Atezolizumab and Cabozantinib for the Treatment of Recurrent Glioblastoma

Inclusion Criteria:

• Signed informed consent form (ICF)

• Ability and willingness to comply with the requirements of the study protocol

• Age >= 18 years

• Have histologically confirmed World Health Organization grade IV glioma (glioblastoma or gliosarcoma). Archival tissue will be required for diagnosisconfirmation. Receipt of archival tissue is not required for the start of treatment

• Patients must have been previously treated with radiation and temozolomide

• Patients must be at least 12 weeks out from completion of concurrent chemoradiation

• Have a performance status of >= 60 on the Karnofsky performance status (KPS)

• Patients at either first or second recurrence will be considered eligible

• A baseline brain magnetic resonance imaging (MRI) obtained no more than 14 daysprior to study enrollment

• Absolute neutrophil count (ANC) >= 1,500 /mcL

• Platelets >= 100,000 /mcL

• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L

• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculatedcreatinine clearance (glomerular filtration rate [GFR] can also be used in place ofcreatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatininelevels > 1.5 X institutional ULN

• Creatinine clearance should be calculated per institutional standard

• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol) OR 24 hour (h)urine protein =< 1g

• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects withtotal bilirubin levels > 1.5 ULN

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN

• Serum albumin >= 2.8 g/dl

• International normalized ratio (INR) or prothrombin time (PT) activated partialthromboplastin time (aPTT) =< 1.3 X ULN

• All screening labs should be performed within 14 days (+3 working days) of treatmentinitiation

• Female subject of childbearing potential should have a negative serum pregnancy testwithin 14 days (+/- 3 working days) of study enrollment

• Female subjects of childbearing potential should be willing to use 2 methods ofbirth control or be surgically sterile, or abstain from heterosexual activity forthe duration of the study and 5 months after the last dose of study treatment.Subjects of childbearing potential are those who have not been surgically sterilizedor have not been free from menses for > 1 year

• Male subjects should agree to use an adequate method of contraception during thecourse of the study and 5 months after the last dose of study treatment

Exclusion Criteria:

• Has received prior interstitial brachytherapy, implanted chemotherapy, ortherapeutics delivered by local injection or convection enhanced delivery. Priortreatment with Gliadel wafers will be excluded. Active treatment with the Optunedevice will be excluded

• Has received radiation therapy for bone metastasis within 2 weeks or any otherradiation therapy within 4 weeks before first dose of study treatment, or systemictreatment with radionuclides within 6 weeks before first dose of study treatment

• Has clinically relevant ongoing complications from prior radiation therapy

• Is currently participating in any other recurrent therapeutic trial after completionof chemoradiation

• Has history of cavitating pulmonary lesion(s) or known endotracheal or endobronchialdisease manifestation

• Any serious medical condition that interferes with adherence to study procedures

• 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 andwith expected curative outcome (such as adequately treated carcinoma in situ of thecervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treatedsurgically with curative intent) or undergoing active surveillance perstandard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0)

• Has known leptomeningeal disease, gliomatosis cerebri, extracranial disease, ormultifocal disease. Subject has multifocal glioblastoma (GBM), defined as discretesites of contrast enhancing disease without contiguous T2/fluid attenuated inversionrecovery (FLAIR) abnormality that require distinct radiotherapy ports. Satellitelesions that are associated with a contiguous area of T2/FLAIR abnormality as themain lesion(s) and that are encompassed within the same radiotherapy port as themain lesion(s) are permitted

• Has history of interstitial lung disease or active, non-infectious pneumonitis

• Has an active infection requiring systemic therapy

• 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

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial

• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the screening visit

• Contraindication for undergoing MRIs

• Inability to comply with study and follow-up procedures

• History or risk of autoimmune disease, including but not limited to systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren'ssyndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmunethyroid disease, vasculitis, or glomerulonephritis

• Patients with a history of autoimmune hypothyroidism on a stable dose ofthyroid replacement hormone may be eligible

• Patients with controlled type 1 diabetes mellitus on a stable insulin regimenmay be eligible

• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided that they meet the following conditions:

• Patients with psoriasis must have a baseline ophthalmologic exam to ruleout ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,fluocinolone 0.01%, desonide 0.05%, aclometasone 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 ororal steroids)

• Has a medical history of idiopathic pulmonary fibrosis, pneumonitis (including druginduced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenicorganizing pneumonia, etc.), or active pneumonitis

• History of radiation pneumonitis in the radiation field (fibrosis) is permitted

• Any other diseases, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or render the patient at high risk from treatmentcomplications

• History of human immunodeficiency virus (HIV) infection or active hepatitis B (HBV) (chronic or acute) or hepatitis C infection

• Patients with past or resolved hepatitis B infection (defined as having anegative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. Patientswill be sampled for HBV DNA and will be referred to a virologist to monitor forHBV re-activation

• Patients positive for hepatitis C virus (HCV) antibody are eligible only ifpolymerase chain reaction (PCR) is negative for HCV RNA

• Active tuberculosis

• Severe infections within 4 weeks prior to cycle 1, day 1, including but not limitedto 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 urinarytract infection or chronic obstructive pulmonary disease) are eligible

• Anticipation of need for a major surgical procedure (e.g., laparoscopic nephrectomy,gastrointestinal [GI] surgery, removal or biopsy of brain metastasis) within 2 weeksbefore first dose of study treatment, or of need for a minor surgery within 10 daysbefore first dose of study treatment. Subjects must have complete wound healing frommajor surgery or minor surgery before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior surgery are not eligible

• Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 oranticipation that such a live, attenuated vaccine will be required during the study

• Influenza vaccination should be given during influenza season only (approximatelyOctober to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks prior to cycle 1, day 1 or at any time during thestudy and for 5 months after last dose of atezolizumab

• Patients may not receive concomitant chemotherapy, hormonal therapy, immunotherapy,or radiotherapy while patients are on study

• MEDICATION-RELATED EXCLUSION CRITERIA:

• Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody orpathway-targeting agents

• Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment

• Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before first dose of study treatment

• Prior treatment with anti-angiogenic (e.g. anti-vascular endothelial growth factor [VEGF]) therapeutic antibody or pathway targeting agents

• Treatment with systemic immunostimulatory agents (including but not limited tointerferon [IFN]- or interleukin [IL]-2) within 6 weeks or five half-lives of thedrug (whichever is shorter) prior to cycle 1, day 1

• Treatment with systemic immunosuppressive medications (including but not limited toprednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1

• Patients who have received acute, low-dose, systemic immunosuppressantmedications (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 adrenocorticalinsufficiency is allowed

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies, fusion proteins or components of cabozantinib

• Patients with prior allogeneic bone marrow transplantation or prior solid organtransplantation

• Evidence of recent hemorrhage on post-operative MRI of the brain, however patientswith clinically asymptomatic presence of hemosiderin, resolving post-operativechanges and punctate intratumoral hemorrhage are permitted

• Known lesions invading or encasing any major blood vessels. Subjects with lesionsinvading the intrahepatic vasculature, including portal vein, hepatic vein, andhepatic artery, are eligible

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment

• Note: if a single ECG shows a QTcF with an absolute value > 500 ms, twoadditional ECGs at intervals of approximately 3 min must be performed within 30minutes after the initial ECG, and the average of these three consecutiveresults for QTcF will be used to determine eligibility

• Inability to swallow tablets

• Inadequately controlled hypertension (defined as systolic blood pressure > 140mmHgand/or diastolic blood pressure > 90mmHg)

• A history of or active nephrotic syndrome

• Prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Assocation (NYHA) grade II or greater congestive heart failure

• History of myocardial infarction or unstable angina within 6 months prior to studyenrollment

• History of stroke or transient ischemic attack (TIA) within 6 months prior to studyenrollment

• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair orrecent peripheral arterial thrombosis) within 6 months prior to study enrollment

• History of clinically significant hematuria, hematemesis, or hemoptysis of > 0.5teaspoon (2.5 ml) of red blood, or any other history of significant bleeding (e.g.pulmonary hemorrhage) within 12 weeks before first dose of study treatment

• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeuticanticoagulation)

• Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitonealshunt or significant traumatic injury within 28 days prior to study enrollment

• Core biopsy (excluding intracranial biopsy) or other minor surgical procedure within 107 days prior to study enrollment. Placement of a central vascular access device ifperformed within 2 days prior to cabozantinib administration

• History of abdominal fistula, bowel obstruction, gastrointestinal perforation orintra-abdominal abscess within 6 months before first dose of study treatment

• Note: complete healing of an intra-abdominal abscess must be confirmed beforefirst dose of study treatment

• History of tumor invading the GI tract, active peptic ulcer disease, inflammatorybowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomaticcholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreaticduct or common bile duct, or gastric outlet obstruction

• History of intracranial abscess within 6 months prior to study enrollment

• Clinically-significant disorders that would preclude safe study participation

• Serious non-healing wound, active ulcer or untreated bone fracture

• Uncompensated/symptomatic hypothyroidism

• Moderate to severe hepatic impairment (Child-Pugh B or C)

• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g. , dabigatran), direct factor Xa inhibitor betrixaban, or plateletinhibitors (e.g., clopidogrel)

• Prophylactic use of low-dose aspirin for cardio-protection (per localapplicable guidelines) and low-dose low molecular weight heparins (LMWH) areallowed

• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastaseswho are on a stable dose of the anticoagulant for at least 1 week before firstdose of study treatment without clinically significant hemorrhagiccomplications from the anticoagulation regimen or the tumor are also allowed