E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Esophageal squamous cell carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Esophageal squamous cell carcinoma occurs most often in the upper and middle portions of the esophagus. |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055476 |
E.1.2 | Term | Esophageal squamous cell carcinoma |
E.1.2 | System Organ Class | 100000004864 |
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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 tiragolumab + atezolizumab compared with double placebo on the basis of investigator (INV) assessed progression free survival and overall survival
• To evaluate the efficacy of placebo + atezolizumab compared with double placebo on the basis of overall survival. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of placebo + atezolizumab compared with double placebo on the basis of INV assessed progression-free survival
• To evaluate the efficacy of tiragolumab + atezolizumab versus placebo + atezolizumab to demonstrate the contribution of tiragolumab on the basis of INV assessed progression free survival and overall survival
• To evaluate the efficacy of tiragolumab + atezolizumab and placebo + atezolizumab compared with double placebo and the efficacy of tiragolumab + atezolizumab versus placebo + atezolizumab to demonstrate the contribution of tiragolumab on the basis of independent review facility (IRF) assessed PFS and, IRF-assessed ORR, and INV assessed ORR
• To evaluate safety and tolerability of tiragolumab + atezolizumab and placebo + atezolizumab compared with double placebo
• To characterize pharmacokinetics of tiragolumab and atezolizumab
• To evaluate immune response to tiragolumab and atezolizumab. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age >=18 years
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus
• Stage II-IVA per American Joint Committee on Cancer/Union for International Cancer Control, 8th edition, unresectable locally advanced disease
• Definitive concurrent chemoradiation treatment according to regional oncology guidelines for esophageal cancer
• Representative archival formalin-fixed, paraffin-embedded tumor specimens < 3 years old, collected prior to initiation of definitive chemoradiotherapy in paraffin blocks or >= 15 unstained slides containing freshly cut, serial sections
• Adequate hematologic and end-organ function
• For women of childbearing potential: agreement to remain abstinent or use contraception 5 months after the final dose of atezolizumab and for 90 days after the final dose of tiragolumab
• For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm, men must remain abstinent or use a condom during the treatment period and for 90 days after the final dose of tiragolumab to avoid exposing the embryo. |
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E.4 | Principal exclusion criteria |
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-TIGIT therapeutic antibodies
• Any unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE) Grade >= 2 from the prior chemoradiation therapy
• Evidence of complete esophageal obstruction not amenable to treatment
• Histology consistent with small cell esophageal carcinoma, esophageal adenocarcinoma, or mixed carcinoma
• Grade >= 2 peripheral neuropathy as defined by NCI CTCAE v5.0 criteria
• High risk for developing esophageal fistula by clinical assessment or imaging, such as prior history or associated symptoms of esophageal fistula, or primary tumor invasion of the great vessels or trachea
• Prior esophagectomy
• 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 scan
• History of malignancy other than esophageal cancer within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Treatment with any other investigational agent, including EGFR inhibitors, with therapeutic intent for esophageal cancer prior to randomization. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression-Free Survival as determined by the investigator (for tiragolumab + atezolizumab compared with double placebo)
2. Overall survival (for tiragolumab + atezolizumab compared with double placebo)
3. Overall Survival (for placebo + atezolizumab compared with double placebo). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-3. Approximately 50 months. |
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E.5.2 | Secondary end point(s) |
1. Progression-Free Survival as determined by the investigator (for placebo + atezolizumab compared with double placebo)
2. Overall Survival (for tiragolumab + atezolizumab versus placebo + atezolizumab to demonstrate the contribution of tiragolumab)
3. Progression-Free Survival as determined by the independent review facility (IRF)
4. Confirmed ORR as determined by the investigator
5. Confirmed ORR as determined by an IRF
6. Duration of response as determined by the investigator
7. Duration of response as determined by the IRF
8. Proportion of patients with clinically meaningful changes in physical functioning, role functioning, global health status/quality of life, and dysphagia, as measured by the respective scales of the European Organisation for Research and Treatment of Cancer Quality of Life-Core 30 Questionnaire and the European Organisation for Research and Treatment of Cancer Quality of Life-Esophageal Cancer, Module 18 Questionnaire
9. Incidence and severity of adverse events
10. Serum concentration of tiragolumab and atezolizumab at specified timepoints
11. Prevalence of anti-drug antibody (ADAs) to tiragolumab at baseline and incidence of ADAs to tiragolumab during the study
12. Prevalence of ADAs to atezolizumab at baseline and incidence of ADAs to atezolizumab during the study. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- 7. Approximately 50 months
8. Day 1 of Cycle 1 and Day 1 of every cycle thereafter until treatment discontinuation, and at the study treatment discontinuation visit and during survival follow-up, every 3 months for 1 year
9. Approximately 50 months
10-12. Day 1 of Cycle 1, Day 1 of Cycle 2-4, 8, 12, 16 and at treatment discontinuation, disease progression, or completion visit. |
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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 |
Immunogenicity, Biomarker (exploratory) and Health Status Utility Objective. |
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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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
China |
Czech Republic |
France |
Germany |
Greece |
Hungary |
Israel |
Italy |
Japan |
Korea, Republic of |
New Zealand |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Switzerland |
Taiwan |
Thailand |
Turkey |
Ukraine |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 50 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 50 |