Safety, Pharmacokinetics and Efficacy of Paxalisib (GDC-0084) in Newly-diagnosed Glioblastoma
brief summary
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).
detailed description
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.
official title
A Phase 2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of the PI3K/mTOR Inhibitor Paxalisib (GDC-0084) Administered to Patients With Glioblastoma Characterized by Unmethylated O6-methylguanine-methyltransferase Promoter Status Following Surgical Resection and Standard Concomitant Chemoradiation Therapy With Temozolomide