Inclusion Criteria:
- - Patients must be 18 years of age or older at the time of consent signing.
- - Patients must have histologically proven WHO grade IV glioblastoma gliosarcoma which
is progressive or recurrent following radiation therapy ± chemotherapy.
Glioblastoma
is defined using the WHO 2021 criteria and include the diagnosis of "molecular GBM"
- - Patients must be IDH wild type by CLIA-certified laboratory assay available at time
of consent.
- - Patients must have evidence of EGFR gene amplification by CLIA-certified laboratory
assay at time of consent.
- - Patients must have measurable disease as per RANO criteria pre-operatively (there is
no requirement for post-operative disease to be present or absent).
[cohort A/B
only]
- - Patients must be able to tolerate MRIs.
- - Patients may have no more than 2 prior therapy regimens.
[cohort A/B only]
- - Patients must have recovered from severe toxicity of prior therapy.
The following
intervals from previous treatments are required to be eligible:
1. 12 weeks from the completion of radiation. 2. 6 weeks from a nitrosourea chemotherapy. 3. 3 weeks from a non-nitrosourea chemotherapy. 4. 4 weeks from any investigational (not FDA-approved) agents. 5. 6 months from the last treatment with bevacizumab. 6. 2 weeks or 5 half-lives from administration of a non-cytotoxic, FDA-approved
agent other than bevacizumab, whichever is longer.
- - Patients must be undergoing surgery that is clinically indicated as determined by
their care providers.
[cohort A/B only] Patients must be eligible for surgical
resection according to the following criteria:
a. Expectation that the surgeon is able to resect at least 500 mg of tumor from
enhancing tumor with low risk of inducing neurological injury.
- - Paraffin embedded tissue must be available from initial surgical resection at
diagnosis (prior to any treatment).
The following amount of tissue is requested: 1
formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 10 FFPE
unstained slides (5µm thick).
- - Patients must have a Karnofsky Performance Status (KPS) ≥60% (i.e. the patient must
be able to care for himself/herself with occasional help from others).
- - Patients must have the following organ and marrow function:
1.
Absolute neutrophil count >1,200/mcL. 2. Platelets >100,000/mcL. 3. Hemoglobin > 9 g/dL .
4. Total bilirubin ≤ institutional upper limit of normal, or ≤ 3.0 mg/dL for
subjects with Gilbert's syndrome. 5. AST (SGOT) and ALT (SGPT) ≤ 3 × institutional upper limit of normal. 6. Creatinine ≤ institutional upper limit of normal OR Creatinine clearance >60
ml/min/1.73m2 for patients with creatinine levels above institutional normal. 7. APTT/PTT ≤ 1.5 x institutional upper limit of normal.
- - Echocardiogram with ejection fraction ≥ 50% and no other clinically significant
finding that, in the opinion of the investigator, would increase the subject's
susceptibility to cardiac toxicity.
a. If ECHO cannot be performed for structural or safety reasons, a MUGA may be
obtained instead after discussion with treating investigator.
- - Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatment
start with QT interval corrected for heart rate (QTc) < 450 msec (using Fridericia's
correction), and no clinically significant abnormalities.
- - Women of childbearing potential must have a negative serum pregnancy test prior to
study entry.
Women of childbearing potential and men treated or enrolled on this
protocol must agree to use adequate contraception (hormonal or barrier method of
birth control; abstinence) prior to study entry, for the duration of study
participation, and for 4 months after completion of treatment administration. Should
a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately.
- - A negative serum pregnancy test for all female subjects (except postmenopausal) at
the screening visit and a negative urine pregnancy test for all female subjects
(except postmenopausal) at baseline before the first dose of study drug.
- - If female, subject must be either postmenopausal, OR permanently surgically sterile
OR, for women of childbearing potential, practicing at least 1 protocol-specified
method of birth control that is effective from study Day 1 through at least 4 months
after the last dose of study drug.
- - If male, and subject is sexually active with female partner(s) of childbearing
potential, he must agree from study Day 1 through 4 months after the last dose of
study drug to practice the protocol-specified contraception.
- - If female, subject must not be pregnant, breastfeeding, or considering becoming
pregnant during the study while receiving study drug and for at least 4 months after
the last dose of study drug.
- - If male, subject must not be considering fathering a child or donating sperm during
the study or for 4 months after the last dose of study drug.
- - No known active viral hepatitis infection (including hepatitis B and C) or human
immunodeficiency virus (HIV) with the following exceptions:
- Subjects with a history of hepatitis B that is considered cured may be enrolled
at the discretion of the treating investigator.
- - Subjects with a history of hepatitis C that is considered cured with definitive
therapy may be enrolled at the discretion of the treating investigator.
- - Subjects with HIV and undetectable viral load, so long as ongoing
antiretroviral therapy does not pose risk of adverse drug-drug interactions, at
the discretion of the treating investigator.
- - Patients must have no concurrent malignancy that requires active therapy.
- - Patients must be able to swallow medication by mouth, either tablets or dispersed in
solution.
Exclusion Criteria:
- - Patients may not be receiving any other investigational agents.
- - Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to any of the investigational agents are
ineligible.
- - Patients with prior therapy with EGFR targeting agents are ineligible because
treatment with EGFR kinase inhibitors or other EGFR-targeted agents has the
potential to deplete the tumor of EGFR-amplified or EGFR mutant cell populations and
confound the evaluation of the investigational regimen.
Patients would only be
eligible if surgery on a recurrence after the EGFR-targeted therapy confirmed
persistence of an EGFR alteration.
- - Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for
treatment on this protocol.
Patients may be on non-enzyme inducing anti-epileptic
drugs or not be taking any anti-epileptic drugs. Patients previously treated with
EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to
the first dose of study drug(s).
- - Patients must not have evidence of significant hematologic, renal, or hepatic
dysfunctioPatients must not have evidence of significant intracranial hemorrhage
(For example, in the recurrent setting, circumstances where the intracranial
hemorrhage would obscure the amount and quality of tissue obtained at the time of
the on-treatment surgery).
- - Patients with uncontrolled intercurrent illness including, but not limited to,
hypertension, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/ social
situations that would limit compliance with study requirements, are ineligible.
- - Participants with clinically significant cardiovascular disease including, but not
limited to:
- No recent history (within 6 months) of congestive heart failure (defined as New
York Heart Association, Class 2 or higher), ischemic cardiovascular event,
cardiac arrhythmia requiring pharmacological or surgical intervention,
pericardial effusion, or pericarditis.
- - Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG, e.g., complete left bundle branch block, second- or third-degree
heart block, PR-interval > 250 ms.
- - Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, hypokalemia, congenital long QT syndrome, or any
concomitant medication know to prolong the QT interval.
- - No history of clinically significant medical and/or psychiatric conditions or any
other reason that, in the opinion of the investigator, would interfere with the
subject's participation in this study or would make the subject an unsuitable
candidate to receive study drug.
- - Pregnant women are excluded from this study because the investigational regimens
have potential for teratogenic or abortifacients effects.
Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother, breastfeeding should be discontinued if the mother is
treated on this study.
- - HIV-positive patients on strong CYP3A4 inducers or inhibitors are ineligible because
of the potential for pharmacokinetic interactions.
- - Patients who have acute or currently active/requiring anti-viral therapy hepatic or
biliary disease are ineligible (with the exception of patients with Gilbert's
syndrome, asymptomatic gallstones, liver metastases from the primary brain tumor, or
stable chronic liver disease per investigator assessment).
- - Patients receiving P-gp inhibitors/P-gp substrates with narrow therapeutic index are
ineligible.
- - Patients who are receiving a drug that has a risk of QTc prolongation with known
risk of if QTc is ≥ 460 msec.
are ineligible.
- - Subject must not have systemically used known moderate or strong cytochrome P450
(CYP)3A inhibitors within 10 days before the first dose of study drug and throughout
the study.
- - Subject must not have received any live vaccine within 2 weeks before the first dose
of study drug, or be expected to need a live vaccination during study participation
including at least 4 weeks after the last dose of study drug.
