A Phase 0/2 Study of BGB-58067, an MTA Cooperative PRMT5 Inhibitor, in Newly Diagnosed Glioblastoma Patients With Methylthioadenosine Phosphorylase (MTAP) Deleted Tumors Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With Pharmacodynamic (PD)-Triggered Expansion Cohorts
Nader Sanai
Summary
This is an open-label, multi-center, Phase 0/2 trial designed to enroll up to 78 total participants with suspected newly diagnosed glioblastoma (nGBM) who are scheduled for surgical resection to accrue at least 14 participants in Arm A and 10 participants in Arm B. The trial will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of BGB-58067. The study is composed of a Phase 0 and expansion Phase 2 component. The Phase 0 primary endpoint will be suppression of symmetric dimethylarginine (SDMA) in tumor tissue measured by immunohistochemistry (IHC). The Phase 2 primary endpoint will be 12-month overall survival rate (OS12). The Phase 0 secondary endpoint will be to characterize the PK of BGB-58067 in tumor tissue, plasma, and cerebrospinal fluid (CSF). The Phase 2 secondary endpoints will include assessing the safety profile of BGB-58067 and evaluating clinical efficacy of BGB 58067 using overall survival (OS) and the 6-month progression-free survival rate (PFS6) estimated by Kaplan-Meier (K-M) methods.
Description
PHASE 0 Participants with nGBM will receive a high dose of BGB-58067 prior to surgical resection. The first 5 participants will receive a smaller dose of BGB-58067 to characterize tumor penetration and PD effects at that dose. Participants without histologically confirmed diagnosis of GBM after the craniotomy will be replaced. MTAP-deletion will be determined using IHC on gadolinium (Gd) enhancing tumor tissue collected during resection, which may be supported by retrospective analysis of next-generation sequencing results. Participants with tumors demonstrating PD response will be eligible…
Eligibility
- Age range
- 18+ years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: * 1\. Suspected newly diagnosed glioblastoma according to 2021 WHO criteria who have not received any tumor directed intervention other than biopsy. * 2\. Has measurable disease (preoperatively), defined as at least one contrast-enhancing lesion with two perpendicular measurements of at least 1 cm. * 3\. Age ≥ 18 at time of consent. * 4\. Has a performance status of ≤ 2 on the ECOG scale. * 5\. Has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility): 1. Adequate Bone Marrow Function…
Interventions
- DrugBGB-58067
During Phase 0, a high dose of BGB-58067 will be administered over several days prior to surgery to determine PK and PD effect in resected tumor tissue. During Phase 2, BGB-58067 dosing will continue with standard radiation therapy (RT) followed with adjuvant therapy. Participants will receive monotherapy or concurrent therapy with temozolomide (TMZ) based on MGMT methylation status.
Location
- St. Joseph's Hospital and Medical CenterPhoenix, Arizona