Clinical trial NCT06072586: A Phase 0/1 Study of BDTX-1535 in Recurrent High-Grade Glioma (rHGG) and Newly Diagnosed Glioblastoma (nGBM) Participants With EGFR Alterations or Fusions
Official title: A Phase 0/1 Study of BDTX-1535 in Recurrent High-Grade Glioma (HGG) and Newly Diagnosed Glioblastoma (nGBM) Participants With EGFR Alterations or Fusions Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With PK-triggered Expansion Cohort
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: High Grade Glioma
Glioblastoma
Lead sponsor: St. Joseph's Hospital and Medical Center, Phoenix
Sponsor class: OTHER
Collaborators: name: Ivy Brain Tumor Center
name: Barrow Neurological Institute
First posted: 2023-10-10
Enrollment: 82
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: The Phase 0 component will include treatment of rHGG (Arms A and B) and nGBM participants (Arms C, D, and E) with BDTX-1535 prior to a planned tumor resection. During surgery, blood, tumor, and CSF samples will be collected to measure the amount of drug that is present in the samples. Arm A includes ascending dose levels with two cohorts, and Arm C includes two dose level cohorts to determine the Optimal Biological Dose (OBD).

The Phase 1 component will include treatment in different dose regimens. Participants with tumors demonstrating PK response (Arms A, B, and C) or PD response (Arms D and E) will continue treatment.

Eligibility criteria: Inclusion Criteria:

* 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.
* Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.
* Provision of signed and dated, written informed consent (personally or by the legally authorized representative, if applicable) prior to any study specific procedures, sampling and analyses.
* Age ≥ 18 at time of consent
* Have a performance status (PS) of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
* Ability to swallow oral medications.
* Participant has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by the local laboratory for eligibility):

  * Absolute neutrophil count ≥ 1,500/mcL
  * Platelets ≥ 100,000/mcL (at time of surgery)
  * Hemoglobin ≥ 8.5 g/dL (Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.)
  * Total bilirubin ≤ 1.5 X ULN (Participants with Gilbert's syndrome with a total bilirubin ≤ 3.0 times ULN and direct bilirubin within normal limits are permitted.)
  * AST (SGOT) ≤ 3 X institutional ULN
  * ALT (SGPT) ≤ 3 X institutional ULN
  * Serum creatinine ≤ 1.5 X ULN or estimated creatinine clearance ≥ 60 mL/min (calculated using Institutional standard method)
* Participants on corticosteroids at baseline must be on stable or decreasing doses for at least 5 days prior to Day 1.
* Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause.
* For females of reproductive potential: use of highly effective contraception and agreement to use such a method during study participation until the end of treatment administration and for 16 weeks after the last dose of study drug.
* For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner until the end of treatment administration and for 16 weeks after the last dose of study drug.
* Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion Criteria:

* 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.
* Significant cardiovascular disease, including NYHA Class III or IV congestive heart failure, myocardial infarction, unstable angina, poorly controlled cardiac arrhythmias, or stroke in the preceding 6 months prior to study Day 1.
* Symptomatic or radiographic leptomeningeal disease.
* Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment \[e.g. estimated creatinine clearance \<30ml/min\], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).
* Concurrent use of prohibited medications: coadministration of strong CYP2C8 and CYP3A4 inhibitors and inducers with BDTX-1535. These should be discontinued 1 week or 5 half-lives (whichever is greater) prior to study Day 1. Strong inhibitors of P-gp (e.g., Amiodarone, carvedilol, dronedarone, propafenone, quinidine, ranolazine, and verapami) and BCRP (e.g., curcumin, cyclosporin A, and eltrombopag) should be used with caution. Sensitive substrates of P-gp, BCRP, and OATP should also be used with caution.
* Therapeutic intent treatment with another investigational drug or other intervention within 5 half-lives of the investigational product whichever is longer.
* With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5) Grade 1 at the time of starting study treatment and patients with chronic Grade 2 unresolved toxicities may be eligible following discussion with the Principal Investigator.

Primary outcomes:
measure: Unbound BDTX-1535 Concentration in Tumor Tissue
timeFrame: Intraoperative
measure: Total BDTX-1535 Concentration in Tumor Tissue
timeFrame: Intraoperative
measure: Incidence of DLTs Observed
timeFrame: From day of first dose to the end of concurrent RT treatment at 10 weeks
measure: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) as Assessed by NCI-CTCAE v5
timeFrame: Day of first dose until 30 days after final day of participation
measure: Number of Participants with Treatment-Related Adverse Events (TRAEs) as Assessed by NCI-CTCAE v5
timeFrame: Day of first dose until 30 days after final day of participation
measure: Number of Participants with Abnormal Laboratory Values as Assessed per NCI-CTCAE v5
timeFrame: Day of first dose until 30 days after final day of participation
Secondary outcomes:
measure: BDTX-1535 Concentration in CSF
timeFrame: Intraoperative
measure: Change in pEGFR Expression in Tumor Tissue
timeFrame: Baseline and intraoperative
measure: Change in pERK Expression in Tumor Tissue
timeFrame: Baseline and intraoperative
measure: 6-Month Progression Free Survival (PFS6) Rate
timeFrame: From the date of Phase 0 surgery to date of disease recurrence or death, whichever occurs first, assessed up to 12 months after study completion
measure: Median Progression Free Survival (PFS)
timeFrame: From the date of Phase 0 surgery until the date of death due to any cause, assessed for up to 12 months after study completion
measure: Median Overall Survival (OS)
timeFrame: From the date of Phase 0 surgery until the date of death due to any cause, assessed for up to 12 months after study completion
Other outcomes:
measure: Total BDTX-1535 Peak Plasma Concentration (Cmax)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Bound BDTX-1535 Peak Plasma Concentration (Cmax)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Total BDTX-1535 Time to Peak Plasma Concentration (Tmax)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Bound BDTX-1535 Time to Peak Plasma Concentration (Tmax)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Total BDTX-1535 Concentration Half-Life (T1/2)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Bound BDTX-1535 Concentration Half-Life (T1/2)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Total BDTX-1535 Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Bound BDTX-1535 Area Under the Plasma Concentration Versus Time Curve (AUC)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Total BDTX-1535 Partition Coefficient (Kp)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Unbound BDTX-1535 Partition Coefficient (Kp,uu)
timeFrame: Day of surgery at pre-dose and 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose
measure: Change in Biomarker Expression in Tumor Tissue
timeFrame: Baseline and intraoperative
measure: Change in Cell Signaling Pathways in Tumor Tissue
timeFrame: Baseline and intraoperative
measure: Change in Single Cell State from Tumor Tissue
timeFrame: Baseline and intraoperative
measure: Germline Mutation Changes in Circulating Tumor Cells (CTCs) and cell-free DNA (cfDNA) from CSF and Blood
timeFrame: Baseline and intraoperative
measure: Transcriptomic Changes in Circulating Tumor Cells (CTCs) from CSF and Blood
timeFrame: Baseline and intraoperative
Locations:
city: Chandler
country: United States
facility: Chandler Regional Medical Center
state: Arizona
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
Study officials:
affiliation: Chief Scientific Officer/Director of the Ivy Brain Tumor Center
name: Nader Sanai, MD
role: PRINCIPAL_INVESTIGATOR
References: