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About
This phase Ib trial tests the safety, side effects, and best dose of the combination of vismodegib and atezolizumab in treating patients with non-small cell lung cancer (NSCLC) that has come back after a period of improvement (recurrent) or has spread from where it first started (primary site) to other places in the body (metastatic). Vismodegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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. Giving a combination of vismodegib and atezolizumab may be safe, tolerable and/or effective than either drug alone in treating patients with recurrent or metastatic NSCLC.
Full description
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of the combination of vismodegib and atezolizumab in patients with advanced NSCLC based upon the Common Terminology Criteria for Adverse Events (CTCAE) version 5 criteria.
SECONDARY OBJECTIVE:
I. To determine the efficacy of the combination of vismodegib and atezolizumab in patients with advanced NSCLC, including progression-free survival (PFS), objective response (ORR), disease control rate (DCR), and overall survival (OS) based on modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
EXPLORATORY OBJECTIVE:
I. To study the effect of vismodegib on the levels of M2-TAMs and CD8+ T cells within the tumor microenvironment (TME) as well as myeloid-derived suppressor cells (MDSCs) in peripheral blood of study patients.
OUTLINE:
Patients receive vismodegib orally (PO) daily on days 1-28 and atezolizumab intravenously (IV) on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the study. Some patients undergo tissue sample collection during screening and on study.
After completion of study treatment, patients are followed up every 12 weeks.
Enrollment
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Ages
Volunteers
Inclusion criteria
Age ≥ 18 years
Confirmed recurrent or metastatic non-small cell carcinoma of the lung of any histology without curative options
Measurable disease based on RECIST v1.1
Patients must have received standard of care chemotherapy and/or immunotherapy. No limits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies are permitted
Patients with adenocarcinoma and known actionable mutations with Food and Drug Administration (FDA) approved treatment options must have received all approved and standard of care treatment options (i.e. osimertinib for epidermal growth factor receptor (EGFR), alectinib for anaplastic lymphoma kinase (ALK), etc.). Mutational testing is not required for patients with squamous cell non-small cell lung carcinoma
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Absolute neutrophil count (ANC) ≥ 1,500 /mcL without granulocyte colony-stimulating factor support
Platelet count ≥ 100,000 /uL without transfusion
Hemoglobin ≥ 90 g/L (9 g/dL) patients may be transfused to meet this criterion
Measured or calculated creatinine clearance (calculated using the Cockcroft-Gault formula) ≥ 60 mL/min for subject with creatinine levels ≤ 1.5 x institutional upper limit of normal (ULN)
Serum total bilirubin ≤ 1.5 x ULN with the following exception:
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x ULN with the following exceptions:
Alkaline phosphatase (ALP) ≤ 2.5 x ULN with the following exceptions:
Albumin ≥ 2.5 g/dL
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy
Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy
Anticipated life expectancy of ≥ 3 months
Willing to comply with study procedures
Female subject of childbearing potential will have a serum pregnancy test at screening. Urine pregnancy tests will be performed at specified subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, for 5 months from last atezolizumab dose and 24 months after the final dose of vismodegib, as defined below:
Be willing and able to understand and sign the written informed consent document
Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block. A recently obtained archival FFPE tumor tissue block (if an FFPE tissue block cannot be provided, 15 unstained slides (10 minimum) will be acceptable) from a primary or metastatic tumor resection or biopsy can be provided if it was obtained within 1 year of trial screening
Be willing to provide tissue from an on-treatment fine needle aspiration (FNA) or core biopsy of a tumor lesion. Subjects must consent to on-treatment biopsy prior to initiation of clinical trial, however subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may still continue on study
Negative HIV test at screening with the following exception: patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count > 200/uL, and have an undetectable viral load
Negative total hepatitis B core antibody (HBcAb) test at screening. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening
Exclusion criteria
Active autoimmune disease requiring treatment or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
Patients with a history of autoimmune-related hypothyroidism who are stable on thyroid-replacement hormone are eligible for the study
Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at doses > 10 mg prednisone or equivalent or other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment
Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
Has symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with asymptomatic CNS lesions will be eligible if considered appropriate by the treating physician. Subjects with previously treated brain metastases may participate provided they have had a stable neurological status for at least 2 weeks after completion of definitive therapy
Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:
Pregnancy or breastfeeding or intention of becoming pregnant during study treatment or within 5 months for atezolizumab or within 24 months after the final dose of vismodegib.
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
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Known active tuberculosis (specific testing is only needed if clinically indicated)
Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
Prior allogeneic stem cell or solid organ transplantation
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation of study treatment, during treatment with atezolizumab, and for 5 months after the last dose of atezolizumab
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
Any patient who experience unacceptable toxicity on prior checkpoint inhibitor therapy:
≥ grade 3 adverse event (AE) related to checkpoint inhibitor
≥ grade 2 immune-related AE associated with checkpoint inhibitor
CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor
Primary purpose
Allocation
Interventional model
Masking
24 participants in 1 patient group
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Central trial contact
The Ohio State Comprehensive Cancer Center
Data sourced from clinicaltrials.gov
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