A Phase I, Multicenter, Open-label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of NBL-015 in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 410
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 dose (RP2D)
研究概览
简要总结
This trial is an open-label, multicenter, dose-escalation and cohort-expansion Phase I clinical study in patients with advanced solid tumors. The aim of this study is to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of NBL-015 in patients with advanced solid tumors.
详细描述
This study is a multicenter, open-label phase I clinical trial conducted in patients with CLDN18.2-positive advanced solid tumors, aiming to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of NBL-015 in patient with advanced solid tumors.
This study consists of two stages: the stage I (dose escalation and dose expansion) and the stage II (NBL-015 monotherapy cohort expansion and combination of NBL-015 with standard treatment cohort expansion).
The dose escalation phase is divided into 5 dose levels. NBL-015 is escalated in order of 1 mg/kg, 3 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg until MTD. If MTD is still not observed in the preset highest dose group, the investigator and the sponsor can jointly decide whether to conduct a higher dose group study. If necessary, intermediate doses may be conducted. The first dose group (1 mg/kg) is the accelerated titration group, in which 1 patient will be enrolled, and the "3+3" dose escalation design will be followed from the second dose group.
If RP2D can be determined based on clinical study data in the dose escalation stage, Stage II cohort expansion will be directly conducted. Alternatively, based on the safety, tolerability and efficacy data obtained from dose-escalation studies, dose expansion and different dosing can be explored if necessary.
Based on available PK and clinical efficacy data, appropriate dose groups will be selected for cohort expansion. The cohort expansion stage includes the NBL-015 monotherapy cohort expansion trial and the combination of NBL-015with standard treatment cohort expansion trial.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18, ≤75 years, (subject to the date of signing the informed consent) who voluntarily sign the informed consent.
- •Positive expression of Claudin 18.2 which is defined as moderate to severe membrane staining (2+/3+) in ≥50% of tumor cells tested by central laboratory immunohistochemistry (IHC).
- •Histologically or cytologically confirmed diagnosis of advanced or metastatic solid tumors.
- •At least one measurable lesion as per RECIST version 1.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or
- •Life expectancy ≥12 weeks.
- •Adequate major organ function within 7 days prior to treatment.
- •Serum pregnancy tests were negative in women of reproductive age (WOCBP) within 7 days prior to initial use of the investigational drug. Patients and their spouses must agree to take adequate contraceptive measures from the time of signing the informed consent until 6 months after the last dose. During this period, women are not breastfeeding and men avoid sperm donation.
排除标准
- •A history of other malignancies within 3 years prior to first dose, except for locally curable cancers.
- •Patients with central nervous system metastases.
- •Gastrointestinal abnormalities include:
- •A) Pyloric obstruction or persistent recurrent vomiting (defined as ≥3 times of vomiting in 24 hours); B) There is a high risk of gastrointestinal bleeding or that there are other gastrointestinal abnormalities affecting the drug toxicity assessment determined by the investigator.
- •Patient with a history of serious cardiovascular disease.
- •A history of severe autoimmune disease that the investigator judged inappropriate for inclusion.
- •Patients with active hepatitis B or C, or active syphilis infection, or HIV positive.
- •Patients who are known to have severe allergic reactions and/or contraindications to prescription ingredients of NPL-015 or monoclonal antibodies, or who are intolerant to combination drugs;
- •Patients who underwent major surgery (excluding needle biopsy) within 4 weeks prior to initial use of the investigational drug, or who required elective surgery during the trial period, or who had severe unhealed wounds, traumatic ulcers, etc.
- •Toxicity of previous antitumor therapy did not return to grade 1 or below (CTCAE V5.0), except for toxicity of alopecia and other toxicity that researchers judged to have no safety risk.
- •Patients have previously been treated with a drug targeting Claudin18.
- •The time interval between the last anti-tumor treatment and the first use of experimental drug should meet the following requirements:
- •A) Received antitumor therapy such as chemotherapy, radiotherapy (except local radiation therapy for pain relief), targeted therapy, immunotherapy, and other investigational agents within 4 weeks prior to initial administration; B) Received oral fluorouracil, small-molecule targeted drugs and traditional Chinese medicine with anti-tumor indications within 2 weeks prior to initial administration.
- •Receiving a corticosteroid (prednisone>10 mg/ day or equivalent dose of the same kind of drug) or other immunosuppressant treatment, except for:
- •A) Local, ocular, intraarticular, intranasal, and inhaled glucocorticoids; B) Short-term use of glucocorticoids for prophylactic treatment (e.g. to prevent contrast allergy).
- •Live attenuated vaccine is received within 2 weeks prior to the first use of the investigational drug or is planned for the study period.
- •Other conditions that the investigator considers inappropriate for participation in this clinical trial.
研究组 & 干预措施
Experimental: solid tumors
Dose-escalation stage: Patients will receive NBL-015 once every two or three weeks, starting at a dose of 1 mg/kg.
Cohort-expansion stage: Patients will receive NBL-015 at selected dose as per the results of dose-escalation stage.
干预措施: NBL-015 (Drug)
结局指标
主要结局
Recommended Phase 2 dose (RP2D)
时间窗: Approximately 2 years
RP2D will be determined using available safety and efficacy data.
Objective response rate (ORR) (in stage Ⅱ)
时间窗: Approximately 2 years in stage Ⅱ
Percentage of participants with CR or PR.
Incidence of serious adverse events (SAEs)
时间窗: Approximately 4 years
Incidence of serious adverse events (SAEs) of single and multiple dose (according to NCI CTCAE 5.0).
Dose Limiting Toxicity (DLT )
时间窗: Up to 28 days after first injection
Dose-limiting toxicity in patients with advanced tumors treated by NBL-015.
Disease control rate (DCR) (in stage Ⅱ)
时间窗: Approximately 2 years in stage Ⅱ
Percentage of participants with CR or PR or SD.
Overall survival (OS) (in stage Ⅱ)
时间窗: Approximately 2 years in stage Ⅱ
OS is defined as the time from first dose to death from any cause.
Incidence of adverse events (AEs)
时间窗: Approximately 4 years
Incidence of adverse events (AEs) of single and multiple dose (according to NCI CTCAE 5.0).An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Maximum tolerated dose (MTD) (if available)
时间窗: Approximately 1 year
MTD is defined as the prior dose level below the dose level at which 2/6 subjects suffer dose limiting toxicities.
Duration of response (DOR) (in stage Ⅱ)
时间窗: Approximately 2 years in stage Ⅱ
DOR is defined as the time from first objective response (CR or PR per RECIST v 1.1) to first occurrence of objective tumor progression (progressive disease per RECIST v 1.1) or death from any cause, whichever occurs first.
Progression-free survival (PFS) (in stage Ⅱ)
时间窗: Approximately 2 years in stage Ⅱ
PFS is defined as the time from first dose to the first observation of disease progression (based on central reading) or death from any cause (as assessed by the independent reviewer).
次要结局
- Pharmacokinetic (PK)(Up to 21 Days after the sixth injection in stage I, after the fifth injection in stage II.)
- Incidence of anti-drug antibody (ADA)(Once before each of the first five doses and once every 3 months thereafter, and 30 Days after the last dose.)
- Objective response rate (ORR) (in stage Ⅰ)(Approximately 2 years in stage Ⅰ)
- Disease control rate (DCR)(in stage Ⅰ)(Approximately 2 years in stage Ⅰ)
- Duration of response (DOR)(in stage Ⅰ)(Approximately 2 years in stage Ⅰ)
- Progression-free survival (PFS) (in stage Ⅰ)(Approximately 2 years in stage Ⅰ)
- Overall survival (OS) (in stage Ⅰ)(Approximately 2 years in stage Ⅰ)