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.
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 to enroll into the Phase 2 component. A positive PD response will be defined as a ≥ 50% decrease in SDMA expression relative to baseline biopsy tissue, if available. In the absence of a pretreatment biopsy, an H-score of 70 or below will be deemed as a positive PD response. Eligible participants will then be allocated into one of two Arms based on MGMT methylation status. Participants with unmethylated tumors will be enrolled into Arm A and participants with methylated tumors will be enrolled into Arm B. Participants that do not proceed to the Phase 2 component will receive treatment per treating physician's recommendation. All participants will complete the end of treatment visit, safety follow-up, and survival monitoring. PHASE 2 ARM A Participants with unmethylated-MGMT and MTAP-deleted GBM demonstrating a positive PD response will continue BGB-58067 treatment concurrently with standard of care upfront radiotherapy (RT). Following completion of RT, participants will receive adjuvant monotherapy with BGB-58067 administered continuously. Study visits, safety assessments, and cycle numbering during adjuvant therapy will follow a fixed days cycle calendar. Participants will receive BGB-58067 until disease progression, unacceptable toxicity or death, withdrawal of consent, loss to follow up, or study termination by the sponsor. ARM B Participants with methylated-MGMT and MTAP-deleted GBM demonstrating a positive PD response will continue BGB-58067 treatment concurrently with standard of care upfront RT and temozolomide (TMZ). Following completion of RT, participants will continue BGB-58067 dosing. If a transition period occurs between completion of concurrent therapy and initiation of adjuvant TMZ, BGB-58067 dosing may be continued to maintain uninterrupted exposure. Adjuvant therapy will then begin with BGB-58067 administered on a continuous dosing schedule combined with TMZ. Study visits, safety assessments, and cycle numbering during adjuvant therapy will follow a fixed days cycle calendar. BGB-58067 will have no planned off-days during TMZ cycles. Following completion of TMZ therapy, BGB-58067 may be administered at the same dose received during adjuvant TMZ therapy until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow up, or study termination by the sponsor. ALL PARTICIPANTS. All participants will return to the clinic for safety monitoring following BGB-58067 treatment discontinuation and will be contacted approximately every 3 months for up to 24 months for survival data collection. The start of follow-up for long-term survival will begin after the safety follow-up visit. MRI scans and review in guidance with RANO criteria will occur approximately every 2-3 months, per standard of care, to monitor disease progression. Longitudinal biomarker analysis through liquid biopsy may be conducted to characterize genomic and/or transcriptomic changes from circulating tumor cells (CTCs) or cell free DNA (cfDNA) isolated from CSF collected during Phase 0 surgery, during Phase 2, or at recurrent craniotomy. At the treating investigator's discretion, an Ommaya reservoir or shunt may be placed during Phase 0 surgery to access CSF from the resection cavity. CSF samples will be collected during Phase 2 only if a participant has the Ommaya reservoir in place. Additional biomarker analysis may be conducted using surgical tissue. If the participant undergoes repeat craniotomy for recurrence or disease progression, to enable longitudinal sample collection and analysis, IVY will request samples from the resected tumor, CSF, or blood to help identify possible resistance mechanisms.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
78
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.
St. Joseph's Hospital and Medical Center
Phoenix, Arizona, United States
Phase 0: Proportion of Participants with ≥ 50% Decrease from Baseline in SDMA Expression, or with SDMA H-Score ≤ 70, in Phase 0 Tumor Tissue Collected Intraoperatively
Decrease in SDMA expression in tumor tissue collected during Phase 0 surgery relative to baseline will be used if pre-treatment biopsy tissue is available. Otherwise, H-score ≤ 70 in tumor tissue collected during Phase 0 surgery will be used.
Time frame: Intraoperatively
Phase 2: Proportion of Participants Alive at 12 Months
Overall survival at 12 months (OS12)
Time frame: Date of Phase 0 surgery to date of death due to any cause, assessed up to 12 months
Phase 0: Mean Total Concentration of BGB-58067 in Gadolinium Enhancing and Non-Enhancing Tumor Tissue
Tumor tissue collected during Phase 0 surgery
Time frame: Intraoperatively
Phase 0: Mean Unbound Concentration of BGB-58067 in Gadolinium Enhancing and Non-Enhancing Tumor Tissue
Tumor tissue collected during Phase 0 surgery
Time frame: Intraoperatively
Phase 0: Median Total Concentration of BGB-58067 in Gadolinium Enhancing and Non-Enhancing Tumor Tissue
Tumor tissue collected during Phase 0 surgery
Time frame: Intraoperatively
Phase 0: Median Unbound Concentration of BGB-58067 in Gadolinium Enhancing and Non-Enhancing Tumor Tissue
Tumor tissue collected during Phase 0 surgery
Time frame: Intraoperatively
Phase 0: Mean CSF Concentration of BGB-58067
CSF collected during Phase 0 surgery
Time frame: Intraoperatively
Phase 0: Median CSF Concentration of BGB-58067
CSF collected during Phase 0 surgery
Time frame: Intraoperatively
Phase 0: Peak Plasma Concentration (Cmax) of BGB-58067
Blood plasma collected prior to dose, during Phase 0 surgery, and post-op
Time frame: Prior to dose (trough level), 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
Phase 0: Time to Peak Plasma Concentration (Tmax) of BGB-58067
Blood plasma collected prior to dose, during Phase 0 surgery, and post-op
Time frame: Prior to dose (trough level), 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
Phase 0: Plasma Concentration Half-Life (t1/2) of BGB-58067
Blood plasma collected prior to dose, during Phase 0 surgery, and post-op
Time frame: Prior to dose (trough level), 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
Phase 0: Area Under the Plasma Concentration Versus Time Curve (AUC) of BGB-58067
Blood plasma collected prior to dose, during Phase 0 surgery, and post-op
Time frame: Prior to dose (trough level), 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
Phase 0: Plasma Concentration-Time Curves (Cp-time) of BGB-58067
Blood plasma collected prior to dose, during Phase 0 surgery, and post-op
Time frame: Prior to dose (trough level), 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
Phase 2: Incidence of Adverse Events as Assessed by CTCAE v5.0
Incidence of the following will be summarized: AEs, SAEs, and AEs of Special Interest (AESIs); treatment discontinuations, dose interruptions, and dose reductions due to AEs; clinically-significant changes in vital signs, body weight, laboratory tests, ECG, and ECOG performance status.
Time frame: Date of first dose until 30-days post last dose
Phase 2: Participant Survival Characteristics Over 24 Months
Overall Survival (OS) will be analyzed using Kaplan-Meier methods. Participants without a death event will be censored at the last known alive date.
Time frame: Date of Phase 0 surgery to date of death from any cause, assessed up to 24 months
Phase 2: Participant Progression-Free Survival Characteristics Over 6 Months
Progression-Free Survival at 6 months (PFS6) will be analyzed using Kaplan-Meier methods.
Time frame: Date of Phase 0 surgery to date of protocol-defined disease progression, assessed up to 6 months
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