Phase 1/2 Study Evaluating the Safety, PK/PD, and Clinical Activity of Oral JBI-778 in Patients With Brain Metastases, Leptomeningeal Disease, or Recurrent High Grade Glioma

JBI-778 is an orally active selective inhibitor of PRMT5 developed for the treatment of cancers involving the central nervous system. This first-in-human Phase 1/2 study includes:

PART 1: Dose-Escalation- The starting dose for JBI-778 is 40 mg orally, once daily in 21-days treatment cycles. In order to reduce the risk of exposing patients to subtherapeutic doses of JBI-778, an accelerated single patient cohort dose escalation approach will be initially adopted using dose doubling until dose level 4 is reached provided that no study drug related ≥ grade 2 adverse event is observed or any toxicity which leads to a dose hold and/or dose reduction. In the absence of such toxicities, a 3+3 design will be implemented for all subsequent cohorts and further dose escalation increments will be limited to 33-75%.

If the toxicities described above are observed at any point in the study 2 changes will be implemented to the study design

* A 3+3 design will be introduced overseen by the SRC * In the absence of a DLT, 33-50% dose increments will be employed with a maximum of 33% when the first DLT is observed. All doses will be rounded up or down based on capsule strength. In the event that any DLTs occur at the starting dose in 2 patients, and with the approval of the Safety Review Committee (SRC), a 20 mg once daily dose level will be evaluated using a 3+3 design. If 20 mg once daily is not tolerated, no further patients will be recruited, and the study will be terminated. With these restrictions, the next dose to be studied will be determined by the Sponsor with approval by the SRC. Population PK-based modeling approach may also be applied for PK characterization and PK covariate analyses. In addition to the PK evaluation, patients in Part 1 dose-escalation will provide pretreatment and on-treatment biopsies to aid in the assessment of the PD effects of the compound. In the 3+3 design, if 3 patients at a dose level complete the DLT evaluation period with no DLT, that dose level ofJBI-778 will be deemed safe, and another 3 patients will be treated at the next higher dose level. If 1 of the first 3 patients experiences a DLT, 3 more patients will be treated at the same JBI-778 dose level. If 2 or more of the 3 to 6 patients in any dose level experience a DLT, dosing will stop at that level, and either the previous dose level will be considered the Maximum Tolerated Dose (MTD) or intermediate doses may be explored to determine MTD, especially if the difference between the non-tolerated dose and the previous dose is \> 50%.

Dose-escalation will continue until any of the following events occur: