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:

• The highest planned dose level is determined to be safe and tolerable (minimum of 6 DLT evaluable patients).
• An MTD is identified. Additional dose levels may be explored based on emerging data. Additional patients (up to 20 patients may be enrolled in 1 or more dose levels that have been shown to be safe and tolerable, defined as backfill enrollment). This backfill enrollment will be done to better estimate the RP2D and to better characterize the safety, efficacy, PK and pharmacodynamics for JBI-778 and may be concurrent with dose-escalation to identify the MTD. The RP2D dose will include up to 12 patients and will be selected based on the totality of the clinical data including PK/PD, preliminary efficacy, and safety.

Study patients who do not complete the DLT period for reasons other than study drug toxicity will be replaced.All patients will be assessed for a response using relevant RECIST 1.1 and RANO criteria. Clinical status will be assessed by the NANO instrument.

Intra-subject dose-escalations are allowed in this study. Patients who complete the DLT period, tolerate the dose, and have been on the treatment for ≥ 2 cycles without significant toxicities may proceed to a higher dose level for the following treatment cycle if the next dose cohort is deemed safe (for both acute and cumulative toxicities) at that time by the Safety ReviewCommittee (SRC), and after consultation with the Sponsor and if the patient has not experienced any ≥ Grade 2 adverse events (deemed treatment-related by the Investigator) during the current treatment with the study drug.

The maximum Intra-subject Dose-Escalation level should be one level below the current actively enrolling dose level if tolerability based on the protocol defined criteria has not yet been established. Patients who do not proceed to a higher dose may continue to receive additional cycles at their original dose.

PART 2: Dose-Expansion Part- Once the RP2D is determined, expansion cohorts will be opened to evaluate the preliminary efficacy of the study drug.

These cohorts will include patients with:

• Progressive or recurrent high-grade glioma
• Brain metastases from NSCLC, breast cancer, or melanoma
• Solid tumors and leptomeningeal disease A SRC will have oversight of safety and will meet at the end of each cohort and approximately quarterly and as needed, during the dose-escalation phase to review cumulative toxicity data, make recommendations to the Sponsor regarding ongoing safety, cohort expansions and dose-escalation. The SRC may recommend protocol amendments to maintain patient safety at any stage. In addition, any serious adverse events (SAEs) will be forwarded to the SRC upon occurrence.

Safety and tolerability of JBI-778 will be characterized by adverse event and serious adverse event type, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0), timing, and relationship to study therapy, and laboratory abnormalities in the first and in subsequent cycles.

Administration of JBI-778 (in the Dose-Escalation and Dose-Expansion phases of this study) may continue until evidence of disease progression, intolerance to study drug, or withdrawal of consent. Stable or responding patients who experience DLTs may continue therapy once DLTs have resolved.

Inclusion criteria

Male or female patients aged ≥18 years.

Histologically or cytologically confirmed:

Solid tumors with stable brain metastases (Dose Escalation Part), or Recurrent/progressive high-grade glioma, or Brain metastases from NSCLC, breast cancer, or melanoma, or Leptomeningeal disease (Dose Expansion Part).

Adequate organ function:

ANC ≥1,500/mm³ Platelets ≥100,000/mm³ Hemoglobin >8.0 g/dL Total bilirubin ≤1.5 × ULN (≤3 × ULN for Gilbert syndrome) AST/ALT ≤2.5 × ULN (≤5 × ULN if liver metastases present) Creatinine clearance ≥60 mL/min PT/aPTT ≤1.5 × ULN (or stable anticoagulation therapy) At least one measurable lesion on MRI according to applicable RANO criteria, or positive CSF cytology for leptomeningeal disease.

Resolution of clinically significant toxicities from prior therapy to Grade ≤1 (except alopecia, Grade 2 peripheral neuropathy, or chronic Grade 2 endocrinopathies due to prior immunotherapy).

ECOG performance status ≤2. Ability to swallow oral medication. Life expectancy ≥3 months. Willing and able to provide written informed consent. Willingness to use effective contraception during treatment and for 3 months after the last dose.

Additional Dose Escalation Cohort Inclusion Criteria:

Histologically or cytologically confirmed solid tumors with stable treated brain metastases and no available effective treatment options.

Neurologically stable brain metastases without progression or hemorrhage for ≥4 weeks following treatment.

Off systemic corticosteroids for symptomatic brain metastases for ≥14 days before enrollment.

Additional Dose Expansion Cohort Inclusion Criteria:

Recurrent or progressive high-grade glioma after standard therapy including radiation and temozolomide.

Brain metastases from melanoma, NSCLC, or breast cancer meeting protocol-defined prior treatment requirements.

Leptomeningeal disease with protocol-defined prior therapy requirements.

Exclusion criteria

Systemic anticancer therapy or investigational therapy within 2 weeks or 5 half-lives before first dose.

Major surgery within 21 days before first dose or not recovered from surgery. Conditions that may significantly impair drug absorption. Radiotherapy within 2 weeks prior to study treatment (except permitted palliative radiation or stereotactic radiosurgery).

Severe or unstable medical conditions including:

NYHA Class III/IV heart failure Uncontrolled hypertension Uncontrolled diabetes Significant psychiatric illness Uncontrolled arrhythmias Myocardial infarction within 6 months Congenital long QT syndrome or QTcF >470 msec. History of optic neuritis or optic neuropathy. Other active malignancy likely to interfere with study assessments. Live vaccine within 30 days before first dose. Known active HIV infection or active hepatitis B or C infection (HCV RNA-negative patients may be eligible).

Use of strong or moderate CYP3A inhibitors within 14 days or 5 half-lives before Cycle 1 Day 1, or grapefruit-containing products within 7 days.

Active gastrointestinal disease or malabsorption syndrome affecting drug absorption.

Acute illness within 14 days before first dose unless approved by investigator and sponsor.

Active infection requiring systemic antimicrobial or antiviral therapy not completed before treatment.

Pregnant or breastfeeding women. Concurrent participation in another investigational drug study. Previous treatment with JBI-778 in this study. Any condition that, in the investigator's opinion, places the patient at unacceptable risk or prevents compliance with study requirements.

For Dose Escalation Part only: ongoing immunosuppressive therapy, including systemic corticosteroids for treatment of brain metastases (except protocol-permitted low-dose corticosteroids).