A Phase 1, Multicenter, Open-Label, Dose-Escalation/Consolidation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of Orally Administered JBI-778 in EGFR Mutated Lung Cancer Patients with or without Brain Metastasis, Isocitrate Dehydrogenase (IDH) Mutated WHO Grade 3/4 Recurrent Glioma and Adenoid Cystic Carcinoma (ACC)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 42
- 试验地点
- 8
- 主要终点
- Primary Endpoint
研究概览
简要总结
This is a phase 1, multicenter, first-in-human, open-label, dose-escalation/consolidation study to investigate the safety, pharmacokinetics, pharmacodynamics, and clinical activity of orally administered JBI-778 in EGFR mutated lung cancer patients with or without brain metastasis, IDH mutated WHO grade 3 /4 recurrent glioma and ACC with evidence of recurrent, metastatic or advanced, incurable disease arising from any primary site. A total of 42 patients will be recruited in the study. The initial dose escalation up to cohort 3 (estimate to be 160mg) or until the pharmacologically active dose is reached, whichever comes first as determined by the safety committee will be performed only in EGFR mutant NSCLC patients with or without stable cerebral metastases and ACC patients. Once this dose level is reached IDH mutant WHO grade 3 /4 glioma patients will be added. Once the RP2D is determined following dose escalation, additional patients, up to 12, will be treated at that dose to obtain further safety data and preliminary efficacy. Approximately 4 to 6 sites is anticipated for the dose-escalation/consolidation, additional sites will be evaluated as needed. Study will be initiated only after receipt of regulatory and ethics committee (EC) approval. After signing the informed consent form, the patients will undergo screening assessments to confirm eligibility. Eligible patients will be considered first for initial dose escalation and once the RP2D is determined following dose escalation, additional patients, up to 12, will be treated at that dose to obtain further safety data and preliminary efficacy. The RP2D will be establish after a detailed analysis of the totality of dose escalation data, including PK, safety, efficacy, CNS penetration based on CSF sample for study drug presence, analysis of PD markers in peripheral blood and both pre-treatment and on treatment tumor biopsies.
The duration of participation for each patient will be as follows: • Screening: - Up to 21 days (-21 to 1 days) • Treatment period: Treatment cycle of 21-day each. Treatment may continue for up to 2 years from the start of treatment, provided that the patient experiences clinical benefit in the opinion of the Investigator and shows no signs or symptoms of unequivocal progression of the disease, unacceptable toxicity, or other reasons for study discontinuation. • End of treatment (EOT)/ Early termination (ET) visit • Safety Follow-up: 30 days after last dose • Survival: Every 3 months
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Males or females aged ≥ 18 years at the time of informed consent.
- •Screening laboratory values: Absolute neutrophil count (ANC) ≥1,500 cells/mm
- •Platelet count ≥100,000 cells/mm
- •Total bilirubin ≤1.5× ULN (upper limit of normal).
- •Patients with Gilbert’s syndrome may be enrolled with up to 3.0×ULN.
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5× ULN (unless liver metastases are present then up to ≤5×ULN is allowed).
- •Creatinine clearance (CrCL) ≥ 40 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation or other equally relevant calculations.
- •(Refer in Appendix VIII) Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT) ≤1.5× ULN if the patient is not on anticoagulants (If the patient is on anticoagulants, the patient must be on a stable dose for at least 2-weeks prior to screening).
排除标准
- •Treatment with systemic anticancer therapy or an investigational agent within 2-weeks or 5 half-lives, whichever is shorter, prior to the start of study drug treatment.
- •Major surgery ≤ 21 days prior to starting study drug or has not recovered from adverse effects of such procedure.
- •Surgery (e.g., stomach bypass) or medical condition that might significantly affect the absorption of medicines (as judged by the investigator).
- •Radiotherapy within 4 week for brain metastases and 2-weeks for the rest of body part prior to the start of study drug treatment.
- •Patients must have recovered from all radiotherapy-related toxicities prior to the start of study treatment.
- •Severe or unstable medical condition, such as congestive heart failure (New York Heart Association [NYHA] Class III or IV), ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an uncontrolled cardiac arrhythmia requiring medication (≥ Grade 2, according to NCI CTCAE V5), myocardial infarction within 6 months prior to starting study treatment, or any other significant or unstable concurrent cardiac illness.
- •Note: stable chronic atrial fibrillation is allowed.
结局指标
主要结局
Primary Endpoint
时间窗: [Timeframe: at 6 months and up to | approximately 2 years]
Incidence of dose-limiting toxicity (DLT)events during the DLT monitoring period.[Timeframe: Baseline through Day 21 of Cycle1].
时间窗: [Timeframe: at 6 months and up to | approximately 2 years]
次要结局
- • Incidence of adverse events (AE)(characterized overall and by type, frequency,seriousness, relationship to study treatment,timing, and severity graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.)
- PK profile as assessed by single-dose and(steady-state such as Cmax, tmax, AUC0-t,)
- • Change from baseline in symmetrical dimethylarginine (SDMA) as a PD measure.
- IDH Mutated WHO Grade 3/4 Recurrent(Glioma)
- Metastatic or advanced, incurable disease(arising from any primary site)
- Brain Metastases and extracerebral disease(• Response rate by response assessment in)
- EGFR Mutated Lung Cancer without(Brain Metastasis)
研究者
Dr Kumar Prabhash
Tata Memorial Centre