| 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 |
| NSCLC is a type of lung 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 | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| 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 atezolizumab in combination with cabozantinib compared with docetaxel monotherapy in patients with metastatic NSCLC who were previously treated with an anti-Programmed death-ligand 1 (PD-L1)/PD-1 antibody and platinum-containing chemotherapy |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the safety of atezolizumab and cabozantinib compared with docetaxel monotherapy in this patient population
To characterize the pharmacokinetic (PK) profile of atezolizumab and cabozantinib
To evaluate the immune response to atezolizumab and cabozantinib
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- Histologically or cytologically confirmed metastatic NSCLC
- Documented radiographic disease progression during or following treatment with platinum-containing doublet chemotherapy and anti-PD-L1/PD-1 antibody, administered concurrently or sequentially for metastatic NSCLC
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 outside the central nervous system (CNS) as assessed by investigator
- Known PD-L1 status or availability of tumor tissue for central PD-L1 testing
- Eastern Cooperative Oncology Group performance status score of 0 or 1
- Recovery to baseline or Grade <= 1 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 from toxicities related to any prior treatments, unless adverse events are clinically nonsignificant and/or stable on supportive therapy in the opinion of the investigator
- Adequate hematologic and end-organ function
- For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs, for 5 months after the final dose of atezo and/or 4 months after the final dose of cabo
- For men: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating sperm for 4 months after the final dose of cabo, or for 6 months after the final dose of docetaxel
|
|
| E.4 | Principal exclusion criteria |
- Prior therapy with the following agents for NSCLC: Cabo, Docetaxel, Combination of an anti-PD-L1/PD-1 antibody concurrently with a vascular endothelial growth factor -targeting tyrosine kinase inhibitor
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Documentation of known sensitizing mutation in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) fusion oncogene
- Patients with known ROS1 rearrangements, BRAF V600E mutations, or other actionable oncogenes with approved therapies if available
- Symptomatic, untreated, or actively progressing CNS metastases
- History of leptomeningeal disease
- Uncontrolled tumor-related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia
- Any other active malignancy at the time of initiation of study treatment or diagnosis of another malignancy within 3 years prior to initiation of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, incidental prostate cancer, or carcinoma in situ of the prostate, cervix, or breast
- Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiring surgical repair or recent peripheral arterial thrombosis) within 6 months of initiation of study treatment
- Significant cardiovascular disease within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
- Stroke, transient ischemic attack, myocardial infarction or other symptomatic ischemic events within 6 months of initiation of study treatment
- Active tuberculosis
- Severe infection within 4 weeks prior to initiation of study treatment or any active infection that, in the opinion of the investigator, could impact patient safety
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
- Current treatment with anti-viral therapy for HBV
- Ongoing Grade ≥ 2 sensory or motor neuropathy
- Active or history of autoimmune disease or immune deficiency
- Pharmacologically uncompensated, symptomatic hypothyroidism
- Administration of 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 final dose of atezolizumab
- Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives prior to initiation of study treatment
- 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
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
- History of severe hypersensitivity to docetaxel or to other drugs formulated with polysorbate 80
- Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitor dabigatran, direct factor Xa inhibitor betrixaban or platelet inhibitors (e.g., Clopidogrel)
- Thromboembolic event within 6 months before initiation of study treatment
- History of risk factors for torsades de pointes
- Corrected QT interval corrected through use of Fridericia's formula > 480 ms per ECG within 14 days before initiation of study treatment
- Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic BP > 90 mm Hg despite optimal antihypertensive treatment
- Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess within 6 months before initiation of study treatment
- Known cavitating pulmonary lesion(s) or known endobronchial disease manifestation
- Lesions invading major pulmonary blood vessels
- 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
- Serious non-healing wound/ulcer/bone fracture
- Malabsorption syndrome
- Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption are also excluded
- Requirement for hemodialysis or peritoneal dialysis
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 47 months |
|
| E.5.2 | Secondary end point(s) |
1. PFS as determined by Investigator according to RECIST v1.1
2. Confirmed objective response rate (ORR) as determined by Investigator
3. Duration of response for patients with confirmed ORR
4. Time to confirmed deterioration in patient-reported physical functioning and global health status as measured by the corresponding scores from the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30)
5. PFS rate assessed by IRF and Investigator at 6 months and at 1 year
6. OS rates at 1 and 2 years
7. Incidence and severity of adverse events according to NCI CTCAE v5.0
8. Serum concentration of atezolizumab at specified timepoints
9. Plasma concentration of cabozantinib at specified timepoints
10. Prevalence of anti-drug antibodies (ADAs) to atezolizumab at baseline and incidence of ADAs to atezolizumab after treatment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-4. Up to approximately 47 months
5. At 6 months and at 1 year, up to approximately 47 months
6. At 1 and 2 years, up to approximately 47 months
7. Up to approximately 47 months
8. Day 1 of Cycle 1-5, Cycle 8, 12, 16, post treatment follow-up (<= 30 days after final dose)
9. Day 1 of Cycle 1-5
10. Day 1 of Cycle 1-4, Cycle 8, 12, 16, post treatment follow-up (<= 30 days after final dose)
|
|
| 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 | 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 83 |
| 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 |
| Austria |
| Belgium |
| France |
| Germany |
| Greece |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Spain |
| United Kingdom |
| United States |
|
| 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 this 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, or the last data point required for safety follow-up is received, whichever occurs later.
* The last patient, last visit has occurred.
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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 47 |
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