This study will administer the investigational drug, BDTX-1535 to eligible patients with recurrent high-grade glioma (HGG) and newly-diagnosed glioblastoma (nGBM). BDTX-1535 was designed to block a growth signal important to some cancers. BDTX-1535 is being tested in this study to see if it can be given safely to people who have tumors that can be dependent on that growth signal because of changes in a protein called EGFR. These gene changes are called amplifications, mutations, fusions or alterations and are found only in the tumors.
The study design includes a Phase 0 component with PK/PD-trigger for participant enrollment into an Expansion Phase 1 component. The primary objective of the Phase 0 component is to evaluate the PK endpoints of BDTX-1535. The primary objective of the Phase 1 component is to establish the safe dose of BDTX-1535 to be used in participants with a specified treatment regimen, three of which include standard of care radiotherapy for nGBM participants.
Arms A & B: Recurrent high grade glioma (2021 WHO Grades 3 and 4), defined as participants who have progressed on or following standard therapy, which includes maximal surgical resection, temozolomide, and fractionated radiotherapy.
Arm C, D, & E: Newly diagnosed glioblastoma (2021 WHO Grade 4), who have not received any tumor directed intervention other than biopsy or resection.
Candidate for clinical resection of rHGG (Arms A & B) or nGBM (Arms C & D).
Adequate archival or biopsy tissue available for testing of EGFR alterations. The tissue must have evidence of EGFR alterations including variants, fusion, and mutations with or without amplifications. rHGG participants with EGFR fusion will be solely enrolled into Arm B.
Pregnancy or breastfeeding.
Known allergic reactions to components of the BDTX-1535.
Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis, as determined by the investigator.
Known active systemic bacterial infection (requiring intravenous [IV] antibiotics or fever >38.5°C at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening of viral infection is not required for enrollment.
Parallel
BDTX-1535
DrugBDTX-1535 is an inhibitor of EGFR mutations
BDTX-1535 combined with radiation therapy
DrugDuring Phase 1, BDTX-1535 concurrently with standard of care upfront RT, followed by adjuvant monotherapy with BDTX-1535 continuously in 28-day cycles after RT.
BDTX-1535 combined with temozolomide and radiation therapy
DrugDuring Phase 1, BDTX-1535 concurrently with standard of care upfront RT and TMZ, followed by adjuvant BDTX-1535 combined with standard of care TMZ continuously in 28-day cycles after RT.
Unbound BDTX-1535 Concentration in Tumor Tissue
Unbound BDTX-1535 concentration in Gd enhancing and Gd non-enhancing tumor tissue will be determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method.
Total BDTX-1535 Concentration in Tumor Tissue
Total BDTX-1535 concentration in Gd enhancing and Gd non-enhancing tumor tissue will be determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method.
Incidence of DLTs Observed
Considered DLTs: Hem toxicity: 8+ days ≥G4 neutropenia/febrile neutropenia; ≥G4, or ≥G3 with clinically significant bleeding, thrombocytopenia; ≥G3 anemia requiring transfusion. Non-hem lab abnormalities: Any AR ≥G3 of ALT/AST or increase in ALT/AST \>3x ULN with concurrent increase in total bilirubin \>2x ULN (per Hy's Law) in pt with baseline \<G1 ALT/AST; Any AR ≥G3 of ALT/AST \>2x baseline or 10x ULN in pt with baseline \>G2 ALT/AST due to liver mets; Non-hem dose limiting toxicity ≥G3 (per Investigator; except for G3 nausea, vomiting, or diarrhea lasting \<72 hrs with adequate antiemetic/supportive care; G3 fatigue or anorexia lasting \<1 week; ≥G3 electrolyte abnormality lasting up to 72 hrs, isn't clinically complicated, and resolves spontaneously or responds to intervention). AR requiring dose reduction in C1, causes \>2 week delay of C2, causes 8+ day dose interruption in C1. DLTs exclude: alopecia; lymphopenia; isolated lab changes w/o clinical sequelae or significance
Number of Participants with Treatment-Emergent Adverse Events (TEAEs) as Assessed by NCI-CTCAE v5
AEs that occur while participants are on study treatment.
BDTX-1535 Concentration in CSF
BDTX-1535 concentration in CSF will be determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method.
Change in pEGFR Expression in Tumor Tissue
BDTX-1535 treated tumor tissue collected during Phase 0 surgery will be compared to archival tissue (baseline) to determine change in pEGFR expression.
Change in pERK Expression in Tumor Tissue
BDTX-1535 treated tumor tissue collected during Phase 0 surgery will be compared to archival tissue (baseline) to determine change in pERK expression.
6-Month Progression Free Survival (PFS6) Rate
PFS6 rate will be determined in participants who take at least one dose of study treatment.
Total BDTX-1535 Peak Plasma Concentration (Cmax)
Bound BDTX-1535 Peak Plasma Concentration (Cmax)
Total BDTX-1535 Time to Peak Plasma Concentration (Tmax)
Bound BDTX-1535 Time to Peak Plasma Concentration (Tmax)
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St. Joseph's Hospital and Medical Center, Phoenix
Lead sponsor
Ivy Brain Tumor Center
Collaborator
Barrow Neurological Institute
Collaborator
