Evaluating the Efficacy of Atezolizumab in Advanced Non-small Cell Lung Cancer (NSCLC)
Condition: Advanced Non-small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Atezolizumab
Intervention description: Atezolizumab will be administered through an IV over 60 minutes at a dose of 1200mg on Day 1 of each 21-day cycle. If the first dose is tolerated without any infusion-related adverse events, the following doses can be administered over 30 minutes.
Intervention MeSH terms: Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a phase II clinical trial aimed at evaluating the efficacy of PD-L1 inhibition with
      atezolizumab in advanced squamous and non-squamous NSCLC patients previously treated with
      anti-PD-1 therapy with either nivolumab or pembrolizumab.

      In order to account for the variability of response kinetics to PD-1 directed therapy,
      patients will be enrolled in 3 parallel cohorts based on the best overall response to PD-1
      directed therapy.

        -  Cohort 1 (progressive disease)

        -  Cohort 2 (stable disease with minimum 12 weeks of therapy)

        -  Cohort 3 (partial to complete response followed by progressive disease)
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with Stage IIIB/IV squamous or non-squamous NSCLC (American Joint Committee
             on Cancer 7th Edition Staging) who have had prior treatment with nivolumab or
             pembrolizumab will be enrolled in one of 3 parallel cohorts based on the following:

               -  Cohort 1: Patient with progressive disease on nivolumab or pembrolizumab as the
                  best overall response. Progressive disease must be confirmed with a confirmatory
                  scan ≤ 4 weeks after the 1st documented date of progression.

               -  Cohort 2: Patients with stable disease as the best overall response on a minimum
                  of 12 weeks of therapy with nivolumab or pembrolizumab.

               -  Cohort 3: Patients with partial or complete response as the best overall response
                  followed by progressive disease, on nivolumab or pembrolizumab. A confirmatory
                  scan at the time of disease progression must be performed ≤ 4 weeks after the 1st
                  documented date of progression.

          -  Both men and women of all races and ethnic groups are eligible for this trial

          -  Patients must have resolution of toxic effects to Grade 1 or less from prior therapy
             (except alopecia).

          -  Patients must sign Informed Consent Form and show ability and willingness to comply
             with the requirements of the study protocol.

          -  18 years of age or older

          -  Willingness to undergo a biopsy ≤ 6 weeks of the start of study treatment to obtain
             formalin-fixed paraffin-embedded tumor specimens in paraffin blocks (blocks are
             preferred) or at least 15 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):

               -  ANC equal to/greater than 1500 cells/µL

               -  WBC counts greater than 2500/µL

               -  Lymphocyte count equal to/greater than 300µ/L

               -  Platelet count equal to/greater than 100,000/µL

               -  Hemoglobin equal to/greater than 9.0 g/dL

               -  Total bilirubin equal to/less than 1.5 x ULN with the following exception:

                    -  Patients with known Gilbert disease who have serum bilirubin level equal
                       to/less than 3 x ULN may be enrolled.

               -  AST and ALT equal to/less than 3.0 x ULN with the following exception:

                    -  Patients with liver involvement: AST and/or ALT equal to/less than 5 x ULN

               -  Alkaline phosphatase equal to/less than 2.5 x ULN with the following exception:

                    -  Patients with documented liver involvement or bone metastases: alkaline
                       phosphatase equal to/less than 5 x ULN

          -  Serum creatinine equal to/less than 1.5 x ULN or creatinine clearance equal to/greater
             than 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate
             estimation.

          -  Measurable disease per RECIST v1.1 for patients with solid malignancies.

          -  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 [less than 1%
             per year] when used consistently and correctly) and to continue its use for 5 months
             after the last dose of Atezolizumab.

          -  Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients with an ECOG
             Performance Status of 2 will be allowed at the discretion of the Treating Investigator
             in agreement with the Sponsor-Investigator.

          -  INR and aPTT equal to/less than 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:

          -  Any approved anticancer therapy, including chemotherapy, hormonal therapy, or
             radiotherapy, within 3 weeks prior to initiation of study treatment; however, the
             following are allowed:

               -  Hormone-replacement therapy or oral contraceptives.

               -  Herbal therapy greater than 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).

               -  Hormonal therapy for prostate cancer or breast cancer provided criteria in 3.2.21
                  are met.

                    -  Palliative radiotherapy (e.g., treatment of known bony metastases) allowed,
                       provided it does not interfere with the assessment of tumor target lesions
                       (e.g. the lesion being irradiated is not the only site of disease, because
                       that would render the patient not evaluable for response by tumor
                       assessments according to RECIST v1.1).

          -  Adverse events from prior anticancer therapy that have not resolved to Grade equal
             to/less than1 except for alopecia.

          -  History of grade 4 immune-related adverse events requiring treatment with prednisone
             or history of grade 3 immune-related adverse events requiring prednisone >10 mg/kg for
             >12 weeks.

          -  Bisphosphonate therapy for symptomatic hypercalcemia (use of bisphosphonate therapy
             for other reasons (e.g., bone metastasis or osteoporosis) is allowed).

          -  Known clinically significant liver disease, including active viral, alcoholic, or
             other hepatitis; cirrhosis; fatty liver; and inherited liver disease.

          -  Patients with acute leukemias, accelerated/blast phase chronic myelogenous leukemia,
             chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory
             myeloma.

          -  Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases.
             Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the
             following criteria are met:

               -  Evaluable or measurable disease outside the CNS.

               -  No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm
                  of the optic apparatus (optic nerves and chiasm).

               -  No history of intracranial hemorrhage or spinal cord hemorrhage.

               -  No ongoing requirement for dexamethasone for CNS disease; patients on a stable
                  dose of anticonvulsants are permitted.

               -  No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day
                  1.

          -  Patients with asymptomatic treated CNS metastases may be enrolled, provided all the
             criteria listed above are met as well as the following:

               -  Radiographic demonstration of improvement upon the completion of CNS directed
                  therapy and no evidence of interim progression between the completion of
                  CNS-directed therapy and the screening radiographic study.

               -  No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle
                  1, Day 1.

               -  Screening CNS radiographic study equal to/greater than 4 weeks from completion of
                  radiotherapy and equal to/greater than 2 weeks from discontinuation of
                  corticosteroids.

          -  Patients who are pregnant, are lactation, or breastfeeding.

          -  Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
             human antibodies.

          -  Inability to comply with study and follow-up procedures.

          -  History or risk of 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%, alclometasone dipropionate 0.05%).

               -  No acute exacerbations of underlying condition within the last 12 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. History of radiation pneumonitis in the radiation field
             (fibrosis) is permitted.

          -  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.

          -  History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C
             infection.

               -  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.

          -  Active tuberculosis.

          -  Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
             hospitalization for complications of infection, bacteremia, or severe pneumonia.

          -  Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1.

          -  Received oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients
             receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection
             or chronic obstructive pulmonary disease) are eligible.

          -  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 enrollment or
             anticipation that such a live attenuated vaccine will be required during the study or
             for 5 months after the last dose of Atezolizumab. 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
             enrollment, at any time during the study, or for 5 months after the last dose of
             Atezolizumab.

          -  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 equal to/less
             than 6, and prostate-specific antigen equal to/less than10 mg/mL, etc.).

          -  Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 (or within
             five half lives of the investigational product, whichever is longer).

          -  Treatment with systemic immunosuppressive medications (including but not limited to
             prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
             necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1.

               -  Patients who have received acute, low dose, systemic immunosuppressant
                  medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled.

               -  The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone)
                  for patients with orthostatic hypotension or adrenocortical insufficiency is
                  allowed.

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion proteins.

          -  Patients with prior allogeneic bone marrow transplantation or prior solid organ
             transplantation.