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

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;