A Study Assessing BGB-290 With Radiation and/or Temozolomide (TMZ) in Subjects With Newly Diagnosed or Recurrent Glioblastoma

An open‑label, multiple‑dose, dose-escalation study to determine the safety, pharmacokinetics
(PK) and pharmacodynamics (PD) of BGB-290 in combination with radiation therapy (RT) and/or
TMZ with 2 arms and a potential third arm.

In dose escalation/Phase 1b, BGB-290 will be combined with RT (Arm A) or RT and TMZ (Arm B)
in subjects with newly diagnosed unmethylated glioblastoma (GB), or BGB-290 will be combined
with TMZ in subjects with methylated or unmethylated recurrent/refractory GB (Arm C).

The dose expansion/Phase 2 phase will enroll up to 4 cohorts: subjects with newly diagnosed
unmethylated GB in Arm A and Arm B, and 2 potential cohorts of subjects with unmethylated and
methylated recurrent/refractory GB in Arm C. Subjects in dose expansion may continue
treatment in the absence of safety concerns and disease progression.

Inclusion Criteria: All subjects

1. Age ≥ 18 years old.

2. Confirmed diagnosis of glioblastoma (WHO Grade IV).

3. Ability to undergo serial MRIs.

4. ECOG status ≤ 1.

5. Adequate bone marrow function.

6. Adequate renal and hepatic function.

7. Females of childbearing potential and non-sterile males must agree to use highly
effective methods of birth control throughout the course of study and at least up to
90 days after last dosing.

8. Ability to swallow whole capsules.

Subjects in Arms A and B (not Arm C) must also meet inclusion criteria 9 - 10:

9. No previous treatment for GB except surgery.

10. Able to start radiation therapy ≤ 49 days after surgery but ≥ 14 days after a biopsy
or ≥28 days after an open biopsy or craniotomy with adequate wound healing.

11. Documented unmethylated MGMT promoter status.

Subjects in Arm C must also meet inclusion criteria # 12 - 14:

12. No prior systemic chemotherapy other than TMZ for GB.

13. Progressive disease > 2 months after completion of first line therapy.

14. At least one measurable lesion by mRANO.

Subjects in Arm C Phase 2, Cohort C1 must also meet criteria # 15. This is not
applicable to subjects enrolled in Arm C, Ph 1b.

15. Documentation of unmethylated MGMT promoter status.

Subjects in Arm C Phase 2, Cohort C2 must also meet Criteria #16. This is not
applicable to subjects enrolled in Arm C Phase 1b.

16. Documentation of methylated MGMT promoter status.

Exclusion Criteria: All subjects

1. Prior chemotherapy, biologic therapy, immunotherapy or investigational agents ≤21 days
prior to start of study treatment.

2. Toxicity of ≥ Grade 2 from prior therapy.

3. Major surgery or significant other injury ≤ 4 weeks prior to start of study treatment.

4. History of other active malignancies within 2 years with exception of (i) adequately
treated in situ cancer of the cervix, (ii) non-melanoma skin cancer, or (iii)
localized adequately treated cancer with curative intent or malignancy diagnosed > 2
years ago with no evidence of disease and no treatment ≤ 2 years prior to study
treatment.

5. Uncontrolled seizure disorder.

6. Active infection requiring systemic treatment.

7. Known human immunodeficiency virus (HIV) or active viral hepatitis.

8. Active, clinically significant cardiac disease or any Class 3 or 4 cardiac disease,
ventricular arrhythmia or CVA ≤ 6 months prior to start of treatment.

9. Active clinically significant gastrointestinal disease.

10. Active bleeding disorder ≤ 6 months prior to start of treatment.

11. Need for therapeutic anti-coagulation with heparin, warfarin or other anticoagulants.

12. Use of any medications or food known to be strong or moderate cytochrome P450, family
3, subfamily A (CYP3A) inhibitors or strong inducers.

13. Pregnant or nursing females.

14. Significant intercurrent illness that may result in subject's death prior to death
from glioblastoma.

15. Known hypersensitivity to any component of TMZ or decarbazine (DTIC). [Subjects in
Arms B and C only.]