| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chemotherapy naïve, EGFR mutant non-squamous NSCLC, stage IIIB/C (not amenable to radical therapy) or IV. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with “non-small cell lung carcinoma” (NSCLC) with a specific mutation (changes) in the EGFR gene. |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| 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 |
| The primary objective of this study is to explore the clinical efficacy of atezolizumab and bevacizumab combined with chemotherapy in EGFR mutated patients after failure of standard EGFR targeted therapies. |
|
| E.2.2 | Secondary objectives of the trial |
To further assess the efficacy and safety of atezolizumab and bevacizumab combined with chemotherapy.
To evaluate symptom-specific and global quality of life.
To explore the relationship between baseline biomarkers and measures of efficacy to protocol treatment.
To assess exploratory biomarkers in archival and/or fresh tumour tissue, blood samples, oropharyngeal swabs and faecal samples and their association with disease status and/or response to study treatment.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Chemotherapy naïve, non-squamous NSCLC, stage IIIB/C (not amenable to radical therapy) or IV. Patients who have received previous adjuvant or neoadjuvant chemotherapy are eligible if the date of last dose of treatment was at least 12 months before randomisation
- Known EGFR mutations genotypes by tissue or ctDNA; patients with common mutations (L858R or Del19) and other rare mutations (e.g. S768I, G719X) are eligible
- Measurable or evaluable disease by RECIST v1.1
- Disease progression (during or after) or unacceptable side effects from prior treatment with at least one EGFR TKI (TKI washout period = 7 days). If most recent line of treatment (1st or 2nd line) was a third-generation EGFR TKI (e.g. osimertinib):
– Patient must be known to be EGFR mutation positive, either on fresh tumour biopsy taken >7 days prior to protocol treatment start or by recent ctDNA analysis (informative ctDNA
test, local test).
– T790M genotype is allowed.
If most recent line of treatment (1st or 2nd line) was a first- or second-generation EGFR TKI (e.g. afatinib, dacomitinib, erlotinib, gefitinib):
– Patient must be known to be tissue EGFR T790M wild type (local test) on most recent line of EGFR TKI or if no tissue re-biopsy, no evidence of T790M on ctDNA but identified L858R, del19, S768I or G719X genotypes (informative ctDNA test, local test).
- Treatment with an EGFR TKI therapy for at least 30 days
- Adequate haematological, renal and liver function (CrCl at least 45ml/min)
- Willing to make available surplus tissue obtained at the time of acquired resistance to EGFR TKI |
|
| E.4 | Principal exclusion criteria |
- Prior systemic cytotoxic chemotherapy for advanced stage NSCLC
- Prior therapy with bevacizumab or other anti-angiogenic agent
- Prior immune checkpoint inhibitor therapy
- More than two lines of EGFR TKI therapy
- Known small-cell lung carcinoma (SCLC) or high grade neuroendocrine carcinoma (if progression biopsy has been performed locally)
- Squamous cell histologic subtype
- Known EGFR T790M positive genotype by tissue on most recent EGFR TKI progression or ctDNA and have not received an approved EGFR TKI targeting T790M
- Active or untreated CNS metastases as determined by brain MRI
- Patients with CNS metastases must be non-progressive by RECIST v1.1 and symptomatically stable with no ongoing requirement for corticosteroids as therapy for CNS disease; anticonvulsants at a stable dose allowed.
- Radiotherapy in target lesions within 4 weeks of randomization
- QTc of grade ≥3 according to CTCAE v5.0
- Active autoimmune disease that has required systemic treatment in past 2 years
- Active or uncontrolled HIV, tuberculosis, hepatitis B or C infection
- Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or
diastolic blood pressure >100 mmHg). Anti-hypertensive therapy to achieve these parameters
is allowable.
- Prior history of hypertensive crisis or hypertensive encephalopathy
- Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization
- History of haemoptysis (>=2.5 ml of bright red blood per episode) within 1 month prior to randomization
- Recent surgery: Core biopsy or other minor surgical procedure, excluding placement of a
vascular access device, within 7 days prior to the first dose of bevacizumab:
- Major surgery of significant traumatic injury within 28 days prior to the first dose of bevacizumab
- Minor surgical procedures within 7 days, or placement of vascular access device 2 days prior to the first dose of bevacizumab
- Serious, non-healing wound, active ulcer, or untreated bone fracture
- Proteinuria, as demonstrated by urine dipstick or >1.0 g of protein in a 24-hour urine collection
- Any unresolved toxicities from prior therapy greater than CTCAE v5.0 grade 1 at the time of starting trial treatment with the exception of Alopecia
- History of active diverticulitis |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) rate at 12 months according to RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| - 12 months from date of randomisation |
|
| E.5.2 | Secondary end point(s) |
- Objective response rate according to RECIST v1.1
- Extra-cranial PFS
- Intracranial PFS
- Overall survival, including OS rate at 12 months
- Adverse events according to CTCAE v5.0
- Patient reported quality of life
- prior use of 3rd generation TKI, EGFR mutation subtype and PD-L1 expression
- Sequencing of specific gene panels
- Tumour mutation burden
- Microbiome analysis |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Objective response: across all assessment time-points from rando until
the end of protocol treatment
- Extra-cranial PFS: from rando to disease progression
- Intracranial PFS: from rando to first documented radiographic evidence
of CNS progression
- Overall survival: time from the date of rando until death from any
cause. Censoring will occur at the last follow-up date.
- Adverse events: from date of signature of the IC until 90 days after last
dose of protocol treatment
- QoL: from baseline up to 12 months after rando
- Prior use of 3rd generation TKI, EGFR mutation subtype and PD-L1
expression: at screening
- Sequencing of specific gene panels: baseline, D1C2, D1C4, progression
- Tumor mutation burden: baseline
- Microbiome analysis: baseline, D1C2, D1C4, progression |
|
| 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 | Yes |
| 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Korea, Republic of |
| Singapore |
| United Kingdom |
| Spain |
| Switzerland |
| Germany |
|
| 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
|
| database lock (90 days after LVLS) |
|
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
