Vismodegib and Atezolizumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer

Inclusion Criteria:

• Age ≥ 18 years

• Confirmed recurrent or metastatic non-small cell carcinoma of the lung of anyhistology without curative options

• Measurable disease based on RECIST v1.1

• Patients must have received standard of care chemotherapy and/or immunotherapy. Nolimits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies arepermitted

• Patients with adenocarcinoma and known actionable mutations with Food and DrugAdministration (FDA) approved treatment options must have received all approved andstandard of care treatment options (i.e. osimertinib for epidermal growth factorreceptor (EGFR), alectinib for anaplastic lymphoma kinase (ALK), etc.). Mutationaltesting is not required for patients with squamous cell non-small cell lungcarcinoma

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Absolute neutrophil count (ANC) ≥ 1,500 /mcL without granulocyte colony-stimulatingfactor 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-Gaultformula) ≥ 60 mL/min for subject with creatinine levels ≤ 1.5 x institutional upperlimit of normal (ULN)

• Serum total bilirubin ≤ 1.5 x ULN with the following exception:

• Patients with known Gilbert disease: serum bilirubin ≤ 3 x ULN

• 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:

• Patients with documented liver metastases: AST and ALT ≤ 5 x ULN

• Both values must be in the specified range

• Alkaline phosphatase (ALP) ≤ 2.5 x ULN with the following exceptions:

• Patients with documented liver or bone metastases: ALP ≤ 5 x ULN

• Albumin ≥ 2.5 g/dL

• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unlesssubject is receiving anticoagulant therapy

• As long as PT or partial thromboplastin time (PTT) is within therapeutic rangeof intended use of anticoagulants

• Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receivinganticoagulant therapy

• As long as PT or PTT is within therapeutic range of intended use ofanticoagulants

• Anticipated life expectancy of ≥ 3 months

• Willing to comply with study procedures

• Female subject of childbearing potential will have a serum pregnancy test atscreening. Urine pregnancy tests will be performed at specified subsequent visits.If a urine pregnancy test is positive, it must be confirmed by a serum pregnancytest

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods, and agreement to refrainfrom donating eggs, as defined below:

• Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the finaldose of atezolizumab and 24 months after the final dose of vismodegib. Womenmust refrain from donating eggs during this same period

• A woman is considered to be of childbearing potential if she is postmenarchal,has not reached a postmenopausal state (≥ 12 continuous months of amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries and/or uterus). The definition ofchildbearing potential may be adapted for alignment with local guidelines orrequirement

• Examples of contraceptive methods with a failure rate of < 1% per yearinclude bilateral tubal ligation, male sterilization, hormonal contraceptivesthat inhibit ovulation, hormone-releasing intrauterine devices, and copperintrauterine devices

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods of contraception

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, and agreement to refrain from donating sperm, for 5months from last atezolizumab dose and 24 months after the final dose of vismodegib,as defined below:

• With a female partner of childbearing potential or pregnant female partner, menmust remain abstinent or use a condom during the treatment period and, for 5months from last atezolizumab dose and 24 months after the final dose ofvismodegib to avoid exposing the embryo. Men must refrain from donating spermduring this same period

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods of preventingdrug exposure

• Be willing and able to understand and sign the written informed consent document

• Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissueblock. A recently obtained archival FFPE tumor tissue block (if an FFPE tissue blockcannot be provided, 15 unstained slides (10 minimum) will be acceptable) from aprimary or metastatic tumor resection or biopsy can be provided if it was obtainedwithin 1 year of trial screening

• Be willing to provide tissue from an on-treatment fine needle aspiration (FNA) orcore biopsy of a tumor lesion. Subjects must consent to on-treatment biopsy prior toinitiation of clinical trial, however subjects for whom newly-obtained samplescannot be provided (e.g. inaccessible or subject safety concern) may still continueon study

• Negative HIV test at screening with the following exception: patients with apositive HIV test at screening are eligible provided they are stable onanti-retroviral therapy, have a CD4 count > 200/uL, and have an undetectableviral load

• Negative total hepatitis B core antibody (HBcAb) test at screening. For patientswith evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load mustbe undetectable on suppressive therapy, if indicated

• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCVantibody test followed by a negative HCV ribonucleic acid (RNA) test at screening

• The HCV RNA test must be performed for patients who have a positive HCVantibody test

Exclusion Criteria:

• Active autoimmune disease requiring treatment or immune deficiency, including, butnot limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barresyndrome, or multiple sclerosis, with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are stable onthyroid-replacement hormone are eligible for the study

• Patients with controlled type 1 diabetes mellitus who are on an insulin regimenare eligible for the study

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover ≤ 10% of body surface area

• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oralcorticosteroids within the previous 12 months

• Is currently participating and receiving study therapy or has participated in astudy of an investigational agent and received study therapy or used aninvestigational device within 4 weeks of the first dose of treatment

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy atdoses > 10 mg prednisone or equivalent or other form of immunosuppressive therapywithin 14 days prior to the first dose of trial treatment

• Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepaticencephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinicallymeaningful ascites is defined as ascites from cirrhosis requiring diuretics orparacentesis

• Has symptomatic central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with asymptomatic CNS lesions will be eligible if consideredappropriate by the treating physician. Subjects with previously treated brainmetastases may participate provided they have had a stable neurological status forat least 2 weeks after completion of definitive therapy

• Asymptomatic patients with treated CNS lesions are eligible, provided that allof the following criteria are met:

• Measurable disease, per RECIST v1.1, must be present outside the CNS

• The patient has no history of intracranial hemorrhage or spinal cordhemorrhage

• The patient has not undergone stereotactic radiotherapy within 7 daysprior to initiation of study treatment, whole-brain radiotherapy within 14days prior to initiation of study treatment, or neurosurgical resectionwithin 28 days prior to initiation of study treatment

• The patient has no ongoing requirement for corticosteroids as therapy forCNS disease

• If the patient is receiving anti-convulsant therapy, the dose isconsidered stable

• Pregnancy or breastfeeding or intention of becoming pregnant during study treatmentor within 5 months for atezolizumab or within 24 months after the final dose ofvismodegib.

• Women of childbearing potential must have a negative serum pregnancy testresult within 14 days prior to initiation of study treatment

• Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan. History ofradiation 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 orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina

• Major surgical procedure, other than for diagnosis, within 4 weeks prior toinitiation of study treatment, or anticipation of need for a major surgicalprocedure during the study

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe 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, orsevere pneumonia, or any active infection that could impact patient safety

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent aurinary tract infection or chronic obstructive pulmonary disease exacerbation) areeligible for the study

• Prior allogeneic stem cell or solid organ transplantation

• Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior toinitiation of study treatment, during treatment with atezolizumab, and for 5 monthsafter 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 humanizedantibodies or fusion proteins

• Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab formulation

• Any patient who experience unacceptable toxicity on prior checkpoint inhibitortherapy:

• ≥ 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

• NOTE: Patients with a prior endocrine AE are permitted to enroll if theyare stably maintained on appropriate replacement therapy and areasymptomatic