| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Urothelial carcinoma (UC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| UC is a type of cancer that typically occurs in the bladder |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To evaluate the efficacy of immunotherapy-based treatment combinations during Stage 1 based on Objective response rate |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of immunotherapy-based treatment combinations during Stage 1 based on progression-free survival, overall survival, overall survival rate, duration of response, disease control
•To evaluate the safety of immunotherapy-based treatment combinations during Stage 1
•To characterize the pharmacokinetic (PK) profile of drugs that are administered as part of an immunotherapy based treatment combination during Stage 1
•To evaluate the immune response to drugs that are administered as part of an immunotherapy-based treatment combination during Stage 1
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Stage 1
- Age >= 18 years
- Life expectancy >= 3 months, as determined by the investigator
- Histologically documented, locally advanced or metastatic UC (M1, Stage IV)
o Patients with mixed histologies are required to have a dominant transitional cell pattern
o Locally advanced bladder cancer must be inoperable on the basis of involvement of pelvic sidewall or adjacent viscera or bulky nodal
metastasis
- 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
Stage 1 and Stage 2
- Ability to comply with the study protocol, in the investigator's judgment
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Measurable disease according to Response Evaluation Criteria in Solid Tumors, Version 1.1
- Adequate hematologic and end-organ function
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen during the 14 days prior to Cycle (C) 1, Day (D) 1
- Negative HIV test at screening
- Negative total hepatitis B core antibody (HBcAb) test, or positive total HBcAb test followed by quantitative hepatitis B virus (HBV) DNA < 500 IU/mL and negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test 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 as outlined for each specific treatment arm - For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm
Stage 2
- Patients in the atezolizumab (Atezo) 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 Atezo 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 1 |
|
| E.4 | Principal exclusion criteria |
Stage 1
- Prior treatment with a T-cell co-stimulating therapy or an immune checkpoint inhibitor 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 any poly (ADP-ribose) polymerase inhibitor, nectin-4 targeting agents, signal regulatory protein α-targeting agents, or agents that block CD38
- Treatment with investigational therapy within 28 days prior to C1D1
- Any approved anti-cancer therapy within 3 weeks prior to initiation of study treatment
- Eligible only for the control arm
Stage 1 and Stage 2
- Prior allogeneic stem cell or solid organ transplantation
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug prior to the C1D1
- Treatment with systemic immunosuppressive medication within 2 weeks prior to C1D1, or anticipation of need for systemic immunosuppressant medication during study treatment
- Treatment with a live, attenuated vaccine within 4 weeks prior to C1D1, or anticipation of need for such a vaccine during Atezo treatment or within 5 months after the last dose of Atezo
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
- Uncontrolled tumor-related pain
- Uncontrolled or symptomatic hypercalcemia
- Symptomatic, untreated or actively progressing central nervous system metastases
- History of leptomeningeal disease
- Active or history of autoimmune disease, idiopathic pulmonary fibrosis, organizing pneumonia drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
- History of malignancy other than UC within 2 years prior to screening
- Active tuberculosis (TB)
- Severe infection within 4 weeks prior to C1D1
- Treatment with therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to C1D1
- Significant cardiovascular disease
- Grade >=3 hemorrhage or bleeding event within 28 days prior to C1D1
- Major surgical procedure, other than for diagnosis, within 4 weeks prior to C1D1, or anticipation of need for a major surgical procedure during study
- Adverse events from prior anti-cancer therapy that have not improved to Grade <=1 or better
- 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 Atezo during Stage 1
- Pregnancy or breastfeeding, or intention of becoming pregnant during the study
For Atezo- enfortumab vedotin (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 x ULN
- Evidence of active keratitis or corneal ulcerations during Stage 1 ophthalmologic examination prior to C1D1will be re-assigned to the control arm
- Patients entering Stage 2: evidence of active keratitis or corneal ulcerations during the Stage 2 ophthalmologic examination prior to C1D1
For Atezo- niraparib (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 RBCs transfused during the 4-week period prior to screening
- History of hemolytic anemia or Evans syndrome in last 3 months
For Atezo- linagliptin (Lina) Arm during Stage 1 and Stage 2
- Known diagnosis of Type 1 and Type 2 diabetes mellitus currently under treatment with DPP-4 inhibitor
- Inability to swallow medication or malabsorption condition that would alter absorption of orally administered medications
For Atezo- tocilizumab (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 or history of recurrence infections
- Active TB requiring treatment within 3 years prior to baseline and untreated latent TB
- Primary or secondary immunodeficiency |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Objective response rate |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival
2. Overall survival
3. Overall survival rate at specific time points
4. Duration of response
5. Disease control
6. Incidence, nature, and severity of adverse events and laboratory abnormalities, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0
7. Change from baseline in vital signs
8. Change from baseline in targeted clinical laboratory test results
9. Plasma or serum concentration of each drug at specified time points
10. For drugs for which anti-drug antibody (ADA) formation is measured: presence of ADAs during the study relative to the presence of ADAs at baseline
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-2. Up to 5 years
3. Up to 5 years (yearly)
4-6. Up to 5 years
7-8. Baseline (Day [D] 1, Cycle [C] 1) to 5 years
9-10. Atezo Control Arm, Atezo-EV Arm, Atezo+ Nira (Preliminary Phase): D1 of C 1, 2, 4, 8, 12, 16 + treatment discontinuation (TD) visit
Atezo-EV Arm (Expansion Phase): D1, 8 of C1, D1 of C2, 4, 8, 12, 16, TD visit
Atezo + Nira (Expansion Phase) and Atezo + Lina Arm: D1, 15 of C1; D1 of C2, 4, 8, 12, 16, TD visit
Atezo + Hu5F9-G4 Arm: D1, 8, 22 of C1; D1 of C2, 4, 8, 12, 16, TD visit
Atezo + isatuximab (Isa) Arm (Preliminary Phase): D1 of C1, 2, 4, 6, 8, 10, 12, 16, TD visit
Atezo + Isa Arm (Expansion Phase): D1, 8, 15 of C1; D1 of C2, 3, 4, 6, 8, 10, 12, 16, TD visit
Atezo + TCZ Arm: D1 of C1, 2, 4, 6, 8, 10, 12, 14, 16; every fourth cycle
after cycle 16, TD visit |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Korea, Republic of |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of this study is defined as the date when the last patient completes the last visit in both stages, including survival follow-up visits conducted by telephone or on-site visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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