Clinical trial NCT03869190: Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatments and Combinations in Patients With Urothelial Carcinoma (MORPHEUS-UC)
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Urothelial Carcinoma
Bladder Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Gilead Sciences, Inc., GlaxoSmithKline plc, Seattle Genetics and Astellas
First posted: 2019-03-11
Enrollment: 272
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Objective Response Rate (ORR) for mUC Cohort Stage 1
timeFrame: Baseline until disease progression or loss of clinical benefit (approximately 5-7 years)
measure: pCR for Muscle Invasive Bladder Cancer (MIBC) Cohorts
timeFrame: Randomization to approximately 5-7 years
Secondary outcomes:
measure: Progression Free Survival (PFS) for mUC Cohort Stage 1
timeFrame: 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
measure: Overall Survival (OS) for mUC Cohort Stage 1
timeFrame: Randomization to death from any cause, through the end of study (approximately 5-7 years)
measure: Overall Survival (at specific time-points) for mUC Cohort Stage 1
timeFrame: 12 months
measure: Duration of Response (DOR) for mUC Cohort Stage 1
timeFrame: 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)
measure: Disease Control Rate (DCR) for mUC Cohort Stage 1
timeFrame: Baseline through end of study (approximately 5-7 years)
measure: Percentage of Participants with Adverse Events for mUC Cohort Stage 1
timeFrame: Baseline to end of study (approximately 5-7 years)
measure: Serum Concentration of Atezolizumab for mUC Cohort Stage 2
timeFrame: At pre-defined intervals from first administration of study drug up to approximately 5-7 years
measure: Serum Concentration of Enfortumab Vedotin for mUC Cohort Stage 2
timeFrame: At pre-defined intervals from first administration of study drug up to approximately 5-7 years
measure: Serum Concentration of Sacituzumab Govitecan for mUC Cohort Stage 2
timeFrame: At pre-defined intervals from first administration of study drug up to approximately 5-7 years
measure: Presence of ADAs to Atezolizumab for mUC Cohort Stage 2
timeFrame: Baseline to approximately 5-7 years
measure: Percentage of Participants with Adverse Events for mUC Cohort Stage 2
timeFrame: Baseline to end of study (approximately 5-7 years)
measure: Landmark Recurrence-Free Survival (RFS) for MIBC Cohorts
timeFrame: 12, 18, 24 months
measure: Landmark Event-Free Survival (EFS) for MIBC Cohorts
timeFrame: 12, 18, 24 months
measure: Landmark Overall Survival (OS) for MIBC Cohorts
timeFrame: 12, 18, 24 months
measure: Percentage of Participants with Adverse Events for MIBC Cohorts
timeFrame: Baseline to approximately 5-7 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Department of Medicine
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Ctr
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Commack
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Caen
country: France
facility: Centre Francois Baclesse
city: Lyon
country: France
facility: Centre Leon Berard
city: Montpellier
country: France
facility: Institut régional du Cancer Montpellier
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Athens
country: Greece
facility: Attiko Hospital University of Athens
city: Athens
country: Greece
facility: Athens Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: L?Hospitalet De Llobregat
country: Spain
facility: ICO I Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet ICO
state: Barcelona
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago (CHUS)
state: LA Coruna
city: Pamplona
country: Spain
facility: Clinica Universitaria de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Vall d?Hebron Institute of Oncology (VHIO), Barcelona
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Cordoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Mara
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Madrid
country: Spain
facility: Hospital Universitario Fundacion Jimenez Diaz.
city: Madrid
country: Spain
facility: Hospital Univ 12 de Octubre
city: Madrid
country: Spain
facility: START Madrid. Centro Integral Oncologico Clara Campal
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Kaohsiung City
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
city: London
country: United Kingdom
facility: Barts and The London
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Foundation Trust
Study officials:
References: