Assessment of a Large US EHR Database as Meeting FDA Fit-for-Purpose Requirements to Provide External Controls for Study BPM31510 in Participants With Glioblastoma

A Retrospective Observational Cohort Study to Assess the Degree to Which the Truveta Dataset Meets FDA Fit-for-Purpose Requirements for Label-Enabling Regulatory Use for BPM31510 in Patients With Newly Diagnosed Glioblastoma

Glioblastoma is a rare, aggressive brain tumor that leads to death within 2 years of diagnosis in more than half of patients. There are currently 123 studies ongoing that are testing treatments for glioblastoma. BPGbio has developed BPM31510 and is executing an ongoing single-arm Phase 2 study (NCT04752813) targeting 50 participants.

Because glioblastoma is a rare and often fatal disease with multiple drugs in development, a randomized placebo-controlled trial is unlikely to be feasible. Therefore, BPGbio is exploring the possible use of untreated patients from the Truveta database to create a control group. The purpose of this study is to explore whether the Truveta database in this indication meets FDA criteria as fit-for-purpose for regulatory use.

This is a retrospective, observational cohort study to assess the degree to which the Truveta dataset meets the United States (US) Food and Drug Administration (FDA) fit-for-purpose requirements for label-enabling regulatory use as an external/synthetic control arm for the single-arm Phase 2 trial BPM31510IV-11 for the study of BPM31510 in subjects with newly diagnosed glioblastoma.

Glioblastoma is a rare disease with approximately 11,000 newly diagnosed cases in the US annually. The application of standard clinical trial eligibility criteria plus the requirement of no prior treatment (radiotherapy, chemotherapy, immunotherapy or targeted agents) in an environment of multiple ongoing Phase 2 and Phase 3 trials in this indication will make recruitment for a randomized, double-blind placebo-controlled trial infeasible. This is likely a core contributor to the lack of new glioblastoma treatments since the approval of temozolomide for newly diagnosed glioblastoma in 2005. Recently, the FDA approved dordaviprone for second-line treatment of diffuse midline glioma with an H3 K27M mutation based on a series of single arm studies with a total of 50 treated participants.

The addition of an external/synthetic control arm to the single-arm, non-randomized, open-label Phase 2 trial (BPM31510IV-11) will provide adequate and well-controlled data demonstrating substantial evidence of effectiveness to serve as the primary basis for approval for BPM31510.

The scientific integrity of this study is dependent on demonstrating that the proposed real-world Truveta database meets FDA requirements for real-world data for label-enabling regulatory submission.

Cohort 1 inclusion Criteria:

1. Between 01-01-2021 and 06-30-2025, an ICD-10-CM code C71.X (malignant brain neoplasm) and/or SNOMED CT 276826005 (malignant glioma of brain)
2. Between 01-01-2021 and 06-30-2025, current procedural terminology (CPT) codes indicating surgery with either a biopsy or excision of a brain tumor
3. Patients must be adults at least 18 years of age at time of surgery
4. CPT codes indicating submission of surgical sample for pathology for IDH testing
5. SNOMED CT codes for "glioblastoma" after IDH testing
6. Note that while a diagnosis can be made based on IDH from a biopsy or resection sample, resection is required for study inclusion.
7. A post-resection CPT code for brain MRI
8. At least one visit meeting all eligibility criteria between 15- and 50-days post-resection.

Cohort 1 exclusion Criteria:

1. History of malignant neoplasm of the brain >12 months before index
2. Patients with prior chemotherapy, radiotherapy, immunotherapy or targeted treatment agents (including anti-angiogenic drugs) less than 12 months before and/or 14 days after resection.

Cohort 2 inclusion Criteria:

Patients must meet all eligibility criteria for Cohort 1 and the following:

1. Brain MRI scan post-resection available for evaluation

2. Karnofsky performance score of at least 60

3. Laboratory values within the following specified ranges:

   1. Absolute neutrophil count of at least 1.5 k/microliter (μL)
   2. Platelet count of at least 100 k/μL
   3. Hemoglobin level of at least 9 gram/deciliter (dL)
   4. Serum creatinine level of at most 1.8 milligram(mg)/dL or creatinine clearance of more than 50 milliliter/min
   5. Bilirubin level of at least 1.5 mg/dL
   6. ALT level of at most 3.0 × upper limit of normal (ULN)
   7. AST of at most 3.0 × ULN
   8. PT of at most 1.5 × ULN
   9. INR of at most 1.5 × ULN
   10. PTT of at most 1.5 × ULN

Cohort 2 exclusion Criteria:

1. No resection was performed

2. One-year pre-index history of spontaneous or tumor-related intracranial hemorrhage

3. One-year pre-index history of diffuse leptomeningeal disease

4. Patients on dexamethasone daily dosing more than 2 mg at index

5. Three-month pre-index history of cardiovascular disease (myocardial infarction, coronary artery disease, arrhythmia, unstable angina pectoris, cerebrovascular accident)

6. Six-month pre-index history of acquired coagulopathies (hemorrhagic disorder due to circulating anticoagulants or acquired coagulation factor deficiency)

7. Six-month pre-index history of clinically significant bleeding

8. Known predisposition for bleeding such as von Willebrand's disease or other such condition(s) (i.e., hereditary deficiency of factor VIII, IX and XI)

9. Six-month pre-index history of significant psychiatric illness

10. Six-month pre-index history of major infection

11. Prior malignancy except for non-melanoma skin cancer and carcinoma in situ of the cervix or bladder

12. Receiving any of the following medications at the index date:

    1. Any anticoagulant, including low-molecular weight heparin and warfarin within two months pre-index
    2. Any digitalis alkaloid (digoxin, digitoxin, lanatoside C) within two months pre-index
    3. Antiangiogenic drugs (e.g., bevacizumab) two weeks before or two weeks after index
    4. Theophylline two weeks before or two weeks after index

13. Patients with a record of pregnancy, pregnancy termination, or hospital admissions for birth/delivery, or a positive laboratory test indicating pregnancy up to 9 months before index date

14. Known to be positive for the human immunodeficiency virus

15. Patients not receiving radiation therapy in the year after diagnosis.