Atezolizumab and Varlilumab in Combination With Radiation Therapy for NSCLC
Condition: Refractory Lung Non-Small Cell Carcinoma; Stage IV Lung Cancer AJCC v8
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Atezolizumab 1200 MG in 20 ML Injection; Stereotactic Body Radiation Therapy; Varlilumab 3 mg/kg
Intervention description: Given IV every 3 weeks (cycle is 21 days); Undergo SBRT between cycle 1 and cycle 2 (each cycle is 21 days); Given IV every 3 weeks (cycle is 21 days)
Intervention MeSH terms: Atezolizumab; Antibodies, Monoclonal; Immunoglobulins; Immunoglobulin G
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase I trial studies the side effects of atezolizumab, varlilumab, and radiation
      therapy in treating patients with non-small cell lung cancer that has spread to other places
      in the body (advanced) and cannot be removed by surgery (unresectable). Immunotherapy with
      monoclonal antibodies such as atezolizumab may help the body's immune system attack the
      cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy
      with monoclonal antibodies such as varlilumab may induce changes in body?s immune system and
      may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high
      energy x-rays to kill tumor cells and shrink tumors. Giving atezolizumab, varlilumab, and
      radiation therapy may increase the amount of time the disease is not active or does not
      spread to another part of the body.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must have signed and dated written informed consent form in accordance with regulatory
             and institutional guidelines

          -  Histological or cytological evidence of advanced, unresectable NSCLC

          -  Patients must be PD-1/PD-L1 experienced with disease progression documented either on
             therapy with anti-PD-1/PD-L1 or within 12 weeks of the last dose. Treatment should be
             initiated at least 4 weeks since last dose of PD-1/PD-L1 targeted therapy

          -  Patients must have progressed on at least one line of prior platinum-based
             chemotherapy in the metastatic setting. Subjects with unresectable stage III NSCLC who
             received platinum-based chemotherapy as part of chemoradiation or consolidation
             chemotherapy after chemoradiation are eligible if they progress within 6 months of
             last dose of chemotherapy. Treatment should be initiated at least 4 weeks since last
             dose of systemic therapy

          -  Subjects with an actionable molecular alteration (such as EGFR mutation, ALK or ROS1
             rearrangement, BRAF V600E mutation) are eligible only after failing standard-of-care
             targeted therapy with tyrosine kinase inhibitor (TKI). Patients with a EGFR T790M
             resistant mutation must have failed a 3rd generation TKI such as osimertinib

          -  Must not have received any prior therapy with immune regulatory molecule (such as
             targeting OX-40, IDO-1, LAG-3) or anti-CD27 monoclonal antibody (including varlilumab)

          -  Must have at least one lesion that has not previously been irradiated (and is not
             within a previously radiated field) and for which palliative radiation is potentially
             indicated. The lesion to be irradiated must be in the lung. Patient must have at least
             one additional measurable lesion (other than the lesion being radiated) as per
             immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria.
             Patient must agree to undergo a mandatory biopsy of the non-irradiated lesion
             pre-treatment and post-treatment (after cycle 2). Pre-treatment tissue obtained by
             biopsy or resection performed according to standard of care may be utilized, provided
             tissue was obtained within 8 weeks of study entry, and subsequent to the last systemic
             anticancer therapy received

          -  Patients should have fewer than 10 metastatic sites and expected survival of more than
             3 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

          -  Treatment to be initiated at least 2 weeks since last dose of prior systemic
             anticancer therapy (chemotherapy, radiation, and/or surgery)

          -  Recovery to grade 1 of any clinically significant toxicity (excluding alopecia, grade
             2 fatigue, vitiligo, endocrinopathies on stable replacement therapy, grade 2
             neuropathy from chemotherapy and grade 2 hearing loss from platinum chemotherapy)
             prior to initiation of study drugs

          -  Female patients of childbearing potential have a negative pregnancy test at baseline.
             Females of childbearing potential are defined as sexually mature women without prior
             hysterectomy or who have had any evidence of menses in the past 12 months. However,
             women who have been amenorrheic for 12 or more months are still considered to be of
             childbearing potential if the amenorrhea is possibly due to prior chemotherapy,
             anti-estrogens, or ovarian suppression

               -  Women of childbearing potential (i.e., menstruating women) must have a negative
                  urine pregnancy test (positive urine tests are to be confirmed by serum test)
                  documented within 14 days of treatment initiation

               -  Sexually active women of childbearing potential enrolled in the study must agree
                  to use 2 forms of accepted methods of contraception during the course of the
                  study and for 12 weeks after their last dose of study drug. Effective birth
                  control includes (a) intrauterine device plus 1 barrier method; (b) on stable
                  doses of hormonal contraception for at least 3 months (e.g., oral, injectable,
                  implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effective
                  barrier methods are male or female condoms, diaphragms, and spermicides (creams
                  or gels that contain a chemical to kill sperm); or (d) a vasectomized partner

               -  For male patients who are sexually active and who are partners of premenopausal
                  women: agreement to use 2 forms of contraception as in criterion above during the
                  treatment period and for 12 weeks after the last dose of study drug

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelet count >= 100,000/uL

          -  Hemoglobin >= 9.0 g/dL

          -  Total bilirubin =< 2 x upper limit of normal (ULN) or =< 3 x ULN for subjects with
             Gilbert?s disease or liver metastases

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (=< 5 x
             ULN if evidence of hepatic involvement by malignant disease)

          -  Creatinine =< 1.5 x ULN or estimated glomerular filtration rate (eGFR) >= 40
             mL/min/1.73m^2

          -  Measurable disease according to irRECIST obtained by imaging within 28 days prior to
             treatment initiation

        Exclusion Criteria:

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 23 weeks (female) or 31 weeks (male) after the last dose of study drug

          -  Treatment with any investigational agent within 28 days prior to registration for
             protocol therapy

          -  History of psychiatric illness or social situations that would limit compliance with
             study requirements. Has a history or current evidence of any condition, therapy, or
             laboratory abnormality that might confound the results of the trial, interfere with
             the subject?s participation for the full duration of the trial, or is not in the best
             interest of the subject to participate, in the opinion of the treating investigator

          -  Known active, untreated central nervous system (CNS) metastases and/or carcinomatous
             meningitis except for patients with =< 3 small (< 0.6 cm) asymptomatic brain lesions
             where treatment is not indicated. Patients with neurological symptoms must undergo a
             head computed tomography (CT) scan or brain magnetic resonance imaging (MRI) to
             exclude brain metastasis. Patients whose brain metastases have been treated may
             participate provided they show radiographic stability (defined as 2 brain images
             obtained after treatment to the brain metastases at least 4 weeks apart and show no
             evidence of intracranial progression)

          -  Known history of human immunodeficiency virus (HIV) or active hepatitis B (by surface
             antigen expression or polymerase chain reaction [PCR]) or active hepatitis C (by PCR)
             infection

          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg daily
             prednisone equivalent) or any other form of immunosuppressive therapy within 7 days
             prior to study registration

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
             drugs) or a documented history of clinically severe autoimmune disease, or a syndrome
             that requires systemic steroids or immunosuppressive agents. Vitiligo, alopecia,
             hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic
             treatment, celiac disease controlled by diet alone or conditions not expected to recur
             in the absence of an external trigger are permitted

          -  Documented history of a cerebral vascular event (stroke or transient ischemic attack),
             unstable angina, myocardial infarction, or cardiac symptoms consistent with New York
             Heart Association (NYHA) class III?IV within 6 months prior to their first dose of
             study drugs

          -  Prior malignancies (except non-melanoma skin cancers, and the following in situ
             cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or
             breast) unless a complete remission was achieved at least 1 year prior to study entry

          -  Any active grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of
             the first dose of the study drugs. Routine antimicrobial prophylaxis is permitted

          -  Active diverticulitis

          -  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 CT scan.
             History of radiation pneumonitis in the radiation field (fibrosis) is permitted