E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Cervical cancer is a disease in which the cells of the cervix become abnormal and start to grow uncontrollably, forming tumors. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 in combination with atezolizumab and of atezolizumab monotherapy based on the objective response rate
• To evaluate the safety and tolerability of tiragolumab in combination with atezolizumab and of atezolizumab monotherapy. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of tiragolumab in combination with atezolizumab and of atezolizumab based on the duration of response, disease control rate, best clinical response rate, progression-free survival (PFS) and overall survival (OS) after randomization, PFS and OS rate at 6 months, and 12 months (only OS rate)
• To characterize the pharmacokinetics of tiragolumab and atezolizumab
• To evaluate the 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
- Life expectancy >= 12 weeks
- Ability to comply with the study protocol
- Eastern Cooperative Oncology Group Performance Status of 0 or 1
- Histologically confirmed primary Stage IVB, recurrent, or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix after at least 1 line of prior therapy that is not amenable to curative treatment with systemic chemotherapy, surgery, and/or radiotherapy
- Measurable disease
- Formalin-fixed, paraffin-embedded (FFPE) cervical cancer tissue specimen that is programmed death-ligand 1 (PD-L1) positive, as determined by the Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay, with positivity defined as tumor and tumor-infiltrating immune cells (TIC) >=5%, as determined by a central laboratory
- Adequate hematologic and end-organ function obtained within 14 days prior to randomization
- Negative HIV test and hepatitis B surface antigen (HBsAg) test at screening
- Positive hepatitis B core 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
- Recovery from the effects of surgery, radiotherapy, or chemoradiotherapy
- No active infection requiring systemic antibiotics
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the final dose of tiragolumab and/or atezolizumab. |
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E.4 | Principal exclusion criteria |
- FFPE cervical cancer tissue specimens that is PD-L1 negative, as determined by the PD-L1 SP263 IHC assay, with positivity defined as TIC < 5%, as determined by a central laboratory
- More than two prior systemic lines of therapy in the metastatic/recurrent setting
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of tiragolumab and/or atezolizumab
- Treatment with investigational therapy with therapeutic intent within 28 days prior to randomization
- Planned surgery during the study
- Current treatment with anti-viral therapy for HBV or HCV
- Known HIV infection
- Substance abuse within 12 months prior to screening, in the investigator's judgment
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
- Bilateral hydronephrosis that cannot be alleviated by ureteral stents or percutaneous drainage
- History of other malignancy within 5 years prior to screening, except for those with an expected negligible risk for metastases or death after curative treatment
- Any central nervous system /brain metastases
- Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for >= 1 week prior to randomization
- Leptomeningeal disease
- Uncontrolled or symptomatic hypercalcemia
- Known, clinically significant liver disease, including active viral, alcoholic, or other hepatitis, cirrhosis, and inherited liver disease, or current alcohol abuse
- Active or history of autoimmune disease or immune deficiency, including, but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis
- Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening
- Active tuberculosis
- Severe infection at the time of randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Significant cardiovascular disease, such as New York Heart Association cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina
- Major surgical procedure other than for diagnosis within 28 days prior to randomization or anticipation of need for a major surgical procedure during the study
- Prior allogeneic bone marrow transplantation or solid organ transplant
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk for treatment complications
- Illnesses or conditions that interfere with the patient’s capacity to understand, follow, and/or comply with study procedures
- Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation that such a live attenuated vaccine will be required during the study
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-CTLA-4, anti-TIGIT, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to randomization
- Treatment with systemic immunosuppressive medications within 1 week prior to randomization or anticipation of need for systemic immunosuppressive medication during study treatment
- History of severe allergic anaphylactic reactions to chimeric, fully humanized, or humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the tiragolumab or atezolizumab formulations. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Objective response rate as determined by the independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)
2. Incidence and severity of adverse events, with severity determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE v5.0). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 36 months
2. Up to 30 days after the final dose of study treatment or until initiation of another anti-cancer therapy. |
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E.5.2 | Secondary end point(s) |
1. Duration of Response as determined by the IRC according to RECIST v1.1
2. Disease control rate as determined by the IRC according to RECIST v1.1
3. Best clinical response rate and Duration of Response as determined by the investigator
4. PFS after randomization
5. PFS rate at 6 months as determined by the IRC according to RECIST v1.1
6. OS after randomization
7. OS rate at 6 months and 12 months
8. Minimum serum concentration (Cmin) of tiragolumab
9. Maximum serum concentration (Cmax) of tiragolumab
10. Minimum serum concentration(Cmin) of atezolizumab
11. Maximum serum concentration (Cmax) of atezolizumab
12. Prevalence of ADAs at baseline and incidence of ADAs to tiragolumab and to atezolizumab during the study. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. Up to 36 months
5. At 6 months
6. Up to 36 months
7. At 6 and 12 months
8-11. Day 1 of Cycle 1-4, 8, 12 and 16 and at treatment discontinuation (TD) visit
12. Baseline (Day –28 to –1), Day 1 of Cycle 1-4, 8, 12 and 16 and at TD 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 |
Tolerability, Immunogenicity and Biomarker |
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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) | 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 | 2 |
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 | 23 |
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 |
Canada |
Costa Rica |
France |
Italy |
Korea, Republic of |
Mexico |
Poland |
Russian Federation |
Spain |
Taiwan |
Thailand |
United Kingdom |
United States |
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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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 31 |
E.8.9.2 | In all countries concerned by the trial months | 36 |