| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non−small cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable Stage III NSCLC is a lung cancer that is in the chest and cannot be surgically removed. |
|
| 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 | 10029519 |
| E.1.2 | Term | Non-small cell lung cancer stage III |
| 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 tiragolumab plus atezolizumab compared with durvalumab in the full analysis set (FAS) on the basis of progression-free survival (PFS), as assessed by an independent review facility (IRF)
● To evaluate the efficacy of tiragolumab plus atezolizumab compared with durvalumab in the programmed death ligand 1 positive analysis set (PPAS) on the basis of PFS, as assessed by an IRF. |
|
| E.2.2 | Secondary objectives of the trial |
● To evaluate the efficacy of tiragolumab plus atezolizumab compared with durvalumab in the FAS and PPAS on the basis of overall survival (OS), PFS as assessed by investigator, Confirmed objective response rate (ORR), as assessed by an IRF and investigator, DOR, as assessed by
an IRF and investigator
● To evaluate the quality of life of patients treated with tiragolumab plus atezolizumab compared with durvalumab in the FAS and PPAS
● To evaluate the efficacy of tiragolumab plus atezolizumab compared with durvalumab on the basis of PFS rate at 12, 18, and 24 months, OS rate at 12, 24, 36, and 48 months, and time to distant metastasis (TTDM)
● To evaluate the safety and tolerability of tiragolumab plus atezolizumab compared with durvalumab. |
|
| 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 documented NSCLC with locally advanced unresectable Stage III NSCLC of either squamous or nonsquamous histology
- Whole-body positron emission tomography (PET)-CT scan for the purposes of staging, performed prior and within 42 days of the first dose of concurrent chemoradiotherapy (cCRT)
- At least two prior cycles of platinum-based chemotherapy administered concurrently with RT, which must be completed within 1 to 42 days prior to randomization in the study (one cycle of cCRT is defined as 21 or 28 days)
- The RT component in the cCRT must have been at a total dose of radiation of 60 Gy±10% (54 Gy to 66 Gy) administered by intensitymodulated radiotherapy (preferred) or 3D-conforming technique
- No progression during or following concurrent platinum-based CRT
- A known programmed death ligand 1 (PD-L1) result, as determined by the investigational Ventana PD-L1 (SP263) CDx assay and documented by means of central testing of a representative tumor tissue, in either a previously obtained archival tumor tissue or fresh tissue obtained from a biopsy collected prior to the first dose of cCRT
- Adequate hematologic and end-organ function. |
|
| E.4 | Principal exclusion criteria |
- Any history of prior NSCLC and/or any history of prior treatment for NSCLC (patients must be newly diagnosed with unresectable Stage III disease)
- NSCLC known to have a mutation in the epidermal growth factor mutation and/or an anaplastic lymphoma kinase (ALK) fusion oncogene
- Any evidence of Stage IV disease
- Treatment with sequential CRT for locally advanced NSCLC
- Patients with locally advanced NSCLC who have progressed during or after the definitive cCRT prior to randomization
- Any Grade > 2 unresolved toxicity from previous CRT
- Grade >=2 pneumonitis from prior CRT
- Active or history of autoimmune disease or immune deficiency, history of idiopathic pulmonary fibrosis, organizing pneumonia
- History of malignancy other than NSCLC within 5 years prior to screening
- 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 patient safety
- Prior allogeneic stem cell or solid organ transplantation
- Active Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection at screening
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies
- Any prior Grade >=3 immune-mediated adverse event or any unresolved Grade >1 immune-mediated adverse event while receiving any previous immunotherapy agent other than immune checkpoint blockade agents
- Current treatment with anti-viral therapy for hepatitis B virus or hepatitis C virus
- Active EBV infection or known or suspected chronic active EBV infection at Screening
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T lymphocyte-associated protein 4, anti-T-cell immunoreceptor with Ig and ITIM domains, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-[anti TNFalpha] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PFS, as assessed by an IRF, defined as the time from randomization to the first occurrence of disease progression, as determined by the IRF according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1), or death from any cause, whichever occurs first (FAS)
2. PFS, as assessed by an IRF (PPAS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Up to approximately 90 months (approximately 8 years) |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival (FAS and PPAS)
2. PFS, as assessed by the investigator (FAS and PPAS)
3. Confirmed ORR, as assessed by an IRF (FAS and PPAS)
4. Confirmed ORR, as assessed by the investigator (FAS and PPAS)
5. DOR, as assessed by an IRF (FAS and PPAS)
6. DOR, as assessed by the investigator (FAS and PPAS)
7. Time to confirmed deterioration (TTCD) (FAS and PPAS)
8. PFS rate at 12, 18, and 24 months
9. OS rate at 12, 24, 36, and 48 months
10. TTDM
11. Incidence and severity of adverse events with severity graded according to the national cancer institute common terminology criteria for adverse events, version 5.0 (NCI CTCAE v5.0). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Up to approximately 90 months (approximately 8 years)
8. At 12 months, 18 months, and 24 months
9. At 12 months, 24 months, 36 months, and 48 months
10-11. Up to approximately 90 months (approximately 8 years) |
|
| 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 and Exploratory Biomarker |
|
| 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 | 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 | 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 | 7 |
| 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 |
| Brazil |
| Canada |
| China |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Taiwan |
| Thailand |
| United States |
| Austria |
| France |
| Poland |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Portugal |
| Turkey |
| United Kingdom |
|
| 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
|
The end of study will occur when all of the following criteria have been met:
- The required number of deaths for the final analysis of OS has been observed
- The last patient, last visit has occurred.
In addition, the Sponsor may decide to terminate the study at any time. If the Sponsor decides to terminate the study, patients who are still receiving study treatment or undergoing survival follow-up may be enrolled in an extension study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 90 |
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