PRIMARY OBJECTIVES:
I. To evaluate the safety of atezolizumab in combination with radiation and temozolomide
during the concurrent stage and in combination with temozolomide during the adjuvant stage.
(Phase I) II. To evaluate the overall survival (OS) of atezolizumab in combination with
radiation and temozolomide and in combination with temozolomide at onset of treatment. (Phase
II)
SECONDARY OBJECTIVES:
I. To evaluate the overall response rate (ORR), duration of response, and progression free
survival (PFS) of atezolizumab in combination with radiation and temozolomide during the
treatment period.
CORRELATIVE OBJECTIVES:
I. Profiling tumor immune cell populations (example: immunohistochemistry [IHC] analyses of
CD4, CD8, programmed death-1 [PD-1], programmed death-ligand 1 [PD-L1], and PD-L2).
II. Profiling of tumor deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA),
microRNA and epigenetic profiling (DNA methylation) and evaluation of whole exome sequencing,
RNA sequencing, microRNA sequencing and cell-free circulating tumor DNA (ctDNA).
III. Peripheral blood collection for evaluation of circulating chemokines/cytokines.
OUTLINE: This is a phase I study followed by a phase II study.
PHASE I (CONCURRENT PHASE): Patients receive temozolomide orally (PO) daily on days 1-42 and
atezolizumab intravenously (IV) over 30-60 minutes on day 1, 15, 29, and 42. Patients undergo
radiation therapy (RT) 5 days per week (Monday-Friday) for 6 weeks in the absence of disease
progression or unacceptable toxicity.
PHASE II (ADJUVANT PHASE): Patients receive temozolomide PO on days 1-5 and atezolizumab IV
over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 12 courses in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3
months.
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 undergone surgery and must not have had any further treatment
following surgery.
- Have a performance status of >= 60 on the Karnofsky performance status (KPS).
- A baseline brain magnetic resonance imaging (MRI) obtained no more than 14 days prior
to study enrollment on a stable or tapering dose of steroids no greater than 4 mg a
day of dexamethasone for at least 5 days.
- Patients must start treatment within 6 weeks of definitive resection.
- Absolute neutrophil count (ANC) >= 1,500 /mcL.
- Platelets >= 100,000 /mcL.
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L.
- Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =<
1.5 x upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels >
1.5 x institutional ULN.
- 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 glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN.
- International normalized ratio (INR) or prothrombin time (PT) activated partial
thromboplastin time (aPTT) </=1.5 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. 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.
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. Prior treatment with the Optune device will be
excluded.
- Is currently participating or has participated in any other newly diagnosed
therapeutic trial before or after chemoradiation.
- Any serious medical condition that interferes with adherence to study procedures.
- Patients may not receive concomitant chemotherapy, hormonal therapy, immunotherapy, or
radiotherapy while patients are on study.
- 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 evidence 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, Sjögren's
syndrome, Bell's palsy, Guillain-Barré 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%, flucinolone 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).
- History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. 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 (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 hepatitis B virus (HBV) deoxyribonucleic acid (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 ribonucleic acid (RNA).
- Active tuberculosis.
- 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 during the course of the study.
- 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.
- 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, localized prostate cancer treated surgically with
curative intent, 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, prostate cancer with Gleason score =< 6, and
prostate-specific antigen [PSA] =< 10 mg/mL, etc.)
- Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway
targeting agents.
- Treatment with systemic immunostimulatory agents (including but not limited to
interferon [IFN]-a 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 or fusion proteins.
- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation.
