Atezolizumab Immunotherapy in Patients With Advanced NSCLC
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Atezolizumab
Intervention description: Single arm phase II trial of induction immunotherapy with anti-PD-L1 for patients with unresectable stage III NSCLC and PS 0-1.
Intervention MeSH terms: Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 64.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No

Summary:

      Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable
      stage IIIA and IIIB NSCLC eligible for chemoradiotherapy with curative intent.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Newly diagnosed stage IIIA/B NSCLC, PS 0-1

          -  No active autoimmune disease or uncontrolled infection, normal bone marrow, renal,
             hepatic function, FEV1 > 1.2L, no significant underlying heart or lung disease

          -  Pathologically proven diagnosis of NSCLC

          -  Measurable Stage IIIA or IIIB disease

          -  Tissue available for PD-L1 testing and for correlative science testing

          -  Patients must be considered unresectable or inoperable. Patients with nodal recurrence
             after surgery for early-stage NSCLC are eligible if the following criteria are met:

               -  No prior chemotherapy or radiation for this lung cancer.

               -  Prior curative-intent surgery at least 3 months prior to the nodal recurrence.

          -  Stage III A or B disease with minimum diagnostic evaluation within 6 weeks to include:

               -  History/physical examination

               -  Contrast enhanced CT of the chest and upper abdomen

               -  MRI of the brain with contrast (or CT with contrast if MRI is medically
                  contraindicated)

               -  PET/CT

          -  If pleural fluid is visible on CT scan thoracentesis to exclude malignancy should be
             obtained. Patients with effusions that are too small to tap are eligible.

          -  Patients must be at least 4 weeks from major surgery and must be fully recovered

          -  Age greater than or equal to 18 years.

          -  Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
             blocks or at least 4 unstained slides, with an associated pathology report, for
             central testing of tumor PD-L1 expression.

               -  If an archived tumor block exists, then either the block or at least 4 unstained
                  slides from the block should be submitted. Tumor tissue should be of good quality
                  based on total and viable tumor content, i.e. at least 50 viable tumor cells and
                  intact tissue architecture. Fine needle aspiration, brushing,and lavage samples
                  are not acceptable. If the block is tissue from a core-needle biopsy, then the
                  block should contain tissue from at least three cores to be sufficient for
                  evaluation.

               -  Patients who do not have existing (archived) tissue specimens meeting eligibility
                  requirements may undergo a biopsy during the screening period. Acceptable samples
                  include core needle biopsies for deep tumor tissue (minimum of three cores) or
                  excisional, or forceps biopsies for endobronchial or nodal lesions. The tissue
                  should be fixed in formalin and embedded on site and sent as a block.

          -  Adequate hematologic and end organ function, defined by the following laboratory
             results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):

               -  ANC ≥ 1500 cells/µL

               -  WBC counts > 2500/µL

               -  Lymphocyte count ≥ 300/µL

               -  Platelet count ≥ 100,000/µL

               -  Hemoglobin ≥ 10.0 g/dL

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN) with the following exception:

          -  Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be
             enrolled.

               -  AST and ALT ≤ 3.0 x ULN

               -  Alkaline phosphatase ≤ 2.5 x ULN

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min on the basis of
                  the Cockcroft-Gault glomerular filtration rate estimation:

          -  (140 - age) x (weight in kg) x (0.85 if female)/ 72 x (serum creatinine in mg/dL)

          -  Measurable disease per RECIST v1.1 (see Appendix 3)

          -  For female patients of childbearing potential and male patients with partners of
             childbearing potential, agreement (by patient and/or partner) to use highly effective
             form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year]
             when used consistently and correctly) and to continue its use for 90 days after the
             last dose of Atezolizumab.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

          -  INR and aPTT ≤ 1.5 x ULN • This applies only to patients who do not receive
             therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as
             low-molecular-weight heparin or warfarin) should be on a stable dose.

        Exclusion Criteria:

          -  Active autoimmune disease

          -  Greater than minimal, exudative, or cytologically positive pleural effusions

          -  Involved contralateral hilar nodes

          -  10% weight loss within the past month

          -  Known EGFR exon 19 or 21 mutation or ALK rearrangement

          -  Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
             for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the
             breast, localized prostate cancer, carcinoma in situ of the oral cavity, or cervix are
             all permissible.

          -  Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
             different cancer is allowable.

          -  Prior radiotherapy to the region of the study cancer that would result in overlap of
             radiation therapy fields.

          -  Prior severe infusion reaction to a monoclonal antibody

          -  Severe, active co-morbidity, defined as follows:

          -  Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension,
             unstable angina, myocardial infarction within the last 6 months, uncontrolled
             congestive heart failure, and cardiomyopathy with decreased ejection fraction.

          -  Acute bacterial or fungal infection requiring intravenous antibiotics at the time of
             registration or within 2 weeks of cycle 1 day 1.

          -  Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
             requiring hospitalization or precluding study therapy within 30 days before
             registration

          -  Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

          -  Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note,
             HIV testing is required for entry into this protocol due to the immunologic basis for
             induction treatment.

          -  Pregnancy, lactation, or inability or unwillingness to use medically acceptable forms
             of contraception if pregnancy is a risk.

          -  Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin;

          -  Uncontrolled neuropathy grade 2 or greater regardless of cause.

          -  Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
             radiotherapy, within 3 weeks prior to initiation of study treatment; however, the
             following are allowed:

             i. Hormone-replacement therapy or oral contraceptives ii. Herbal therapy > 1 week
             prior to Cycle 1, Day 1 (herbal therapy intended as anticancer therapy must be
             discontinued at least 1 week prior to Cycle 1, Day 1)

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease

          -  Patients with past or resolved hepatitis B infection (defined as having a negative
             hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to
             hepatitis B core antigen] antibody test) are eligible.

          -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
             chain reaction (PCR) is negative for HCV RNA.

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies

          -  Inability to comply with study and follow-up procedures

          -  History of active autoimmune disease, including but not limited to systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
             associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
             syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
             thyroid disease, vasculitis, or glomerulonephritis

          -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
             replacement hormone may be eligible.

          -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be
             eligible.

          -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
             dermatologic manifestations only (e.g., patients with psoriatic arthritis would be
             excluded) are permitted provided that they meet the following conditions:

          -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular
             manifestations

          -  Rash must cover less than 10% of body surface area (BSA)

          -  Disease is well controlled at baseline and only requiring low potency topical steroids
             (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide
             0.05%, alcometasone dipropionate 0.05%)

          -  No acute exacerbations of underlying condition within the last 6 months (not requiring
             psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic
             agents, oral calcineurin inhibitors; high potency or oral steroids)

          -  History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
             organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
             pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
             tomography (CT) scan

          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the patient at high risk from treatment
             complications

          -  Active tuberculosis

          -  Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
             need for a major surgical procedure during the course of the study

          -  Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
             anticipation that such a live, attenuated vaccine will be required during the study

          -  Influenza vaccination should be given during influenza season only (approximately
             October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
             FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.

          -  Malignancies other than the disease under study within 5 years prior to Cycle 1, Day
             1, with the exception of those with a negligible risk of metastasis or death and 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, or ductal carcinoma in situ treated surgically with curative intent)
             or undergoing active surveillance per standard-of-care management (e.g., chronic
             lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and
             prostate-specific antigen [PSA] ≤ 10 mg/mL, etc.)

        Medication-Related Exclusion Criteria:

          -  Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
             targeting agents

          -  Treatment with systemic immunostimulatory agents (including but not limited to
             interferon [IFN]