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

Prior treatment

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

Other illness

• Severe or unstable medical conditions including:
• Active gastrointestinal disease or malabsorption syndrome affecting drug absorption.
• Active infection requiring systemic antimicrobial or antiviral therapy not completed before treatment.

Lab values

• 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).

• 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.