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 Identifier:
WO39613
CT.gov Identifier:
EudraCT Identifier:
EU Trial (CTIS) Number:
Study Contact Information:
N/A
Study Complete
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Study Summary
To evaluate the efficacy and safety of multiple immunotherapy-based treatment combinations in patients with locally advanced or metastatic urothelial carcinoma after failure with platinum-containing chemotherapy
To evaluate Hu5F9-G4 with atezolizumab in patients with urothelial cancer.
Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
I/II
Sex
Female & Male
Age
18+ years
Study Drug
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Study Status
Indicates the current recruitment status or the expanded access status
Study Complete
Requirements information
Inclusion criteria
- Age >=18 years
- Life expectancy >= 3 months, as determined by the investigator
- Ineligible for cisplatin-based chemotherapy
- Histologically documented, locally advanced or metastatic UC (M1, Stage IV)
- 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
- Patients in the atezolizumab control arm: ability to initiate Stage 2 treatment within 3 months after loss of clinical benefit as determined by the investigator while receiving control treatment
- Patients in an experimental arm during Stage 1: ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
- Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage
- 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
- 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
- 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
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
- Adverse events from prior anti-cancer therapy that have not improved to Grade <=1 or better, with the exception of alopecia of any grade and Grade <=2 peripheral neuropathy
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug
- History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
- Known intolerance or hypersensitivity to any of the study drugs or their excipients and any of the drugs required for premedication
- Patients entering Stage 2: inability to tolerate atezolizumab during Stage 1
- Pregnancy or breastfeeding, or intention of becoming pregnant during the study
- Patients entering Stage 2: recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent
- For Atezo-EV Arm during Stage 1 and Stage 2
- Ongoing sensory or motor neuropathy Grade >= 2
- Active keratitis or corneal ulcerations
- Uncontrolled diabetes
- AST or ALT >= 3.0 × ULN
- Evidence of active keratitis or corneal ulcerations during the Stage 1 and 2 ophthalmologic examination prior to Cycle 1, Day 1 will be re-assigned to the control arm and Atezo-Lina arm
- For Atezo-Nira Arm during Stage 1
- Inability to swallow medication or a malabsorption condition that would alter the absorption of orally administered medications
- Patients with uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, or superior vena cava syndrome
- For Atezo-Hu5F9-G4 Arm during Stage 1
- RBC transfusion dependence, defined as requiring more than 2 units of red blood cells transfused during the 4-week period prior to screening
- History of hemolytic anemia or Evans syndrome in the last 3 months
- For Atezo-Lina Arm during Stage 1 and Stage 2
- Known diagnosis of Type 1 diabetes mellitus and Type 2 diabetes mellitus currently under treatment with DPP-4 inhibitor
- Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
- For Atezo-TCZ Arm during Stage 1
- Preexisting central nervous system demyelinating or seizure disorders
- History of diverticulitis, diverticulosis requiring antibiotic treatment, or other symptomatic lower gastrointestinal conditions that might predispose to perforations
- Current liver disease unrelated to the underlying cancer diagnosis
- Active current infection
- Active TB requiring treatment within 3 years prior to baseline and untreated latent TB
- Primary or secondary immunodeficiency
- 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.
Clinical Study Information for Healthcare Providers
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Study Locations
Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Recruitment Complete
Condition(s) Treated at Site
Urinary tract
Bladder