A Phase 0/1 Study of BDTX-1535 in Recurrent High-Grade Glioma (rHGG) and Newly Diagnosed Glioblastoma (nGBM) Participants With EGFR Alterations or Fusions

Inclusion Criteria:

• Arms A & B: Recurrent high grade glioma (2021 WHO Grades 3 and 4), defined asparticipants who have progressed on or following standard therapy, which includesmaximal surgical resection, temozolomide, and fractionated radiotherapy.

• Arm C, D, & E: Newly diagnosed glioblastoma (2021 WHO Grade 4), who have notreceived any tumor directed intervention other than biopsy or resection.

• Candidate for clinical resection of rHGG (Arms A & B) or nGBM (Arms C & D).

• Adequate archival or biopsy tissue available for testing of EGFR alterations. Thetissue must have evidence of EGFR alterations including variants, fusion, andmutations with or without amplifications. rHGG participants with EGFR fusion will besolely enrolled into Arm B.

• Participants must have measurable disease preoperatively, defined as at least 1contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.

• Provision of signed and dated, written informed consent (personally or by thelegally authorized representative, if applicable) prior to any study specificprocedures, sampling and analyses.

• Age ≥ 18 at time of consent

• Have a performance status (PS) of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.

• Ability to swallow oral medications.

• Participant has adequate bone marrow and organ function as defined by the followinglaboratory values (as assessed by the local laboratory for eligibility):

• Absolute neutrophil count ≥ 1,500/mcL

• Platelets ≥ 100,000/mcL (at time of surgery)

• Hemoglobin ≥ 8.5 g/dL (Participants may receive erythrocyte transfusions toachieve this hemoglobin level at the discretion of the investigator. Initialtreatment must not begin earlier than the day after the erythrocytetransfusion.)

• Total bilirubin ≤ 1.5 X ULN (Participants with Gilbert's syndrome with a totalbilirubin ≤ 3.0 times ULN and direct bilirubin within normal limits arepermitted.)

• AST (SGOT) ≤ 3 X institutional ULN

• ALT (SGPT) ≤ 3 X institutional ULN

• Serum creatinine ≤ 1.5 X ULN or estimated creatinine clearance ≥ 60 mL/min (calculated using Institutional standard method)

• Participants on corticosteroids at baseline must be on stable or decreasing dosesfor at least 5 days prior to Day 1.

• Confirmed negative serum pregnancy test (β-hCG) before starting study treatment orparticipant who is no longer of childbearing potential due to surgical, chemical, ornatural menopause.

• For females of reproductive potential: use of highly effective contraception andagreement to use such a method during study participation until the end of treatmentadministration and for 16 weeks after the last dose of study drug.

• For males of reproductive potential: use of condoms or other methods to ensureeffective contraception with partner until the end of treatment administration andfor 16 weeks after the last dose of study drug.

• Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria:

• Pregnancy or breastfeeding.

• Known allergic reactions to components of the BDTX-1535.

• Known to have active (acute or chronic) or uncontrolled severe infection, liverdisease such as cirrhosis, decompensated liver disease, and active and chronichepatitis, as determined by the investigator.

• Known active systemic bacterial infection (requiring intravenous [IV] antibiotics orfever >38.5°C at time of initiating study treatment), fungal infection, ordetectable viral infection (such as known human immunodeficiency virus positivity orwith known active hepatitis B or C [for example, hepatitis B surface antigenpositive]. Screening of viral infection is not required for enrollment.

• Significant cardiovascular disease, including NYHA Class III or IV congestive heartfailure, myocardial infarction, unstable angina, poorly controlled cardiacarrhythmias, or stroke in the preceding 6 months prior to study Day 1.

• Symptomatic or radiographic leptomeningeal disease.

• Participant has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this study (forexample, interstitial lung disease, severe dyspnea at rest or requiring oxygentherapy, severe renal impairment [e.g. estimated creatinine clearance <30ml/min],history of major surgical resection involving the stomach or small bowel, orpreexisting Crohn's disease or ulcerative colitis or a preexisting chronic conditionresulting in baseline Grade 2 or higher diarrhea).

• Concurrent use of prohibited medications: coadministration of strong CYP2C8 andCYP3A4 inhibitors and inducers with BDTX-1535. These should be discontinued 1 weekor 5 half-lives (whichever is greater) prior to study Day 1. Strong inhibitors ofP-gp (e.g., Amiodarone, carvedilol, dronedarone, propafenone, quinidine, ranolazine,and verapami) and BCRP (e.g., curcumin, cyclosporin A, and eltrombopag) should beused with caution. Sensitive substrates of P-gp, BCRP, and OATP should also be usedwith caution.

• Therapeutic intent treatment with another investigational drug or other interventionwithin 5 half-lives of the investigational product whichever is longer.

• With the exception of alopecia, any unresolved toxicities from prior therapy greaterthan National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5) Grade 1 at the time of starting study treatment and patients withchronic Grade 2 unresolved toxicities may be eligible following discussion with thePrincipal Investigator.