Vismodegib Combined With Atezolizumab in Platinum Resistant Ovarian, Fallopian Tube, and Primary Peritoneal Cancer

Inclusion Criteria:

• Signed Informed Consent Form

• Ability to comply with the study protocol, in the investigator's judgment

• Histologically or cytologically confirmed epithelial ovarian, fallopian tube orprimary peritoneal cancer

• Platinum status, defined by disease progression during or following treatment withplatinum-based chemotherapy within 6 months of completing therapy

• Measurable or non-measurable but evaluable disease per RECIST v1.1 {Previouslyirradiated lesions can be considered as measurable disease only if progressivedisease has been unequivocally documented at that site since radiation.}

• Availability of a representative tumor specimen for exploratory biomarker researchwill be required for 12 patients (see Section 5.4.5 for information on tumorspecimens)

• ECOG Performance Status of 0-1

• Life expectancy ≥ 3 months

• Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 14 days prior to initiation of study treatment: ANC ≥ 1.5 ⋅ 109/L (1500/μL) without granulocyte colony-stimulating factor support;Lymphocyte count ≥ 0.5 ⋅ 109/L (500/μL); Platelet count ≥ 100 ⋅ 109/L (100,000/μL)without transfusion; Hemoglobin ≥ 80 g/L (8 g/dL) (Patients may be transfused tomeet this criterion.)

• AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 ⋅ upper limit of normal (ULN),with the following exceptions:

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

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

• Serum bilirubin ≤ 1.5 ⋅ ULN with the following exception:

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

• Serum creatinine ≤ 1.5 ⋅ ULN

• Serum albumin ≥ 25 g/L (2.5 g/dL)

• For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 ⋅ ULN

• For patients receiving therapeutic anticoagulation: stable anticoagulantregimen

• Negative HIV test at screening, with the following exception: patients with apositive HIV test at screening are eligible if they are stable on anti-retroviraltherapy, have a CD4 count > 200, and have an undetectable viral load.

• Negative hepatitis B surface antigen (HBsAg) test at screening

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods 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 final doseof atezolizumab and for 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 orrequirements.

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit 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 ofcontraception.

Exclusion Criteria:

• Inability or unwillingness to swallow capsules

• Inability or unwillingness to comply with study procedures

• History of leptomeningeal disease

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently) o Patients with indwelling catheters (e.g., PleurX→) are allowed.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)

• Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barrésyndrome, or multiple sclerosis (see Appendix 9) for a more comprehensive list ofautoimmune diseases and immune deficiencies), with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are 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-potency topicalcorticosteroids

• No occurrence of acute exacerbations of the underlying condition requiring psoralenplus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oralcalcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months

• 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).

• Active tuberculosis

• 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

• History of malignancy other than ovarian cancer within 5 years prior to screening,with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of thecervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma insitu, or Stage I uterine cancer

• Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment

• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tractinfection or chronic obstructive pulmonary disease exacerbation) are eligiblefor the study.

• Prior allogeneic stem cell or solid organ transplantation

• 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

• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during atezolizumabtreatment or within 5 months after the final dose of atezolizumab

• Current treatment with anti-viral therapy for HBV

• Treatment with investigational therapy within 28 days prior to initiation of studytreatment

• 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

• Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-α agents) within 2 weeks prior to initiation of study treatment, oranticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study afterPrincipal Investigator confirmation has been obtained.

• Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

• 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

• Known allergy or hypersensitivity to any component of the vismodegib formulation

• Agreement not to donate blood or blood products during the study and for 24 monthsafter discontinuation of vismodegib.

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

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