A ClinicalI trial of atezolizumab plus bevacizumab, with carboplatin-paclitaxel or pemetrexed, in EGFR mutant non-small cell lung carcinoma with acquired resistance
- Conditions
- Neoplasms
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- All
- Target Recruitment
- 30
7.1.1. Patients (male/female) must be =18 years of age.
7.1.2. Chemotherapy naïve, non-squamous NSCLC, stage IIIB/C (not amenable to radical therapy)
or stage IV according to 8th TNM classification. 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
7.1.3. 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
7.1.4. Measurable or evaluable disease as defined by RECIST v1.1
7.1.5. Disease progression (during or after) or unacceptable side effects from prior treatment with at
least one EGFR 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)
7.1.6. Treatment with an EGFR TKI therapy for at least 10 days
7.1.7. Adequate haematological function:
• Haemoglobin ?90 g/L
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• Absolute neutrophils count (ANC) ?1.5× 109
/L
• Platelet count ?100× 109
/L
7.1.8. Adequate renal function:
• Creatinine ?1.5× ULN OR
• Creatinine clearance ?45 mL/min (using the Cockcroft-Gault formula below):
Cockcroft-Gault formula
mL
min =
(140-age[years])×actual body weight [kg]
72×Creatinineserum (
mg
dL)
(×0.85 if female)
7.1.9. Adequate liver function:
• ALT and AST ?2.5× ULN. If the patient has liver metastases, ALT and AST must be =5×
ULN
• Total bilirubin ?1.5x ULN. If the patient has liver metastases or documented Gilbert’s
syndrome (unconjugated hyperbilirubinaemia) ?3x ULN.
7.1.10. Willingness to provide any surplus tumour sample obtained at the time of acquired resistance
to prior EGFR TKI
7.1.11. Men and women of childbearing potential must agree to use adequate contraception
7.1.12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
7.1.13. Life expectancy ?12 weeks
7.1.14. Women of childbearing potential, including women who had their last menstrual period in the
last 2 years, must have a negative serum or urine pregnancy test within 7 days before
randomisation.
7.1.15. Patient is willing and able to comply with the protocol for the duration of the trial including
undergoing treatment and scheduled visits and examinations including follow up.
7.2.1. Prior systemic cytotoxic chemotherapy for advanced stage NSCLC.
Patients who had received previous adjuvant or neoadjuvant chemotherapy are eligible if the
last dose of treatment was at least 12 months before randomisation.
7.2.2. Prior therapy with bevacizumab or other anti-angiogenic agent
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7.2.3. Prior immune checkpoint inhibitor therapy
7.2.4. More than two lines of EGFR TKI therapy
7.2.5. Known small-cell lung carcinoma (SCLC) or high grade neuroendocrine carcinoma (if
progression biopsy has been performed locally).
7.2.6. Squamous cell histologic subtype
7.2.7. 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 (e.g. a thirdgeneration
EGFR TKI such as osimertinib).
7.2.8. Active or untreated CNS metastases as determined by brain MRI
– Patients with CNS metastases must be non-progressive by RECIST and
symptomatically stable with no ongoing requirement for corticosteroids as therapy
for CNS disease; anticonvulsants at a stable dose allowed
7.2.9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation
within 4 weeks of randomization.
7.2.10. Presence or history of a malignant disease that has been diagnosed and/or required therapy
within the past 3 years. Exceptions to this exclusion include the following: completely
resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ
of any type.
7.2.11. Clear tumour infiltration into the thoracic great vessels (seen on imaging)
7.2.12. QTc of grade =3 according to CTCAE v5.0
7.2.13. Active autoimmune disease that has required systemic treatment in past 2 years. Patients with
vitiligo, controlled type I diabetes mellitus on stable insulin, or residual autoimmune-related
hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic
treatment are permitted
7.2.14. Active or uncontrolled HIV, tuberculosis, hepatitis B or C infection
7.2.15. Live attenuated vaccination within 4 weeks prior to randomisation.
7.2.16. Subject receiving any biologic drugs targeting the immune system (for example, TNF
blockers, anakinra, rituximab, abatacept, or tocilizumab).
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7.2.17. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis,
idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed
tomography scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
7.2.18. 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.
7.2.19. Prior history of hypertensive crisis or hypertensive encephalopathy
7.2.20. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent peripheral
arterial thrombosis) within 6 months prior to randomization
7.2.21. History of haemoptysis (?2.5mL of bright red blood per episode) within 1 month prior to
randomization
7.2.22. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
7.2.23. Current or recent (within 10 days of randomization) use of aspirin (>325 mg/day) or treatment
with dipyramidole, ticlopidine, clopidogrel, and clostazol
7.2.24. Current use
Study & Design
- Study Type
- Interventional Study
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Progression-free survival rate at 12 months according to RECIST v1.1
- Secondary Outcome Measures
Name Time Method Objective response (OR) 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