Inclusion Criteria:
- - Patients must have histologically confirmed IDH wildtype World Health Organization
(WHO) grade IV glioblastoma at first or second relapse.
- - Documented progression of disease as defined by modified Response Assessment in
Neuro-Oncology (mRANO) criteria at least 12 weeks after completion of radiotherapy,
unless the recurrence is outside the radiation field or has been histologically
documented.
Because no dosing or adverse event data are currently available on
the use of atezolizumab in combination with tiragolumab in patients < 18 years of
age, children are excluded from this study.
- - Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky ≥ 60%)
- Leukocytes ≥ 2,000/mcL.
- - Lymphocyte count ≥ 500/mcL.
- - Absolute neutrophil count ≥ 1,500/mcL without granulocyte colony-stimulating factor
support.
- - Platelets ≥ 100,000/mcL without transfusion.
- - Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (however, patients
with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled)
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤
2.5 x institutional ULN or ≤ 5 x ULN for patients with liver metastases.
- - Alkaline phosphatase ≤ 2.5 x ULN (≤ 5 x ULN for patients with documented liver or
bone metastases)
- Glomerular filtration rate (GFR) ≥ 30 mL/min.
- - International normalized ratio (INR) and activated partial thromboplastin time
(aPTT) ≤ 1.5 x ULN (This applies only to patients who do not receive therapeutic
anticoagulation; patients receiving therapeutic anticoagulation, such as low-weight
heparin or warfarin, should be on a stable dose.
)
- - Serum albumin ≥ 2.5 g/dL.
- - Negative human immunodeficiency virus (HIV) test at screening with the following
exception: individuals with a positive HIV test at screening are eligible provided
they are stable on anti-retroviral therapy, have a CD4+ T cell count ≥ 200/uL, and
have an undetectable viral load.
- - Negative hepatitis B surface antigen (HBsAg) test at screening.
- - Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb
at screening accompanied by either of the following:
- Negative total hepatitis B core antibody (HBcAb)
- Positive total HBcAb test followed by quantitative hepatitis B virus (HBV)
deoxyribonucleic acid (DNA) < 500 IU/mL.
The HBV DNA test will be performed
only for patients who have a negative HBsAg test, a negative HBsAb test, and a
positive total HBcAb test.
- - Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV
antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening.
The HCV RNA test will be performed only for patients who have a positive HCV
antibody test.
- - Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial.
- - Patients must be undergoing surgery that is clinically indicated as determined by
their care providers.
- - Ability to understand and the willingness to sign a written informed consent
document.
Exclusion Criteria:
- - Patients with IDH mutations will be excluded from the study.
- - Patients who have had previous treatment with anti PD1, PDL1, CTLA-4 or other immune
checkpoint inhibitors.
- - Patients who have undergone tumor directed therapy for the most recent disease
progression.
- - Patients who have not recovered to grade 0 or 1 or pre-treatment baseline from
clinically significant adverse events due to prior anti-cancer therapy (i.e., have
residual toxicities > grade 1) with the exception of alopecia.
- - Patients who are receiving any other investigational agents.
- - Patients with a diagnosis of immunodeficiency or who require treatment with high
dose systemic corticosteroids defined as dexamethasone > 2 mg/day or bioequivalent
for at least 3 consecutive days within 1 week of start of study drug.
- - Patients with severe, uncontrolled intercurrent illness, comorbidity, or any other
significant condition(s) that would make participation in this protocol unreasonably
hazardous.
- - Patients who are pregnant or breastfeeding or are expecting to conceive or father
children within the projected duration of the study, starting with the screening
visit through 5 months after the last dose of study treatment.
Women of childbearing
potential (WOCPB) must have a negative serum pregnancy test result within 14 days
prior to initiation of study treatment. A WOCBP who has a positive urine pregnancy
test (e.g., within 72 hours) prior to treatment will be excluded from the study. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required. A woman is considered to be of childbearing potential if she
is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of
amenorrhea with no identified cause other than menopause), and has not undergone
surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) or
another cause as determined by the investigator (e.g., Müllerian agenesis). Per this
definition, a woman with a tubal ligation is considered to be of childbearing
potential. The definition of childbearing potential may be adapted for alignment
with local guidelines or regulations. Pregnant women are excluded from this study
because atezolizumab and tiragolumab are monoclonal antibodies with the potential
for teratogenic or abortifacient effects. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
atezolizumab and/or tiragolumab, breastfeeding should be discontinued if the mother
is treated with atezolizumab and/or tiragolumab. To avoid pregnancy, WOCBPs and men
must agree to use adequate contraception (i.e., contraceptive methods with a failure
rate of < 1% per year such as bilateral tubal ligation, male sterilization, hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and
copper intrauterine devices) prior to the study, during treatment, and for 5 months
after treatment ends. Should a woman become pregnant or suspect she is pregnant
while she or her partner is participating in this study, she should inform her
treating physician immediately.
- - Patients unable to comply with the protocol and/or not willing or who will not be
available for follow-up assessments, specifically MRI scans.
- - Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre
syndrome, or multiple sclerosis, with the exceptions listed below:
- Patients with a history of autoimmune-related hypothyroidism who are on thyroid
replacement hormone are eligible for the study.
- - Patients with controlled type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- - Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
- Rash must cover < 10% of body surface area.
- - Disease is well controlled at baseline and requires only low-potency
topical corticosteroids.
- - There has been no occurrence of acute exacerbations of the underlying
condition requiring psoralen plus ultraviolet A radiation, methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors, or high potency
or oral corticosteroids within the previous 12 months.
- - Treatment with systemic immunosuppressive medication (including, but not limited to,
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
anti-tumor necrosis factor-alpha [TNF-alpha] agents) within 2 weeks prior to
initiation of study treatment, or anticipation of need for systemic
immunosuppressive medication during study treatment, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are eligible for the study.
- - Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study.
- - Patients with presence of extracranial metastatic or leptomeningeal disease.
- - Patients that have received anti-angiogenic or anti-VEGF targeted agents (e.g.,
bevacizumab, cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc.)
- Patients with patent active tuberculosis (TB)
- Patients with prior allogeneic bone marrow transplantation or prior solid organ
transplantation.
- - Patients being treated with systemic immunostimulatory agents (including, but not
limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 4 weeks prior to
cycle 1, day 1.
The study principal investigator (PI) must be consulted if a patient
was being treated with any antibody within 4 half-lives of said antibody.
- - History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis.
- - Patients treated with therapeutic oral (PO) or IV antibiotics within 2 weeks prior
to initiation of study treatment.
Patients receiving prophylactic antibiotics (e.g.,
to prevent a urinary tract infection or chronic obstructive pulmonary disease
exacerbation) are eligible for the study.
- - Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia, or any active infection that could impact patient safety.
- - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently).
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)
- Uncontrolled tumor-related pain:
- Patients requiring pain medication must be on a stable regimen at study entry.
- - Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment.
Patients should be recovered from the effects of radiation. There
is no required minimum recovery period.
- - Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural compression) should be
considered for loco-regional therapy if appropriate prior to enrollment.
- - Significant cardiovascular disease (such as New York Heart Association class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrythmia, or unstable
angina.
- - Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during study treatment,
within 90 days after the final dose of tiragolumab, or within 5 months after the
final dose of atezolizumab.
- - Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM) test
at screening.
An EBV polymerase chain reaction (PCR) test should be performed as
clinically indicated to screen for acute infection or suspected chronic active
infection. Patients with a positive EBV PCR test are excluded.
- - History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins.
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab or tiragolumab formulation
