Study of ABBV-637 or ABBV-155 With ERAS-801 for People With Glioblastoma

Inclusion Criteria:

• Patients must be 18 years of age or older at the time of consent signing.

• All Patients must have WHO Grade IV Glioblastoma/Gliosarcoma using WHO 2021 criteriaand include the diagnosis of molecular GBM, recurrent patients must be progressiveor recurrent following radiation therapy +/- chemotherapy

• Patients must be IDH wild type by CLIA-certified laboratory assay available at timeof consent.

• Patients must have evidence of EGFR gene amplification by CLIA-certified laboratoryassay at time of consent.

• Patients must have measurable disease as per RANO criteria pre-operatively (there isno requirement for post-operative disease to be present or absent). [cohort A/Bonly]

• 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 followingintervals 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, Chemotherapiesother than bevacizumab, whichever is shorter

• Patients must be undergoing surgery that is clinically indicated as determined bytheir care providers. [cohort A/B only] Patients must be eligible for surgicalresection according to the following criteria: a. Expectation that the surgeon is able to resect at least 500 mg of tumor fromenhancing tumor with low risk of inducing neurological injury.

• Paraffin embedded tissue must be available from initial surgical resection atdiagnosis (prior to any treatment). The following amount of tissue is requested: 1formalin-fixed, paraffin embedded (FFPE) tissue block (preferred) or 10 FFPEunstained slides (5µm thick).

• Patients must have a Karnofsky Performance Status (KPS) ≥60% (i.e. the patient mustbe 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 forsubjects 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 >60ml/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 significantfinding that, in the opinion of the investigator, would increase the subject'ssusceptibility to cardiac toxicity. a. If ECHO cannot be performed for structural or safety reasons, a MUGA may beobtained instead after discussion with treating investigator.

• Patients must have a 12-lead electrocardiogram performed within 2 weeks of treatmentstart with QT interval corrected for heart rate (QTc) < 450 msec (using Fridericia'scorrection), and no clinically significant abnormalities. (Cohorts A, B, E & F only)

• Women of childbearing potential must have a negative serum pregnancy test prior tostudy entry. Women of childbearing potential and men treated or enrolled on thisprotocol must agree to use adequate contraception (hormonal or barrier method ofbirth control; abstinence) prior to study entry, for the duration of studyparticipation, and for 4 months after completion of treatment administration. Shoulda woman become pregnant or suspect she is pregnant while participating in thisstudy, she should inform her treating physician immediately.

• A negative serum pregnancy test for all female subjects (except postmenopausal) atthe 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 sterileOR, for women of childbearing potential, practicing at least 1 protocol-specifiedmethod of birth control that is effective from study Day 1 through at least 4 monthsafter the last dose of study drug.

• If male, and subject is sexually active with female partner(s) of childbearingpotential, he must agree from study Day 1 through 4 months after the last dose ofstudy drug to practice the protocol-specified contraception.

• If female, subject must not be pregnant, breastfeeding, or considering becomingpregnant during the study while receiving study drug and for at least 4 months afterthe last dose of study drug.

• If male, subject must not be considering fathering a child or donating sperm duringthe study or for 4 months after the last dose of study drug.

• No known active viral hepatitis infection (including hepatitis B and C) or humanimmunodeficiency virus (HIV) with the following exceptions:

• Subjects with a history of hepatitis B that is considered cured may be enrolledat the discretion of the treating investigator.

• Subjects with a history of hepatitis C that is considered cured with definitivetherapy may be enrolled at the discretion of the treating investigator.

• Subjects with HIV and undetectable viral load, so long as ongoingantiretroviral therapy does not pose risk of adverse drug-drug interactions, atthe 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 insolution.

Exclusion Criteria:

• Patients may not be receiving any other investigational agents.

• Patients with a history of allergic reactions attributed to compounds of similarchemical or biologic composition to any of the investigational agents areineligible.

• Patients with prior therapy with EGFR targeting agents are ineligible becausetreatment with EGFR kinase inhibitors or other EGFR-targeted agents has thepotential to deplete the tumor of EGFR-amplified or EGFR mutant cell populations andconfound the evaluation of the investigational regimen. Patients would only beeligible if surgery on a recurrence after the EGFR-targeted therapy confirmedpersistence of an EGFR alteration.

• Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible fortreatment on this protocol. Patients may be on non-enzyme inducing anti-epilepticdrugs or not be taking any anti-epileptic drugs. Patients previously treated withEIAED may be enrolled if they have been off the EIAED for 10 days or more prior tothe first dose of study drug(s).

• Patients must not have evidence of significant hematologic, renal, or hepaticdysfunctioPatients must not have evidence of significant intracranial hemorrhage (For example, in the recurrent setting, circumstances where the intracranialhemorrhage would obscure the amount and quality of tissue obtained at the time ofthe 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/ socialsituations that would limit compliance with study requirements, are ineligible.

• Participants with clinically significant cardiovascular disease including, but notlimited to:

• No recent history (within 6 months) of congestive heart failure (defined as NewYork 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 ofresting ECG, e.g., complete left bundle branch block, second- or third-degreeheart block, PR-interval > 250 ms.

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as heart failure, hypokalemia, congenital long QT syndrome, or anyconcomitant medication know to prolong the QT interval.

• No history of clinically significant medical and/or psychiatric conditions or anyother reason that, in the opinion of the investigator, would interfere with thesubject's participation in this study or would make the subject an unsuitablecandidate to receive study drug

• Pregnant women are excluded from this study because the investigational regimenshave potential for teratogenic or abortifacients effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother, breastfeeding should be discontinued if the mother istreated on this study.

• HIV-positive patients on strong CYP3A4 inducers or inhibitors are ineligible becauseof the potential for pharmacokinetic interactions.

• Patients who have acute or currently active/requiring anti-viral therapy hepatic orbiliary disease are ineligible (with the exception of patients with Gilbert'ssyndrome, asymptomatic gallstones, liver metastases from the primary brain tumor, orstable chronic liver disease per investigator assessment).

• Patients receiving P-gp inhibitors/P-gp substrates with narrow therapeutic index areineligible.

• Patients who are receiving a drug that has a risk of QTc prolongation with knownrisk of if QTc is ≥ 460 msec. are ineligible. (Temozolomide is allowed for cohortsC,D, E and F)

• 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 throughoutthe study.

• Subject must not have received any live vaccine within 2 weeks before the first doseof study drug, or be expected to need a live vaccination during study participationincluding at least 4 weeks after the last dose of study drug.