Clinical trial NCT03102242: Atezolizumab Immunotherapy in Patients With Advanced NSCLC
Official title: Phase II Trial of Induction Immunotherapy With Atezolizumab for Patients With Unresectable Stage IIIA and IIIB NSCLC Eligible for Chemoradiotherapy With Curative Intent.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Alliance Foundation Trials, LLC.
Sponsor class: OTHER
First posted: 2017-04-05
Enrollment: 64
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed 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.

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 \[IFN\]

Primary outcomes:
measure: Disease Control Rate (DCR) After 12 Weeks Induction
timeFrame: 12 weeks
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 12 weeks
measure: Median PFS
timeFrame: 38.3 months
measure: Progression Free Survival (PFS) at 12 and 24 Months
timeFrame: 12 and 24 Months
measure: Median OS
timeFrame: 38.3 Months
measure: Overall Survival at 12 and 24 Months
timeFrame: 12 and 24 Months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Hospital
state: Arizona
city: La Jolla
country: United States
facility: UCSD Moores Cancer Center
state: California
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Brewer
country: United States
facility: EMMC Cancer Care
state: Maine
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: Saint Joseph Mercy Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Metro MN Community Oncology Research Consortium
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Columbus
country: United States
facility: Ohio State University James Cancer Center
state: Ohio
city: Wynnewood
country: United States
facility: Lankenau Medical Center
state: Pennsylvania
city: Greenville
country: United States
facility: Prisma Health Greenville Memorial Hospital
state: South Carolina
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
Study officials:
affiliation: Mayo Clinic
name: Helen Ross, MD
role: STUDY_CHAIR
affiliation: Alliance Foundation Trials
name: Monica Bertagnolli, MD
role: PRINCIPAL_INVESTIGATOR
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