| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Early Stage Resectable Non-small cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early Stage NSCLC is lung cancer that has developed in the lungs and/or the lymph nodes near the lungs that can 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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 neoadjuvant treatment with atezolizumab in combination with platinum-based chemotherapy followed by adjuvant atezolizumab based independent review facility (IRF)-assessed event-free survival (EFS) |
|
| E.2.2 | Secondary objectives of the trial |
• Efficacy of neoadjuvant treatment with atezolizumab in combination with platinum-based chemotherapy based on pathological complete
response (pCR) and major pathological response (MPR) and objective response rate
• Efficacy of neoadjuvant treatment with atezolizumab in combination with platinum-based chemotherapy followed by adjuvant atezolizumab based on, overall survival (OS),investigator assessed EFS and disease free survival (DFS), 2-year and 3-year OS, 2-year and 3-year investigator and IRF assessed EFS
• Clinical benefit of atezolizumab in combination with platinum-based chemotherapy in terms of impact on health-related quality of life
• Safety of neoadjuvant treatment with atezolizumab in combination with platinum-based chemotherapy followed by adjuvant atezolizumab
• The immune response to atezolizumab
• The pharmacokinetic (PK) profile of atezolizumab when given in combination with platinum-based chemotherapy and PK profile of atezolizumab alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age ≥ 18 years
• Ability to comply with the study protocol, in the investigator's judgment
• Pathologically documented Stage II, IIIA, or select IIIB (T3N2 only)
NSCLC of squamous or non-squamous histology
Staging should be based on the 8th edition of the American Joint
Committee on Cancer / Union Internationale Contre le Cancer NSCLC
staging system
- T4 primary NSCLC will be allowed only on the basis of size (tumors > 7
cm). Invasion of the diaphragm, mediastinum, heart, great vessels,
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina,
and separate tumor nodules in a different ipsilateral lobe is not
permitted
- Patients with mixed NSCLC histology or NSCLC not otherwise specified
are eligible
- Patients may be screened based on clinical stage, but mandatory preoperative
documentation of N2 nodal involvement by invasive
mediastinal staging is required for N2 PET positive nodes. Pre-operative
staging of levels 5/6 nodes is optional.
• Solid or subsolid appearance of NSCLC on CT scan with no appearance
of purely ground-glass opacity (GGO)
For subsolid lesions, the tumor size should be measured based on solid
component only, exclusive of the GGO component.
• Evaluation by the operating attending surgeon and involved medical
oncologist prior to study enrollment to verify study eligibility for R0
resection with curative intent
• Adequate pulmonary function to be eligible for surgical resection with
curative intent, as assessed by Pulmonary function tests (PFTs)
performed within 6 months of planned resection and repeated at
screening, if clinically indicated, including lung volumes, spirometry, and
a diffusion capacity and meeting at least one of the following criteria:
- Predicted post-operative (ppo) forced expiratory volume in 1 second
(FEV1) and ppo diffusion capacity (DLCO) ≥40%
- Maximal oxygen consumption (VO2max) ≥15 mL/kg/min
● If either ppo FEV1 or ppo DLCO is < 40% or a pneumonectomy is
planned, cardiopulmonary exercise testing must be performed and
VO2max ≥ 15 mL/kg/min
- If PFTs were performed before 6 months of planned resection or have
never been performed, they must be performed during the screening period
• Adequate cardiac function to be eligible for surgical resection with curative intent
• Measurable disease as assessed by the investigator per RECIST v1.1
• Eligibility to receive a platinum-based chemotherapy regimen
• Availability of a representative tumor specimen suitable for determination of PD-L1 status via central testing
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
- Absolute neutrophil count ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support
- Lymphocyte count ≥ 0.5 × 109/L (500/μL)
- Platelet count ≥ 100 × 109/L (100,000/μL) without transfusion
- Hemoglobin ≥ 90 g/L (9.0 g/dL). Patients may be transfused to meet this criterion.
- Aspartate transaminase Test, Alanine aminotransferase Test, and Alkaline phosphatase level ≤ 2.5 × upper limit of normal (ULN)
- Serum bilirubin ≤ 1.5 × ULN with the following exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 × ULN
- Creatinine clearance ≥ 45 mL/min
- For patients intended to receive cisplatin: creatinine clearance ≥ 60 mL/min
- Serum albumin ≥ 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤1.5 × ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Negative HIV test at screening
• Negative hepatitis B surface antigen or Negative total hepatitis B core antibody (HBcAb) test, or a positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by negative HCV RNA test at screening
• For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, 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 last dose of atezo, 30 days after the last dose of nabpaclitaxel, or 6 months after the last dose of pemetrexed, carboplatin, or cisplatin, whichever is later
• For men: men must remain abstinent or use a condom during the treatment period and for 30 days after last dose of nab-paclitaxel or 6
months after the last dose of pemetrexed, gemcitabine, carboplatin, or cisplatin, whichever is later, to avoid exposing the embryo. Men must
refrain from donating sperm during this same period. Male patients should be advised regarding the conservation of sperm prior to treatment because of the possibility of irreversible infertility resulting from therapy with gemcitabine |
|
| E.4 | Principal exclusion criteria |
• Illness or condition that may interfere with a patient's capacity to
understand, follow, and/or comply with study procedures
• Any prior therapy for lung cancer, including chemotherapy, or
radiotherapy
• Major surgical procedure, other than for diagnosis, within 28 days
prior to initiation of study treatment, or anticipation of need for nonprotocol-
mandated major surgical procedure during the study
• Activating mutation in the epidermal growth factor receptor or with an
anaplastic lymphoma kinase (ALK) fusion oncogene
• 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,
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome,
or multiple sclerosis
• History of idiopathic pulmonary fibrosis, organizing pneumonia druginduced
pneumonitis, or idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest computed tomography scan
• Active tuberculosis
• Significant cardiovascular disease within 3 months prior to initiation of
study treatment, unstable arrhythmia, or unstable angina
• History of malignancy other than NSCLC within 5 years prior to
screening, with the exception of malignancies with a negligible risk of
metastasis or death such as adequately treated carcinoma in situ of the
cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal
carcinoma in situ, or Stage I uterine cancer
• 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
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior
to initiation of study treatment
• 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 atezolizumab treatment or within 5 months after the last dose of
atezolizumab
• Current treatment with anti-viral therapy for HBV
• Treatment with investigational therapy within 42 days prior to
initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade
therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic
antibodies
• Treatment with systemic immunostimulatory agents within 4 weeks or
5 half-lives of the drug prior to initiation of 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 formulation
• Known allergy or hypersensitivity to any component of the
chemotherapy regimen the patient will be assigned to
• For patients intended to receive cisplatin, any hearing impairment
• Pregnancy or breastfeeding, or intention of becoming pregnant during
study treatment or within 5 months after last dose of atezolizumab, 30
days after the last dose of nab-paclitaxel, or 6 months after last dose of
pemetrexed, gemcitabine, carboplatin, or cisplatin |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. EFS, as assessed by the IRF |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Approximately up to 96 months |
|
| E.5.2 | Secondary end point(s) |
1. IRF-assessed pCR
2. IRF-assessed MPR
3. OS
4. Investigator-assessed EFS
5. Objective response by the investigator according to RECIST v1.1
6. MPR and pCR, as assessed by the investigator site pathology
laboratory
7. 2-year and 3-year OS and investigator-assessed EFS
8. DFS as determined by the investigator
9. Change from baseline in health-related quality of life (HRQoL) scores as assessed through use of the two-item global health status (GHS)/QoL subscale (Questions 29 and 30) of the European
Organisation for Research and Treatment of Cancer Quality-of-Life
Questionnaire Core 30 at each assessment timepoint during the study through the completion of adjuvant treatment and observation follow up assessments
10. Occurrence and severity of adverse events, including serious adverse events and immune-related adverse events, with severity determined according to NCI CTCAE v5.0
11. Incidence and length of surgical delays, incidence of operative and post-operative complications, and/or reasons for surgical cancellations
12. Pharmacokinetics and pharmacodynamics of atezolizmab
13. Incidence of anti-drug antibodies (ADAs) against atezolizumab
during the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 1-13. Approximately up to 96 months |
|
| 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Placebo + platinum-based chemotherapy |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| Costa Rica |
| Guatemala |
| Israel |
| Korea, Republic of |
| Mexico |
| Panama |
| Peru |
| South Africa |
| Taiwan |
| Thailand |
| United States |
| Turkey |
| Austria |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Slovenia |
| Spain |
| Sweden |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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