A Phase 1, Open-label, Controlled, Dose-escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics and Pharmacodynamics of GKL-006 Injection in Combination With Transarterial Chemoembolization (TACE) Versus TACE Alone in Patients With Unresectable Hepatocellular Carcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 13
- 试验地点
- 2
- 主要终点
- Maximum Tolerated Dose（MTD）of GKL-006
研究概览
简要总结
This Phase Ia study evaluated the safety and tolerability of a single escalating dose via intravenous infusion of the autologous invariant natural killer T cells (iNKT-cell) product GKL-006 in combination with transarterial chemoembolisation (TACE) in participants with unresectable hepatocellular carcinoma (uHCC). The study aimed to characterise dose-limiting toxicities (DLT), determine the maximum tolerated dose (MTD), and assess pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumour activity.
详细描述
The study used a 3+3 dose-escalation design with three GKL-006 dose levels: (1.0±0.3)×10^8, (3.0±0.9)×10^8, and (9.0±2.7)×10^8 iNKT cells/m^2. Each cohort was planned to include three participants receiving GKL-006 plus TACE and one concurrent participant receiving TACE alone. All participants underwent one TACE procedure during the 28-day treatment period, which also served as the DLT observation period. Nineteen participants were screened and 13 were enrolled; one enrolled participant underwent leukapheresis but did not receive the cell infusion, leaving 12 participants who completed the protocol-specified treatment and DLT evaluation. After treatment, efficacy was assessed every 8 weeks, with continued safety, imaging, and survival follow-up.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Voluntarily participates and provides written informed consent.
- •Aged ≥18 years, male or female.
- •Unresectable primary hepatocellular carcinoma (HCC) confirmed by histology, cytology, or imaging (dynamic CT or MRI). Unresectable disease includes technically unresectable disease or disease for which surgery is not feasible or is declined for other reasons.
- •CNLC stage II-IIIa.
- •Suitable for TACE and total tumour volume ≤50% of the liver volume.
- •At least one measurable HCC lesion per mRECIST.
- •Tumour confined to the liver, with no extrahepatic spread or major vascular invasion (Vp3 or Vp4 portal vein tumour thrombus).
- •Child-Pugh score ≤9 within 7 days before enrolment.
- •ECOG performance status of 0-2
- •Life expectancy ≥24 weeks.
- •Adequate haematologic and organ function:
- •WBC ≥2 × 10^9/L;
- •haemoglobin ≥90 g/L;
- •ANC ≥1.5 × 10^9/L;
- •platelets ≥50 × 10^9/L;
- •PT or APTT ≤2 × ULN;
- •serum creatinine ≤ULN;
- •AST and ALT ≤5 × ULN;
- •total bilirubin ≤3 × ULN.
- •For patients with HBV or HCV infection, viral load must not exceed the lower limit of detection (HBV DNA ≤2,000 IU/mL and HCV RNA ≤100 IU/mL).
- •No radiotherapy, chemotherapy, targeted therapy, or immunosuppressive therapy within 4 weeks before screening.
- •Participants of reproductive potential must use at least one medically accepted contraceptive method during study treatment and for 6 months after treatment.
- •Able to communicate with investigators, comply with study visits, and understand and follow study requirements.
排除标准
- •Hypersensitivity to immunotherapy or related medications.
- •Another malignancy within the previous 5 years or a concurrent uncontrolled malignancy, except cured basal cell carcinoma, carcinoma in situ, or breast cancer with no recurrence for >3 years after curative surgery.
- •History of organ transplantation.
- •Any contraindication to TACE, as determined by the investigator.
- •Histologically or cytologically confirmed combined HCC-cholangiocarcinoma, fibrolamellar HCC, sarcomatoid HCC, or another mixed carcinoma.
- •Active, known, or suspected autoimmune disease.
- •Systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive therapy within 4 weeks before screening.
- •Infiltrative tumour growth or extrahepatic metastasis on imaging.
- •Hepatic encephalopathy.
- •Symptomatic ascites or pleural effusion.
- •History or current evidence of idiopathic pulmonary fibrosis, interstitial pneumonitis, pneumoconiosis, drug-induced pneumonitis, or active pneumonitis on screening CT.
- •Poorly controlled cardiovascular disease.
- •Uncontrolled hypertension despite medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg).
- •Urine protein ≥2+ within 7 days before enrolment with confirmed 24-hour urine protein >1.0 g.
- •Any of the following bleeding risks:
- •CTCAE v5.0 Grade ≥2 bleeding within 4 weeks before enrolment;
- •tumour invasion of a major vessel or a high risk of life-threatening bleeding, as determined by the investigator;
- •gastrointestinal bleeding within 6 months;
- •known hereditary or acquired bleeding or thrombotic disorder.
- •Arterial or venous thromboembolic event within 6 months.
- •Signs or symptoms of intestinal or gastrointestinal obstruction within 1 month.
- •Active infection within 2 weeks before enrolment.
- •AST or ALT >5 × ULN within 7 days before enrolment.
- •Congenital or acquired immunodeficiency, including HIV infection; syphilis; or another serious active infection.
- •Pregnant or breastfeeding women.
- •Receipt of a live attenuated vaccine or COVID-19 vaccine within 4 weeks before screening.
- •Participation in another interventional clinical trial.
- •Any serious concomitant disease, clinically significant laboratory abnormality, psychiatric condition, or family or social circumstance that may compromise participant safety or interfere with data or sample collection, as determined by the investigator.
- •Any other condition that, in the investigator's opinion, makes the participant unsuitable for enrolment or study completion.
研究组 & 干预措施
TACE
Participants will receive transarterial chemoembolization (TACE) alone according to the study protocol.
干预措施: transarterial chemoembolization (Drug)
Low-Dose Cohort
Participants will receive TACE and (1.0±0.3)×10^8 iNKT cells/m^2 of GKL-006 Injection sequentially according to the study protocol.
干预措施: transarterial chemoembolization (Drug)
Low-Dose Cohort
Participants will receive TACE and (1.0±0.3)×10^8 iNKT cells/m^2 of GKL-006 Injection sequentially according to the study protocol.
干预措施: GKL-006 Injection (Biological)
Medium-Dose Cohort
Participants will receive TACE and (3.0±0.9)×10^8 iNKT cells/m^2 of GKL-006 Injection sequentially according to the study protocol.
干预措施: GKL-006 Injection (Biological)
Medium-Dose Cohort
Participants will receive TACE and (3.0±0.9)×10^8 iNKT cells/m^2 of GKL-006 Injection sequentially according to the study protocol.
干预措施: transarterial chemoembolization (Drug)
High-Dose Cohort
Participants will receive TACE and (9.0±2.7)×10^8 iNKT cells/m^2 of GKL-006 Injection sequentially according to the study protocol.
干预措施: GKL-006 Injection (Biological)
High-Dose Cohort
Participants will receive TACE and (9.0±2.7)×10^8 iNKT cells/m^2 of GKL-006 Injection sequentially according to the study protocol.
干预措施: transarterial chemoembolization (Drug)
结局指标
主要结局
Maximum Tolerated Dose（MTD）of GKL-006
时间窗: From the GKL-006 infusion until 28 days.
The MTD determined from protocol-defined DLTs under the 3+3 dose-escalation design.
Incidence of Dose-Limiting Toxicities (DLTs)
时间窗: From GKL-006 infusion through Day 28
Observe the dose limiting toxicity, and Incidence of dose-limiting toxicities(DLT) will be assessed
次要结局
- Incidence and Severity of Adverse Events(From GKL-006 infusion though 28 days.)
- Cmax(From 1 hour pre-dose of GKL-006 injection through 12 weeks)
- Tmax(From 1 hour pre-dose of GKL-006 injection through 12 weeks)
- AUC(From 1 hour pre-dose of GKL-006 injection through 12 weeks)
- t1/2z(From 1 hour pre-dose of GKL-006 injection through 12 weeks)
- Changes in Peripheral Blood Immune Cell Subsets(From 1 hour pre-dose of GKL-006 injection through 12 weeks)
- Changes in Plasma Cytokines and Cytotoxic Effector Molecules(From 1 hour pre-dose of GKL-006 injection through 12 weeks)
- PFS(Approximate 14 months)
- DCR(Approximate 14 months)
- ORR(Approximate 14 months)
- DOR(Approximate 14 months)
- TTP(Approximate 14 months)
- 1Y-OS(Approximate 14 months)
- OS(From enrollment to death, approximate 5 years.)