Safety, Pharmacokinetics and Efficacy of Paxalisib (GDC-0084) in Newly-diagnosed Glioblastoma

Stage 1 Dose-Escalation and Maximum Tolerated Dose The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to determine the MTD for QD dosing.

Approximately 6 - 12 patients with newly diagnosed GBM will be enrolled in Stage 1.

The MTD for QD dosing will be determined. The initial dose level for QD dosing will be 60 mg (Dose Level 0). This dose is based on the phase 1 findings outlined in the rationale in the protocol, adding 1 dose level to test for a potential MTD increase.

Dose-escalation will occur in Stage 1:

• The initial dose (Dose Level 0) for QD MTD determination in Step 1 will be 60 mg. Dose levels will increase in 15 mg steps;
• The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to assess the safety, tolerability, and PK of paxalisib administered orally in 28-day cycles;

Decisions regarding dose-escalation and selection will be made by a Cohort Review Committee (CRC).

All AEs, including DLTs, will be reported, with severity assessed according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

After determination of the MTD, patients continue to receive their protocol-assigned dose levels of paxalisib until progression of their disease or an unacceptable toxicity, whichever occurs first.

Stage 2 Expansion stage (2) of the study will be a two-arm, randomized, open-label expansion study to further characterize the safety, tolerability and PK of paxalisib as well as to provide a preliminary assessment of single-agent activity of paxalisib in patients with GBM. Approximately 20 patients will be enrolled in the expansion cohort in 2 treatment arms (10 per am) to examine the PK of paxalisib in fed and fasted-conditions, according to the defined study eligibility criteria.

Stage 2 of the study will be initiated with recruitment of new patients as soon as the MTD has been determined.

Patients enrolled in Stage 2 may continue the study at the dose allocated until disease progression or unacceptable toxicity.

Inclusion criteria

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

• Age ≥ 18 years;
• Life expectancy > 12 weeks;
• 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;
• 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;
• 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;
• KPS ≥ 70;
• Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior to or on the day of the Randomization/Week 1 Visit;
• Stable or decreasing corticosteroid dose within 7 days prior to the first dose;
• Adequate bone marrow/hematological function within 7 days prior to Day 1;
• Adequate liver and renal function within 14 days prior to Day 1;
• International normalized ratio (INR) or prothrombin time (PT) (secs) and activated partial thromboplastin time (aPTT) within 7 days prior to randomization:
• Patients must be willing to forego other drug therapy against the tumor while enrolled in the study.

Exclusion criteria

• 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;
• Any prior or anticipated concomitant treatment involving a medical device (such as Optune®) applying tumor treating fields (TTF);
• QT interval time of ≥ 470 msec;
• Undetermined/indeterminate MGMT status;
• Diabetic patients; prediabetic patients treated with metformin;
• Use of any CYP3A4 inducing or inhibiting agents;
• Significant medical illnesses;
• Women who are pregnant or who are lactating;
• Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;
• Evidence of recent hemorrhage on postoperative MRI of the brain;
• 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;