| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously Untreated Locally Advanced or Metastatic Urothelial Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Urothelial Cancer is common type of cancer that has spread outside of the bladder to other parts of the body, this causes back pain, painful urination, frequent urination, and blood in urine. |
|
| 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 | 10046714 |
| E.1.2 | Term | Urothelial carcinoma bladder |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 tobemstomig and tobemstomig in combination with tiragolumab compared to atezolizumab on the basis of confirmed objective response rate (ORR) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of tobemstomig and tobemstomig in combination with tiragolumab compared to atezolizumab on the basis of PFS, OS, DOR, PFS rate (6 and 12 months), OS rate (6, 12 and 18 months) and DCR
• To evaluate the safety of tobemstomig and tobemstomig in combination with tiragolumab compared to atezolizumab
• To evaluate the quality of life of participants treated with tobemstomig and tobemstomig in combination with tiragolumab compared to atezolizumab
• To characterize the tobemstomig PK profile after administration of tobemstomig and tobemstomig in combination with tiragolumab
• To characterize the PK profile of tiragolumab after administration of tiragolumab in combination with tobemstomig
• To characterize the PK profile of atezolizumab after administration of atezolizumab
• To evaluate the immune response to tobemstomig |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
• Histologically or cytologically documented locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium. Patients with squamous, sarcomatoid, micropapillary, and glandular variant histologies are eligible for inclusion in the study, provided that an urothelial component is present in the tumor specimen. Patients with other variant histologies or pure variant histologies are not eligible for inclusion in the study.
• Considered to be ineligible ("unfit") to receive platinum-based chemotherapy defined by one of the following criteria:
• ECOG Performance Status of 0 with baseline GFR ≥ 15 mL/min/1.73 m2 and ≤30 mL/min/1.73 m2
• ECOG Performance Status of 1 or 2 with baseline GFR ≥ 15 mL/min/1.73 m2 and ≤ 45 mL/min/1.73 m2
• ECOG Performance Status of 0-2 with Grade ≥2 neuropathy
• Patients for whom chemotherapy is not deemed appropriate
• No prior chemotherapy for inoperable locally advanced or metastatic or recurrent urothelial carcinoma (UC)
• Measurable disease; at least one measurable lesion as defined by response evaluation criteria in solid tumors, version 1.1 (RECIST v1.1)
• Availability of a representative leftover tumor specimen that meet the criteria outlined prior to study enrollment, and that is suitable for determination of programmed death-ligand 1 (PD-L1) status, for stratification and for exploratory biomarker research as assessed by a central laboratory
• Life expectancy ≥ 12 weeks
• Adequate hematologic and end-organ function
• For patients receiving therapeutic anticoagulation: stable anticoagulation regimen during the 14 days prior to initiation of study treatment
• Negative human immunodeficiency virus (HIV) test at screening
• Negative hepatitis B surface antigen (HBsAg) test at screening
• Positive hepatitis B surface antibody (HBsAb) test at screening, or a negative HBsAb at screening
• Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening
• Adequate cardiovascular function with the following criteria:
- New York Heart Association (NYHA) Heart Failure Class ≤ 2
- baseline-corrected QT (QTcF) interval ≤ 480 ms. If the QTcF interval is longer than 480 ms but shorter than 500 ms, the participant may undergo a cardiac evaluation and be considered for treatment in case of no clinically significant findings
• Resting systolic blood pressure ≤ 150 mmHg and diastolic blood pressure ≤ 100 mmHg
• Resting heart rate between 45-100 bpm
• Left ventricular ejection fraction (LVEF) ≥ 50% assessed by either transthoracic echocardiogram (TTE) or multiple-gated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to initiation of study treatment
• Troponin T (TnT) or troponin I (TnI) ≤ 3 x institutional upper limit of normal (ULN). Participants with TnT or TnI levels between >1 and <3 x ULN should have a further TnT or TnI reading within 3-6 hours and will be permitted to enter the study only if repeat levels remain ≤ 3 x ULN and have not changed by > 20% compared to the first reading. These participants should also undergo a cardiac evaluation and consider consulting a cardiologist to confirm no clinically significant findings before they receive study treatment
• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs during the treatment period and for 5 months after the final dose of atezolizumab, 4 months after the final dose of tobemstomig, or 90 days after the final dose of tiragolumab
• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm |
|
| E.4 | Principal exclusion criteria |
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the final dose of atezolizumab, 4 months after the final dose of tobemstomig, or 90 days after the final dose of tiragolumab
• Glomerular filtration rate (GFR) < 15 mL/min/1.73 m2 as calculated through use of the chronic kidney disease epidemiology collaboration (CKD-EPI) equation or receiving dialysis
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• 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 on screening chest computed tomography (CT) scan
• Active tuberculosis (TB)
• Acute Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening
• Significant cardiovascular/cerebrovascular disease within 3 months prior to initiation of study treatment
• 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
• History of another primary malignancy other than urothelial carcinoma within 2 years prior initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with therapeutic oral or intravenous antibiotics within 2 weeks prior to initiation of study treatment, with the exception of oral
antibiotics prescribed for urinary tract infections
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment or within 5 months after the final dose of atezolizumab, 4 months after the final dose of tobemstomig, or 90 days after the final dose of tiragolumab
• Current treatment with anti-viral therapy for HBV
• Treatment with any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to initiation of study treatment
• Treatment with investigational therapy within 4 weeks of 5 drugs elimination half-lives (whichever is longer) prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies
• Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab, tobemstomig, or tiragolumab formulation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Confirmed ORR, defined as the proportion of participants with a complete response (CR) or partial response (PR) on two consecutive occasions >= 4 weeks apart after randomization, as determined by the investigator according to RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 30 months for each individual |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival (PFS) after randomization defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
2. Overall survival (OS) after randomization, defined as the time from randomization to death from any cause
3. Duration of response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1
4. PFS rate at 6 months and 12 months, defined as the proportion of participants who have not experienced disease progression or death from any cause as determined by the investigator according RECIST v1.1
5. OS rate at 6 months, 12 months, and 18 months, defined as the proportion of participants who have not experienced death from any cause at 6 months, 12 months, and 18 months
6. Disease control rate (DCR), defined as the proportion of participants with confirmed CR or PR as best response, or stable disease maintained for ≥ 12 weeks, per RECIST v1.1
7. Incidence and severity of adverse events, with severity determined according to national cancer institute common terminology criteria for adverse events, version 5.0 (NCI CTCAE v5), with the exception of Cytokine Release Syndrome (CRS) event severity which will be determined according to the American Society for Transplantation and Cellular Therapy (ASTCT)
8. Time to confirmed deterioration (TTCD) from randomization, in patient-reported pain, physical functioning, role functioning, and global health status (GHS)/ quality of life (QoL) scales as assessed through use of the European Organisation for Research and Treatment of Cancer (EORTC) item library (IL) 187; confirmed deterioration is defined as a decrease from baseline of ≥ 10 points (for the physical functioning, role functioning, and GHS/QoL scales) or an increase from baseline of ≥ 10 points (for the pain scale) that is either maintained for two consecutive assessments or followed by death from any cause within 3 weeks
9. Mean and mean change from baseline in patient-reported pain, physical functioning, role functioning, and GHS/QoL scales as assessed through use of the EORTC IL187
10. Maximum concentration of tobemstomig
11. Time of maximum concentration of tobemstomig
12. Clearance of tobemstomig
13. Volume of distribution at steady state of tobemstomig
14. Area under the curve of tobemstomig
15. Half-life of tobemstomig
16. Sparse pharmacokinetic (PK) of tiragolumab at specified timepoints
17. Sparse PK of atezolizumab at specified timepoints
18. Incidence of anti-drug antibodies (ADAs) to tobemstomig
19. Impact of ADAs to tobemstomig on exposure, activity, and safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to approximately 30 months
4. At 6 and 12 months
5. At 6, 12, and 18 months
6. Up to 12 weeks
7. Until 90 days after the final dose of study treatment
8. From baseline up to 3 weeks
9. From baseline at Day 1 of Cycles 1-5, and at every other cycle thereafter until up to approximately 30 months, at Treatment Discontinuation Visit and during first Long-Term Follow-Up assessment.
10-15. At Day 1 of every cycle, at Days 8 and 15 of Cycle 1 and Cycle 5, at time of disease progression or at the Treatment Discontinuation visit (if samples were not already collected at time of disease progression).
16-17. At Day 1 of Cycles 1, 2, 3, 4, 8, 12, 16, and at the Treatment Discontinuation visit
18-19. At Day 1 of every cycle and at the Treatment Discontinuation 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 | No |
| 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 | No |
| 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 | 3 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Australia |
| Brazil |
| China |
| Korea, Republic of |
| United Kingdom |
| United States |
| France |
| Germany |
| Greece |
| Italy |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| A participant is considered to have completed the study if he or she has completed all phases of the study, including the last visit/last scheduled procedure shown in the schedule of activities (see Section 1.3, Table 1 in the Protocol). The end of the study is expected to occur approximately 30 months after the last participant is enrolled |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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