A phase 2a study to evaluate the safety, pharmacokinetics and clinical activity of the PI3K/mTOR inhibitor GDC-0084 administered to patients with glioblastoma multiforme characterized by unmethylated O6-methylguanine-methyltransferase promoter status

This protocol has a 2-part design:

This phase 2 study is an open-label, multicenter, dose-escalation and expansion study to
assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and
clinical activity of paxalisib in patients with newly-diagnosed glioblastoma (GBM) with
unmethylated MGMT promoter status as adjuvant therapy following surgical resection and
initial chemoradiation with temozolomide (TMZ).

Inclusion Criteria:

Patients must meet all the following inclusion criteria to be eligible for enrollment into
the study:

1. Age ≥ 18 years;

2. Life expectancy > 12 weeks;

3. Present with histologically confirmed intracranial (supratentorial) unmethylated MGMT
promotor status GBM (WHO Grade lV astrocytoma) with a MGMT status that has been
confirmed by validated PCR or validated alternate genomic analysis;

4. Have undergone maximal surgical resection of their tumor and within 6 weeks of surgery
received initial treatment with XRT/TMZ which consisted of XRT by external beam to a
partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to
the tumor of 60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in accordance with the
Stupp regimen;

5. Must have measurable disease, according to RANO criteria for inclusion in the
expansion cohort. Patients with non-measurable disease can be included in the
dose-escalation cohorts;

6. KPS ≥ 70;

7. Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior
to or on the day of the Randomization/Week 1 Visit;

8. Stable or decreasing corticosteroid dose within 7 days prior to the first dose;

9. Adequate bone marrow/hematological function within 7 days prior to Day 1;

10. Adequate liver and renal function within 14 days prior to Day 1;

11. International normalized ratio (INR) or prothrombin time (PT) (secs) and activated
partial thromboplastin time (aPTT) within 7 days prior to randomization:

12. Patients must be willing to forego other drug therapy against the tumor while enrolled
in the study.

Exclusion Criteria:

1. Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel®
wafers) in addition to the required postoperative radiation plus TMZ, non-cytotoxic
drug therapy, or experimental drug therapy directed against the brain tumor prior to
this regimen, will be excluded. Patients may have received or be receiving
corticosteroids, analgesics, and other drugs to treat symptoms or prevent
complications but the dose must be stable at treatment start. NOTE: 5 aminolevulinic
acid-mediated photodynamic therapy administered prior to surgery to aid in optimal
surgical resection is not considered a chemotherapy agent;

2. Any prior or anticipated concomitant treatment involving a medical device (such as
Optune®) applying tumor treating fields (TTF);

3. QT interval time of ≥ 470 msec;

4. Undetermined/indeterminate MGMT status;

5. Diabetic patients; prediabetic patients treated with metformin;

6. Use of any CYP3A4 inducing or inhibiting agents;

7. Significant medical illnesses;

8. Women who are pregnant or who are lactating;

9. Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;

10. Evidence of recent hemorrhage on postoperative MRI of the brain;

11. Any previous malignancy; except for adequately controlled limited basal cell carcinoma
of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix, or one
which has been absent for ≥3 years;