| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Untreated Locally Advanced Unresectable or Metastatic Renal Cell Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Clear Cell Renal cell carcinoma (RCC), is the most common type of kidney cancer. |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073251 |
| E.1.2 | Term | Clear cell renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 25.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10086821 |
| E.1.2 | Term | Advanced renal cell carcinoma |
| 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 Arm A (tobemstomig + axitinib) vs. Control Arm (pembrolizumab+ axitinib) and Arm B (Tiragolumab + tobemstomig + axitinib) vs. Control Arm in the Full Analysis Set (FAS)
● To evaluate the safety and tolerability of Arm A vs. Control Arm and Arm B vs. Control Arm in the safety evaluable (SE) population |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the efficacy of Arm A vs. Control Arm and Arm B vs. Control Arm
● To evaluate the immune response to tiragolumab, and tobemstomig
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
● Age >= 18 years
● Ability to comply with the protocol and provide written informed consent
● Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
● International Metastatic Renal Cell Carcinoma Database Consortium IMDC risk intermediate (score of 1 or 2), or poor (score of 3 to 6)
● Measurable disease, at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
● Adequate hematologic and end-organ function (within 14 days prior to study treatment)
● Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment
● Histologically confirmed clear-cell renal cell carcinoma renal cell carcinoma (ccRCC) with or without
sarcomatoid features; non-clear-cell renal cell carcinoma (nccRCC) subtypes (papillary, chromophobe, and unclassified) are not allowed.
● Archival tissues will be collected from all participants for exploratory biomarker research
● Negative HIV testing at screening
● Negative hepatitis B surface antigen (HBsAg) test at screening
● Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening
● Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
● For female participants of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs during the treatment period and for 90 days after the final dose of tiragolumab for 4 months after the final dose of tobemstomig and pembrolizumab, or for 1 week after the final dose of axitinib, whichever occurs last
● For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm during the treatment period, for 4 months after the last dose of tobemstomig and pembrolizumab, for 90 days after the last dose of tiragolumab and 1 week after the last dose of axitinib whichever occurs last to avoid exposing the embryo
● For participants enrolled in the extended China enrollment phase at China's sites: must be current residents of mainland China, Hong Kong, or Taiwan, and of Chinese ancestry |
|
| E.4 | Principal exclusion criteria |
● Inability to swallow tablet or malabsorption syndrome
● Prior treatment for localized and/or metastatic RCC with systemic RCC directed therapy
● Ongoing use or anticipated need for treatment with a strong CYP3A4/5 inhibitor or inducer
● 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
● Uncontrolled or symptomatic hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
● Participants who are receiving bisphosphonate therapy or denosumab specifically to prevent skeletal events and who do not have a history of clinically significant hypercalcemia are eligible
● Symptomatic, untreated, or actively progressing CNS metastases
● Asymptomatic patients with treated CNS lesions are eligible
● History of leptomeningeal disease
● Uncontrolled tumor-related pain
● Symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrollment.
● Asymptomatic metastatic lesions that would likely cause functional deficit or intractable pain with further growth should be considered for loco-regional therapy if appropriate prior to enrollment.
● Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
● Participants with indwelling catheters are allowed
● Moderate to severe hepatic impairment (Child-Pugh B or C)
● Uncontrolled hypertension
● Prior history of hypertensive crisis or hypertensive encephalopathy
● Significant cardiovascular/cerebrovascular disease within 3 months prior to randomization
● Left ventricular ejection fraction (LVEF) <=50% assessed by either a transthoracic echocardiogram (TTE) or multiple-gated acquisition (MUGA)
● History of clinically significant ventricular dysrhythmias or risk factors for ventricular dysrhythmias
● History of congenital QT syndrome
● History or presence of an abnormal ECG that is clinically significant in investigator's opinion
● Troponin T (TnT) or troponin I (TnI) <=institutional upper limit of normal (ULN)
● Resting heart rate (HR) ≥ 100 bpm (or clinically significant tachycardia)
● Stroke, myocardial infarction, or other symptomatic ischemic event, or thromboembolic event within 3 months before randomization
● Significant vascular disease within 3 months prior to Day 1 of Cycle 1
● Tumors invading pulmonary blood vessels, cavitating pulmonary lesions or known endobronchial disease.
● Tumor invading the gastrointestinal (GI) tract, including abdominal or tracheoesophageal fistulas.
● Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
● Active peptic ulcer disease, acute pancreatitis, acute obstruction of pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, diverticulitis, gastric outlet obstruction.
● Intra-abdominal abscess within 6 months before initiation of study treatment
● Complete healing of an intra-abdominal abscess must be confirmed before initiation of study treatment
● Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
● Evidence of bleeding diathesis or significant coagulopathy
● Grade >= hemorrhage or bleeding event within 28 days prior to initiation of study treatment
● Clinically significant hematuria, hematemesis, hemoptysis of >0.5 teaspoon (2.5 mL) of red blood, coagulopathy, or other history of significant bleeding within 3 months before initiation of study treatment
● Active or history of autoimmune disease or immune deficiency
● 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
● Prior allogeneic stem cell or solid organ transplantation
● 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.
● History of another primary malignancy other than RCC within 2 years prior to Screening
● Administration of live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live, attenuated vaccine will be required during the study
● Active tuberculosis (TB)
● Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that, in the opinion of the investigator, could impact participant safety
● Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
● Concurrent enrollment in another interventional clinical study, except for an observational study
● Known hypersensitivity to Chinese hamster ovary cell products or to any component of tobemstomig, tiragolumab, pembrolizumab, or axitinib |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Progression-free survival, defined as the time from randomization to the first occurrence of disease progression according to RECIST version 1.1, as assessed by the investigator, or death from any cause, whichever occurs first
2. Incidence and severity of adverse events, with severity graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. 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) CRS Consensus Grading scale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival (OS) defined as the time from randomization to death from any cause
2. Confirmed objective response rate (ORR) defined as the proportion of participants with a CR or PR on two consecutive occasions at least 4 weeks apart as determined by the investigator according to RECIST v1.1
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. Prevalence of anti-drug antibodies (ADAs) to tiragolumab at baseline and incidence of ADAs to tiragolumab during the study
5. Prevalence of ADAs to tobemstomig at baseline and incidence of ADAs to tobemstomig during the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-3. Up to 24 months
4. Day 1 of Cycle 1; Day 1 of Cycle 2, 3, 4, 8, 12, 16; at end of treatment visit
5. Day 1 of every cycle; Day 8 and 15 of Cycle 5; at end of treatment 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 | No |
| 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 | No |
| 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) | No |
| 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 | 30 |
| 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 |
| China |
| Korea, Republic of |
| United Kingdom |
| United States |
| France |
| Germany |
| Poland |
| Spain |
|
| 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 at which the last data point required for statistical analysis or safety follow-up is received from the last participant whichever occurs later.
In addition, the Sponsor may decide to terminate the study at any time. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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