A Phase 1/2, Multicenter, Open-Label, Dose-Escalation/Expansion Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered JBI-778 in Patients With Brain Metastasis, Leptomeningeal Disease, or High Grade Recurrent Glioma
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 113
- 主要终点
- Phase 2 Leptomeningeal Disease Cohort: Overall Survival (OS)
研究概览
简要总结
This is a Phase 1/2, multicenter, open-label, dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), cerebrospinal fluid penetration, and preliminary antitumor activity of orally administered JBI-778, a selective PRMT5 inhibitor, in patients with brain metastases, leptomeningeal disease, or recurrent high-grade glioma. The study consists of a dose-escalation phase to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), followed by expansion cohorts to evaluate preliminary efficacy at the RP2D.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 ≤
- •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.
排除标准
- •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).
研究组 & 干预措施
Arm 4 - Leptomeningeal Disease Expansion Cohort
Intervention Drug: JBI-778
Oral capsule Strengths: 20 mg, 100 mg, 250 mg Starting dose: 40 mg daily Continuous once-daily administration in 21-day cycles
干预措施: JBI-778 (Drug)
Arm 3 - Brain Metastases Expansion Cohort
Intervention Drug: JBI-778
Oral capsule Strengths: 20 mg, 100 mg, 250 mg Starting dose: 40 mg daily Continuous once-daily administration in 21-day cycles
干预措施: JBI-778 (Drug)
Arm 1 - Dose-Escalation Phase
Intervention Drug: JBI-778
Oral capsule Strengths: 20 mg, 100 mg, 250 mg Starting dose: 40 mg daily Continuous once-daily administration in 21-day cycles
干预措施: JBI-778 (Drug)
Arm 2 - High-Grade Glioma Expansion Cohort
Intervention Drug: JBI-778
Oral capsule Strengths: 20 mg, 100 mg, 250 mg Starting dose: 40 mg daily Continuous once-daily administration in 21-day cycles
干预措施: JBI-778 (Drug)
结局指标
主要结局
Phase 2 Leptomeningeal Disease Cohort: Overall Survival (OS)
时间窗: Up to 2 years.
Overall survival in participants with leptomeningeal disease.
Phase 1 - Incidence of Dose Limiting Toxicities (DLTs)
时间窗: At the end of Cycle 1 (each cycle is 21 days)
Number of participants with dose-limiting toxicity (DLT) events during the DLT monitoring period. DLTs are defined per protocol criteria and graded using NCI CTCAE Version 5.0.
Phase 2 High-Grade Glioma Cohort: Objective Response Rate (ORR)
时间窗: Up to 2 years
Investigator-assessed ORR according to Response Assessment in Neuro-Oncology (RANO) criteria.
Phase 2 Brain Metastases Cohort: Objective Response Rate (ORR)
时间窗: Up to 2 years.
Investigator-assessed ORR according to RANO Brain Metastases (RANO-BM) criteria.
次要结局
- Incidence of Adverse Events(Up to 2 years)
- Maximum Plasma Concentration (Cmax) of JBI-778(From Cycle 1 Day 1 up to Cycle 2 Day 1 (each cycle is 21 days))
- Area Under the Plasma Concentration-Time Curve (AUC0-t) of JBI-778(From Cycle 1 Day 1 up to Cycle 2 Day 1 (each cycle is 21 days))
- Time to Maximum Plasma Concentration (Tmax) of JBI-778(From Cycle 1 Day 1 up to Cycle 2 Day 1 (each cycle is 21 days))