| Eligibility |
Inclusion Criteria
- Male or female, 18 years of age or older
- Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1
- Histologically or cytologically confirmed, Stage IV non-squamous NSCLC (per the Union
Internationale contre le Cancer/American Joint Committee on Cancer staging system, 8th
edition).
- Patients with tumors of mixed histology (i.e., squamous and non-squamous) are eligible
if the major histological component appears to be non-squamous.
- As the stage IV non-squamous NSCLC treatment, no prior cytotoxic treatment is allowed
and the patients treated with below tyrosine kinase inhibitor prior to the enrollment
- Patients with a sensitizing mutation in the epidermal growth factor receptor (EGFR)
gene must have experienced disease progression (during or after treatment) or
intolerance to treatment with one or more EGFR TKIs, such as erlotinib, gefitinib,
osimertinib or another EGFR tyrosine kinase inhibitor (TKI) appropriate for the
treatment of EGFR mutant NSCLC.
If the patients have identified T790M mutation after 1st or 2nd generation EGFR TKI
failure, the patient must be treated with the second line 3rd generation EGFR TKI
treatment, such as osimertinib, before the study participation.
Patients with an anaplastic lymphoma kinase (ALK) fusion oncogene must have experienced
disease progression (during or after treatment) or intolerance to treatment with one or
more ALK inhibitors (i.e., crizotinib) appropriate for the treatment of NSCLC in patients
having an ALK fusion oncogene.
Patients with unknown EGFR and/or ALK status require test results at screening. ALK and/or
EGFR may be assessed locally or at a main investigator laboratory.
Inoperable stage III non-squamous NSCLC treatment, no prior cytotoxic treatment is allowed
and the patients treated with below tyrosine kinase inhibitor prior to the enrollment
- Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or
chemoradiotherapy with curative intent for non-metastatic disease must have
experienced a treatment free interval of at least 6 months from randomization since
the last chemotherapy, radiotherapy, or chemoradiotherapy.
- Patients with a history of treated asymptomatic Central Nervous System(CNS) metastases
are eligible, provided they meet all of the following criteria:
No ongoing requirement for corticosteroids as therapy for Central Nervous System(CNS)
disease No stereotactic radiation within 7 days or whole-brain radiation within 14 days
prior to randomization No evidence of interim progression between the completion of Central
Nervous System(CNS)-directed therapy and the screening radiographic study
- Patients with new asymptomatic Central Nervous System(CNS) metastases detected at the
screening scan may be eligible without the need for an additional radiation therapy
and/or surgery for Central Nervous System(CNS) metastases by investigator's decision.
- Patients who are available to provide tissue from previously obtained archival tumor
tissue or tissue obtained from a biopsy at screening for the PD-L1 test.
( in case, if patient cannot provides any slides, the enrollment can still be considered
with individual discussion with the principal investigator)
- Biopsy and blood sample requirement are as follows for the Whole exome and transcriptome
sequencing: A representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in
paraffin block (preferred) or 10 or more unstained, freshly cut, serial sections on slides
from an FFPE tumor specimen is required for participation in this study. If fewer than 10
slides are available, patient can be still considered for the enrollment based on the
discussion and the decision with the principal investigator. This specimen must be
accompanied by the associated pathology report.
Fine-needle aspiration (defined as samples that do not preserve tissue architecture and
yield cell suspension and/or cell smears), brushing, cell pellet specimens (e.g., from
pleural effusion, and lavage samples) are not acceptable.
Tumor tissue from bone metastases that is subject to decalcification is not acceptable.
Endobronchial ultrasonographic biopsy samples are not preferred but acceptable. For core
needle biopsy specimens, preferably at least three cores embedded in a single paraffin
block, should be submitted for evaluation.
30ml of peripheral blood sample acquired during the screening period
- Measurable disease, as defined by RECIST v1.1 Previously irradiated lesions can only be
considered as measurable disease if disease progression has been unequivocally documented
at that site since radiation and the previously irradiated lesion is not the only site of
disease.
Adequate hematologic and end organ function, defined by the following laboratory results
obtained within 14 days prior to randomization:
ANC = 1500 cells/µL without granulocyte colony stimulating factor support Lymphocyte count
=500/µL Platelet count = 100,000/µL without transfusion Hemoglobin = 9.0 g/dL Patients may
be transfused to meet this criterion. INR or aPTT = 1.5 x upper limit of normal (ULN) This
applies only to patients who are not receiving therapeutic anticoagulation; patients
receiving therapeutic anticoagulation should be on a stable dose.
AST, ALT, and alkaline phosphatase = 2.5 x ULN, with the following exceptions:
Patients with documented liver metastases: AST and/or ALT = 5 x ULN Patients with
documented liver or bone metastases: alkaline phosphatase = 5 x ULN.
Serum bilirubin = 1.25 x ULN Patients with known Gilbert disease who have serum bilirubin
level = 3 x ULN may be enrolled.
Serum creatinine = 1.5 x ULN
- For female patients of childbearing potential, agreement (by patient and/or partner)
to use a highly effective form(s) of contraception that results in a low failure rate
(< 1% per year) when used consistently and correctly, and to continue its use for 5
months after the last dose of atezolizumab and/or 6 months after the last dose of
bevacizumab or paclitaxel, whichever is later). Such methods include: combined
(estrogen and progestogen containing) hormonal contraception, progestogen-only
hormonal contraception associated with inhibition of ovulation together with another
additional barrier method always containing a spermicide, intrauterine device (IUD):
intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized
partner (on the understanding that this is the only one partner during the whole study
duration), and sexual abstinence.
- For male patients with female partners of childbearing potential, agreement (by
patient and/or partner) to use a highly effective form(s) of contraception that
results in a low failure rate [< 1% per year] when used consistently and correctly,
and to continue its use for 6 months after the last dose of bevacizumab, carboplatin,
or paclitaxel. Male patients should not donate sperm during this study and for at
least 6 months after the last dose of bevacizumab, carboplatin, or paclitaxel.
- Oral contraception should always be combined with an additional contraceptive method
because of a potential interaction with the study drug. The same rules are valid for
male patients involved in this clinical study if they have a partner of childbirth
potential. Male patients must always use a condom.
- Women who are not postmenopausal ( 12 months of non therapy-induced amenorrhea) or
surgically sterile must have a negative serum pregnancy test result within 14 days
prior to initiation of study drug
Exclusion Criteria
Patients who meet any of the criteria below will be excluded from study entry.
Cancer-Specific Exclusions Active or untreated symptomatic Central Nervous System(CNS)
metastases as determined by CT or magnetic resonance imaging (MRI) evaluation during
screening and prior radiographic assessments Spinal cord compression not definitively
treated with surgery and/or radiation or previously diagnosed and treated spinal cord
compression without evidence that disease has been clinically stable for > 2 weeks prior to
randomization Leptomeningeal disease Uncontrolled tumor-related pain Patients requiring
pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to
palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement)
should be treated prior to randomization. Patients should be recovered from the effects of
radiation. There is no required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional deficits
or intractable pain (e.g., epidural metastasis that is not currently associated with spinal
cord compression) should be considered for locoregional therapy, if appropriate, prior to
randomization.
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently) Patients with indwelling catheters
(e.g., PleurX®) are allowed. Uncontrolled or symptomatic hypercalcemia (> 1.5 mmol/L
ionized calcium or Ca > 12 mg/dL) Malignancies other than NSCLC within 5 years prior to
randomization, with the exception of those with a negligible risk of metastasis or death
(e.g., expected 5 year OS > 90%) treated with expected curative outcome (such as adequately
treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized
prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated
surgically with curative intent)
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