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Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA and IIIB NSCLC eligible for chemoradiotherapy with curative intent.
Full description
This phase II pilot trial will combine neoadjuvant immunotherapy with Atezolizumab q 21 days for 12 weeks with standard chemoradiotherapy with curative intent for good PS patients with unresectable stage IIIA/B NSCLC. Because of the consequences of progression in this curative-intent population, restaging CT scans will be carried out after the first 2 cycles of neoadjuvant therapy. Non progressing patients will complete a total of one year of anti-PDL1 therapy with an interruption during chemoradiotherapy. Patients with evidence of progression at the first restaging evaluation will proceed immediately to chemoradiotherapy if still eligible for curative intent therapy.
Enrollment
Sex
Ages
Volunteers
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:
Stage III A or B disease with minimum diagnostic evaluation within 6 weeks to include:
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.
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):
Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
(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:
Primary purpose
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64 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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