD) by mouth.
• 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.
• Tiragolumab
Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21-day cycle.
• 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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
France	Centre Francois Baclesse; Pharmacie	Caen
France	Centre Leon Berard	Lyon
France	Institut régional du Cancer Montpellier	Montpellier
France	Institut Claudius Regaud; Radiotherapie	Toulouse
France	Gustave Roussy Cancer Campus	Villejuif
Greece	Alexandras General Hospital of Athens; Oncology Department	Athens
Greece	Athens Medical Center; Dept. of Oncology	Athens
Greece	Attiko Hospital University of Athens; 2Nd Dept. of Propaedeutic Medicine	Athens
Greece	University Hospital of Patras Medical Oncology	Patras
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital; Yonsei Cancer Center; Yonsei University College of Medicine	Seoul
Spain	Hospital Clinic i Provincial; Servicio de Neurologia	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Vall d?Hebron Institute of Oncology (VHIO), Barcelona	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	ICO I Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet ICO	L?Hospitalet De Llobregat	Barcelona
Spain	Hospital General Universitario Gregorio Mara	Madrid
Spain	Hospital Univ 12 de Octubre	Madrid
Spain	Hospital Universitario Fundacion Jimenez Diaz.	Madrid
Spain	MD Anderson Cancer Center	Madrid
Spain	START Madrid. Centro Integral Oncologico Clara Campal; CIOCC	Madrid
Spain	Clinica Universitaria de Navarra	Pamplona	Navarra
Spain	Complejo Hospitalario Universitario de Santiago (CHUS) ; Intermedios y Urgencias Pediatricas	Santiago de Compostela	LA Coruña
Spain	Hospital Clinico Universitario de Valencia	Valencia
Taiwan	National Taiwan University Hospital, Yun-Lin Branch	Huwei Township
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung City
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	Taipei Veterans General Hospital	Taipei City
United Kingdom	Barts and The London	London
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	Churchill Hospital; Pharmacy Clinical Trials Office, Pharmacy Department	Oxford
United Kingdom	Royal Marsden NHS Foundation Trust	Sutton
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Memorial Sloan-Kettering Cancer Center	Commack	New York
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	UCLA Department of Medicine	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Stanford Cancer Center	Palo Alto	California
United States	UCSF Comprehensive Cancer Ctr	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Gilead Sciences, Inc., GlaxoSmithKline plc, Seattle Genetics and Astellas

Countries where clinical trial is conducted

United States,  France,  Greece,  Korea, Republic of,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate (ORR) for mUC Cohort Stage 1	Objective response rate, defined as the proportion of participants with a CR or PR on two consecutive occasions >=4 weeks apart during Stage 1, as determined by the investigator according to RECIST v1.1.	Baseline until disease progression or loss of clinical benefit (approximately 5-7 years)
Primary	pCR for Muscle Invasive Bladder Cancer (MIBC) Cohorts	pCR, defined as the proportion of participants with an absence of residual invasive cancer of the complete resected specimen.	Randomization to approximately 5-7 years
Secondary	Progression Free Survival (PFS) for mUC Cohort Stage 1	PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first) in Stage 1, as determined by the investigator according to RECIST v1.1.	Randomization until the first occurrence of disease progression or death from any cause, which ever occurs first, through the end of study (approximately 5-7 years) as determined by the investigator according to RECIST 1.1
Secondary	Overall Survival (OS) for mUC Cohort Stage 1	OS after randomization,defined as the time from randomization to death from any cause.	Randomization to death from any cause, through the end of study (approximately 5-7 years)
Secondary	Overall Survival (at specific time-points) for mUC Cohort Stage 1	OS rate at specific timepoints, defined as the proportion of patients who have not experienced death from any cause at that timepoint.	12 months
Secondary	Duration of Response (DOR) for mUC Cohort Stage 1	DOR, defined as the time from the first occurrence of a documented objective response during Stage 1 to disease progression or death from anycause (whichever occurs first), as determined by the investigator according to RECIST v1.1.	Randomization until first occurrence of a documented objective response to the first recorded occurrence of disease progression or death from any cause (whichever occurs first), through end of study (approximately 5-7 years)
Secondary	Disease Control Rate (DCR) for mUC Cohort Stage 1	Disease control, defined as stable disease >= 18 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1.	Baseline through end of study (approximately 5-7 years)
Secondary	Percentage of Participants with Adverse Events for mUC Cohort Stage 1		Baseline to end of study (approximately 5-7 years)
Secondary	Serum Concentration of Atezolizumab for mUC Cohort Stage 2		At pre-defined intervals from first administration of study drug up to approximately 5-7 years
Secondary	Serum Concentration of Enfortumab Vedotin for mUC Cohort Stage 2		At pre-defined intervals from first administration of study drug up to approximately 5-7 years
Secondary	Serum Concentration of Sacituzumab Govitecan for mUC Cohort Stage 2		At pre-defined intervals from first administration of study drug up to approximately 5-7 years
Secondary	Presence of ADAs to Atezolizumab for mUC Cohort Stage 2	For drugs for which ADA formation is measured: presence of ADAs during the study relative to the presence of ADAs at baseline.	Baseline to approximately 5-7 years
Secondary	Percentage of Participants with Adverse Events for mUC Cohort Stage 2		Baseline to end of study (approximately 5-7 years)
Secondary	Landmark Recurrence-Free Survival (RFS) for MIBC Cohorts	Landmark RFS, defined as RFS at specific timepoints.	12, 18, 24 months
Secondary	Landmark Event-Free Survival (EFS) for MIBC Cohorts	Landmark EFS, defined as EFS at specific timepoints.	12, 18, 24 months
Secondary	Landmark Overall Survival (OS) for MIBC Cohorts	Landmark OS, defined as OS at specific timepoints.	12, 18, 24 months
Secondary	Percentage of Participants with Adverse Events for MIBC Cohorts		Baseline to approximately 5-7 years