Clinical trial NCT05376800: A Study to Determine How BI 907828 (Brigimadlin) is Taken up in the Tumor (Phase 0) and to Determine the Highest Dose of BI 907828 (Brigimadlin) That Could be Tolerated (Phase 1a) in Combination With Radiation Therapy in People With a Brain Tumor Called Glioblastoma
Official title: A Phase 0/Ia Study of BI 907828 (Brigimadlin) Concentrations in Brain Tissue and a Non-randomized Open-label, Dose Escalation Study of BI 907828 (Brigimadlin) in Combination With Radiotherapy in Patients With Newly Diagnosed Glioblastoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Glioblastoma
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2022-05-17
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Phase 0 part: measurement of BI 907828 (Brigimadlin) concentrations in brain tissue Phase Ia part: dose escalation
Primary purpose: TREATMENT

Brief summary: This study is open to adults with newly diagnosed glioblastoma, a type of brain tumor. The study has two parts. Part 1 is open to people who can get their brain tumor removed by surgery. Part 2 is open to people who already had such a brain surgery.

This study tests a medicine called BI 907828 (Brigimadlin). BI 907828 (Brigimadlin) is a socalled MDM2 inhibitor that is being developed to treat cancer.

The purpose of Part 1 of the study is to find out how BI 907828 (Brigimadlin) is taken up in the tumor. Participants take a single dose of BI 907828 (Brigimadlin) as a tablet before the brain surgery. Part 1 of the study takes about 1 month. During this time, participants have their brain tumor removed by surgery and visit the study site about 8 times.

The purpose of Part 2 is to find the highest dose of BI 907828 (Brigimadlin) that the participants can tolerate in combination with standard radiation therapy. During the first 6 weeks, participants get standard radiation therapy. In addition, they take a dose of BI 907828 (Brigimadlin) once every 3 weeks. Participants may continue to take BI 907828 (Brigimadlin) as long as they benefit from treatment and can tolerate it. They visit the study site regularly.

During the entire study, doctors also regularly check participants' health and take note of any unwanted effects.


Eligibility criteria: Inclusion criteria

* Inclusion criteria Part Phase 0:

  * Histologically (if prior biopsy) or radiologically diagnosed glioblastoma.
  * Neurosurgical tumor resection is indicated and planned according to the assessment of the treating physician.
  * Patients must be at least 18 years old.
  * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (an ECOG of 2 is acceptable, if it is due to non-cancer-related disability, and after agreement with the sponsor).
* Inclusion criteria Part Phase Ia:

  * Histologically demonstrated diagnosis of TP53 wild type glioblastoma harboring unmethylated O6-methylguanine-DNA-methyltransferase (MGMT) promoters. Glioblastoma definition according to 2021 World Health Organization (WHO) Classification of Central Nervous System (CNS) tumors, i.e. IDH- wild type only.
  * Patient has undergone neurosurgical tumor resection and is eligible for standard radiotherapy.
  * Patients must be neurologically stable based on the judgement of the treating physician. The use of corticosteroids and anti-seizure medication is allowed and should be at a stable or decreasing dose for at least 7 days before inclusion in the trial. Anti-seizure medication should not include agents that interact with BI 907828 (Brigimadlin).
  * For patients, who have participated in Phase 0, the interval between the single dose of BI 907828 (Brigimadlin) and subsequent Phase 1a treatment must be at least 21 days.

Further inclusion criteria applies.

Exclusion criteria

* Exclusion criteria Part Phase 0:

  * Known TP53 mutant glioblastoma (Note: testing is not mandatory for inclusion).
  * Known Isocitrate dehydrogenase (IDH) mutant grade IV astrocytoma (Note: testing is not mandatory for inclusion).
  * Patient who must receive or intends to receive restricted medications.
  * Patients with pacemakers or other metallic implants that can interfere with the magnetic field during Magnetic Resonance Imaging (MRI) investigations.
  * Inability to undergo contrast-enhanced MRI (Glomerular Filtration Rate (GFR) \<30 mL/min).
* Exclusion criteria Part Phase Ia:

  * Patients who have received previous systemic therapy (with the exception of patients who participated in Phase 0) or radiotherapy for glioblastoma.
  * Patients who must or intend to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial.
  * Patients with pacemakers or other metallic implants that can interfere with the magnetic field during MRI investigations.
  * Inability to undergo contrast-enhanced MRI (GFR \<30 mL/min). Further exclusion criteria applies.

Primary outcomes:
measure: Phase 0: Measured total concentration of BI 907828 (Brigimadlin) in brain tissue homogenate from noncontrast enhancing and contrast enhancing brain tumor regions
timeFrame: Up to 24 hours (h)
measure: Phase 0: Calculated unbound concentration of BI 907828 (Brigimadlin) in brain tissue homogenate from noncontrast enhancing and contrast enhancing brain tumor regions
timeFrame: Up to 24 hours (h)
measure: Phase Ia: Occurrence of dose-limiting toxicity (DLT), graded according to Common Terminology Criteria for Adverse Events version 5.0, during the Maximum Tolerated Dose (MTD) evaluation period
timeFrame: Up to 63 Days
measure: Phase Ia: Occurrence of adverse events (AEs) graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 during the entire treatment period
timeFrame: Up to 7 months.
Secondary outcomes:
measure: Phase 0: Dose-dependent changes of expression levels of Tumor suppressor protein p53 (TP53) target genes in contrast enhancing brain regions and non-contrast enhancing brain regions
timeFrame: Up to 24 hours (h)
measure: Phase Ia: Progression-free survival (PFS)
timeFrame: Up to 8 months.
measure: Phase Ia: Maximum plasma concentration (Cmax) of BI 907828 (Brigimadlin) in plasma at Cycle 1
timeFrame: Up to Day 17
measure: Phase Ia: Area under the Curve of BI 907828 (Brigimadlin) in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz)
timeFrame: Up to Day 17
measure: Phase Ia: Area under the Curve of BI 907828 (Brigimadlin) in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞)
timeFrame: Up to Day 17
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic-Arizona
state: Arizona
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Jacksonville
country: United States
facility: Mayo Clinic Cancer Center
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Leuven
country: Belgium
facility: UZ Leuven
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
Study officials:
References: