Inclusion Criteria:
- - Signed informed consent form (ICF)
- Ability and willingness to comply with the requirements of the study protocol.
- - Have histologically confirmed World Health Organization grade IV glioma (glioblastoma
or gliosarcoma).
Archival tissue will be required for diagnosis confirmation. 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 days prior
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 calculated
creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine
levels > 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 with total
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 partial
thromboplastin time (aPTT) =< 1.3 X ULN.
- - All screening labs should be performed within 14 days (+3 working days) of treatment
initiation.
- - Female subject of childbearing potential should have a negative serum pregnancy test
within 14 days (+/- 3 working days) of study enrollment.
- - Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
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 sterilized or have not
been free from menses for > 1 year.
- - Male subjects should agree to use an adequate method of contraception during the
course of the study and 5 months after the last dose of study treatment.
Exclusion Criteria:
- - Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
delivered by local injection or convection enhanced delivery.
Prior treatment with
Gliadel wafers will be excluded. Active treatment with the Optune device will be
excluded.
- - Has received radiation therapy for bone metastasis within 2 weeks or any other
radiation therapy within 4 weeks before first dose of study treatment, or systemic
treatment 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 completion
of chemoradiation.
- - Has history of cavitating pulmonary lesion(s) or known endotracheal or endobronchial
disease 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 and with
expected curative outcome (such as adequately treated carcinoma in situ of the cervix,
basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically
with curative intent) or undergoing active surveillance per standard-of-care
management (e.g., chronic lymphocytic leukemia Rai Stage 0)
- Has known leptomeningeal disease, gliomatosis cerebri, extracranial disease, or
multifocal disease.
Subject has multifocal glioblastoma (GBM), defined as discrete
sites of contrast enhancing disease without contiguous T2/fluid attenuated inversion
recovery (FLAIR) abnormality that require distinct radiotherapy ports. Satellite
lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main
lesion(s) and that are encompassed within the same radiotherapy port as the main
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 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.
- - Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- - Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected 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 lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's
syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis.
- - Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible.
- - Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may
be eligible.
- - Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out
ocular manifestations.
- - Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency
topical 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 or
oral steroids)
- Has a medical history of idiopathic pulmonary fibrosis, pneumonitis (including drug
induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
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 clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications.
- - 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 a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible.
Patients will
be sampled for HBV DNA and will be referred to a virologist to monitor for HBV
re-activation.
- - Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA.
- - Severe infections within 4 weeks prior to cycle 1, day 1, including but not limited to
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 urinary
tract 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 weeks
before first dose of study treatment, or of need for a minor surgery within 10 days
before first dose of study treatment.
Subjects must have complete wound healing from
major surgery or minor surgery before first dose of study treatment. Subjects with
clinically relevant ongoing complications from prior surgery are not eligible.
- - Administration of a live, attenuated vaccine within 4 weeks before cycle 1, day 1 or
anticipation that such a live, attenuated vaccine will be required during the study.
- - Influenza vaccination should be given during influenza season only (approximately
October 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 the study 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 or
pathway-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 investigational
kinase 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 to
interferon [IFN]- or interleukin [IL]-2) within 6 weeks or five half-lives of the drug
(whichever is shorter) prior to cycle 1, day 1.
- - Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1.
- - Patients who have received acute, low-dose, systemic immunosuppressant
medications (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 adrenocortical insufficiency is
allowed.
- - History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies, fusion proteins or components of cabozantinib.
- - Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation.
- - Evidence of recent hemorrhage on post-operative MRI of the brain, however patients
with clinically asymptomatic presence of hemosiderin, resolving post-operative changes
and punctate intratumoral hemorrhage are permitted.
- - Known lesions invading or encasing any major blood vessels.
Subjects with lesions
invading the intrahepatic vasculature, including portal vein, hepatic vein, and
hepatic artery, are eligible.
- - Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment.
- - Note: if a single ECG shows a QTcF with an absolute value > 500 ms, two
additional ECGs at intervals of approximately 3 min must be performed within 30
minutes after the initial ECG, and the average of these three consecutive results
for QTcF will be used to determine eligibility.
- - Inability to swallow tablets.
- - Inadequately controlled hypertension (defined as systolic blood pressure > 140mmHg
and/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 study
enrollment.
- - History of stroke or transient ischemic attack (TIA) within 6 months prior to study
enrollment.
- - Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent
peripheral arterial thrombosis) within 6 months prior to study enrollment.
- - History of clinically significant hematuria, hematemesis, or hemoptysis of > 0.5
teaspoon (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 therapeutic
anticoagulation)
- Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt
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 if
performed within 2 days prior to cabozantinib administration.
- - History of abdominal fistula, bowel obstruction, gastrointestinal perforation or
intra-abdominal abscess within 6 months before first dose of study treatment.
- - Note: complete healing of an intra-abdominal abscess must be confirmed before
first dose of study treatment.
- - History of tumor invading the GI tract, active peptic ulcer disease, inflammatory
bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic
duct 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 thrombin
inhibitors (e.g. , dabigatran), direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel)
- Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH) are allowed.
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor are also allowed
