A Phase Ib/II, Open, Dose-escalation and Expansion Study to Evaluate LB1410 in Combination With LB4330 in Patients With Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 194
- 试验地点
- 1
- 主要终点
- Disease control rate (DCR)
研究概览
简要总结
This is a phase Ib/II, open, dose-escalation and expansion study of an anti-PD1/TIM3 bispecific antibody，LB1410 in combination with an anti-Claudin18.2/IL-10 fusion protein, LB4330 in patients with advanced or metastatic solid tumors.
详细描述
The phase Ib/II clinical study in Chinese patients with advanced or metastatic solid tumors to evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD), anti-tumor efficacy, and biomarkers of LB1410 in combination with LB4330.
The study will include 2 parts: dose escalation (Phase Ib) and dose expansion (Phase II). Repeated intravenous infusion of LB1410 in combination with LB4330 in patients with metastatic or advanced pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, ovarian, fallopian tube, or primary peritoneal cancer, non-small cell lung cancer, gastric and gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, renal cell carcinoma, cervical squamous cell carcinoma, and endometrial carcinoma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Must be ≥ 18 years of age when signing informed consent.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 without deterioration in the past 2 weeks.
- •Estimated life expectancy of ≥12 weeks.
- •Baseline IL-6 levels below 40 pg/mL.
- •Histologically or cytologically documented advanced and metastatic solid tumors for which can't tolerate standard treatment, standard treatment fails, or no standard treatment is available at this stage.
- •Must have at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 at screening.
- •Adequate hematologic function prior to registration for protocol therapy defined as the following criteria:
- •absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, without the use of granulocyte colony-stimulating factor such as filgrastim in the 2 weeks prior to study treatment (≤ 14 days);
- •platelet count ≥ 120 × 10^9/L, without transfusion or use of drugs like recombinant human platelet growth factor in the 2 weeks prior to study treatment (≤ 14 days), for HCC patients, platelet count ≥ 100 × 10^9/L;
- •hemoglobin ≥ 90 g/L, without transfusion or use of drugs like erythropoietin in the 2 weeks prior to study treatment (≤ 14 days).
- •Both AST and ALT ≤ 3 × ULN (both AST and ALT < 5 × ULN for subjects with known hepatocellular carcinoma or hepatic metastases); total bilirubin ≤ 1.5 × ULN (except for subjects with elevated serum bilirubin due to documented underlying conditions such as Gilbert's syndrome or familial benign unconjugated hyperbilirubinemia); for bile duct cancer patients, total bilirubin ≤ 2 × ULN; and serum albumin ≥ 30 g/L.
- •Adequate renal function defined as: serum creatinine ≤ 1.5 × ULN, and creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula).
- •Requirements for coagulation function are as follows:
- •activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;
- •international normalized ratio (INR) ≤ 1.5 × ULN (INR ≤ 3 × ULN for subjects receiving warfarin anticoagulant therapy).
- •Any prior anti-tumor therapies (including endocrine/chemotherapy/targeted therapy/immunotherapy) before treatment should washout:
- •at least 4 weeks for biological therapy (e.g., antibodies);
- •at least 2 weeks or 5 half-lives (whichever is longer) for small molecule drugs, including 5-FU or its derivatives; at least 6 weeks for nitrosoureas and mitomycin;
- •at least 2 weeks for Chinese herbal medicine used for indications of anti-tumor activity;
- •at least 4 weeks for any systemic therapeutic investigational drugs;
- •at least 2 weeks for any radiotherapy;
- •any related toxicities or prior adverse events resolved to baseline or ≤ NCI CTCAE 5.0 grade 1 (excluding toxicities without safety risk judged by the investigator, such as alopecia, grade 2 peripheral neuropathy, stable hypothyroidism under hormone replacement therapy, etc.).
- •Phase Ib dose escalation additional inclusion criteria: histologically or cytologically documented advanced malignant solid tumors (preferably pancreatic ductal adenocarcinoma, cholangiocarcinoma, ovarian cancer, microsatellite stable colorectal cancer, advanced solid tumors previously treated with anti-PD-1/PD-L1 inhibitors, such as gastric or gastroesophageal junction adenocarcinoma, or other solid tumors determined by the investigator and sponsor);
- •Phase II (phase IIa and IIb) dose expansion cohort A additional inclusion criteria:
- •must have received at least one but no more than two prior lines of systemic therapy;
- •CA199 < 1000 IU/mL during screening period
- •must not have received any immune checkpoint inhibitor (ICI) therapy.
- •Phase II (phase IIa and IIb) dose expansion cohort B additional inclusion criteria:
- •must have received at least one but no more than three prior lines of systemic therapy;
- •without C-Met, FGFR, IDH1 mutations or the genotype is unknown;
- •CA199 < 1000 IU/mL during screening period.
- •Phase II (phase IIa and IIb) dose expansion cohort C additional inclusion criteria:
- •must have received at least one but no more than three prior lines of systemic therapy;
- •CA199 < 1000 IU/mL during screening period;
- •must not have received any immune checkpoint inhibitor (ICI) therapy;
- •KRAS, NRAS and BRAF are wild type;
- •without hepatic metastasis.
- •Phase II (phase IIa and IIb) dose expansion cohort D additional inclusion criteria:
- •recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer;
- •must have received at least one but no more than three prior lines of systemic therapy;
- •must not have received any immune checkpoint inhibitor (ICI) therapy;
- •PD-L1 positive;
- •have received one prior treatment regime of platinum-based chemotherapy;
- •subjects with BRCA germline mutation (gBRCA mut) should been treated with a polyADP ribose polymerase inhibitor (PARPi), such as Olaparib, Rucaparib, or Niraparib.
- •Phase II (phase IIa and IIb) dose expansion cohort E additional inclusion criteria:
- •includes non-small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, kidney carcinoma, cervical squamous cell carcinoma, and endometrial carcinoma;
- •must have received at least one but no more than two prior lines of systemic therapy, of which only one prior line of therapy contained an anti-PD-1/PD-L1;
- •subjects with PD-1/PD-L1 primary resistance are required to be known PD-L1 positive.
- •non-squamous NSCLC must have documented test results of EGFR mutation, ALK fusion and ROS1 fusions, and the above driver genes must be wild type;
- •non-squamous NSCLC, if RET, MET, NTRK gene testing has been performed previously, the results must be wild type;
- 另有 51 项未显示
排除标准
- 未提供
研究组 & 干预措施
Phase Ib, Dose Escalation of LB1410 in combination with LB4330
Up to 4 dose cohorts will be enrolled in the dose-escalation part with the standard 3+3 dose escalation algorithm approach.
干预措施: LB1410 (Drug)
Phase Ib, Dose Escalation of LB1410 in combination with LB4330
Up to 4 dose cohorts will be enrolled in the dose-escalation part with the standard 3+3 dose escalation algorithm approach.
干预措施: LB4330 (Drug)
Phase II, Expansion Cohorts of LB1410 in combination with LB4330
This part includes IIa and IIb. Phase IIa will be enrolled subjects at the dose level with initial anti-tumor activity observed in Phase Ib, the numbers of patients enrolled in the phase IIa could be adjusted based on previously available safety and preliminary efficacy data; the dose level of the phase IIb is the RP2D dose level determined in the phase Ib. The planned expanded cohorts are as follows:
Cohort A: pancreatic ductal adenocarcinoma;
Cohort B: cholangiocarcinoma;
Cohort C: colorectal cancer;
Cohort D: recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer;
Cohort E: other solid tumors (non-small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, renal cell carcinoma, cervical squamous cell carcinoma, and endometrial carcinoma).
干预措施: LB1410 (Drug)
Phase II, Expansion Cohorts of LB1410 in combination with LB4330
This part includes IIa and IIb. Phase IIa will be enrolled subjects at the dose level with initial anti-tumor activity observed in Phase Ib, the numbers of patients enrolled in the phase IIa could be adjusted based on previously available safety and preliminary efficacy data; the dose level of the phase IIb is the RP2D dose level determined in the phase Ib. The planned expanded cohorts are as follows:
Cohort A: pancreatic ductal adenocarcinoma;
Cohort B: cholangiocarcinoma;
Cohort C: colorectal cancer;
Cohort D: recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer;
Cohort E: other solid tumors (non-small cell lung cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, hepatocellular carcinoma, renal cell carcinoma, cervical squamous cell carcinoma, and endometrial carcinoma).
干预措施: LB4330 (Drug)
结局指标
主要结局
Disease control rate (DCR)
时间窗: From first participant until last participant assessment, an average of 8 months
Percentage of patients whose best overall response is either a Complete Response, a Partial Response or Stable Disease according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) criteria over the total number of evaluable patients.
Duration of overall Response (DoR) by RECIST version 1.1
时间窗: From first participant until last participant assessment, an average of 8 months
Time from the date of first documented response (CR or PR) to the date of first documented disease progression according to RECIST 1.1 criteria or the date of death due to underlying cancer.
Overall response rate (ORR)
时间窗: From first participant until last participant assessment, an average of 8 months
Percentage of patients whose best overall response is either a Complete Response or a Partial Response according to Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) criteria over the total number of evaluable patients
Incidence and severity of serious adverse events (SAEs) and other special interest (immune-related AEs)
时间窗: up to 60 days following last dose
According to NCI-CTCAE v5.0
Incidence of Dose limiting toxicity (DLT)
时间窗: At the end of Cycle 1 (each cycle is 28 days)
The DLT for this study is defined per CTCAE 5.0 and will be evaluated in the Cycle 1 of treatment in the dose escalation part. If dosing delay occurs, the DLT evaluation should be correspondingly extended to 14 days after the second dosing.
Maximum tolerance toxicity (MTD) and recommended dose for Phase II (RP2D) definition
时间窗: up to 1 year
MTD and RP2D based on the safety data collected during the dose escalation phase (Phase I)
Overall Survival (OS) duration
时间窗: From first participant until last participant assessment, an average of 1 year
Time from first LB1410 and LB4330 infusion to the date of death due to any cause over evaluable patients.
Safety and tolerability (Adverse Event reported per NCI-CTCAE v5.0)
时间窗: up to 60 days following last dose
Incidence of treatment-emergent adverse events (TEAEs) and treatment-related adverse events reported per NCI-CTCAE v5.0
Progression Free Survival (PFS) by RECIST version 1.1
时间窗: From first participant until last participant assessment, an average of 8 months
Time from the first infusion of LB1410 and LB4330 to the date of first documented tumor progression according to RECIST 1.1 criteria or death due to any cause, whichever occurs first over evaluable patients.
DDC
时间窗: From first participant until last participant assessment, an average of 8 months
Time from the date of first documented CR, PR or SD to the date of first documented disease progression according to RECIST 1.1 criteria or the date of death due to any cause.
次要结局
- Pharmacokinetics of LB1410 and LB4330: Maximum plasma concentration of the study drug (Cmax)(Through study completion, an average of 1 year)
- Pharmacokinetics of LB1410 and LB4330: Area Under the concentration-time curve (AUC)(Through study completion, an average of 1 year)
- Pharmacokinetics of LB1410 and LB4330: Clearance(Through study completion, an average of 1 year)
- Pharmacokinetics of LB1410 and LB4330: Terminal elimination half-life ( T½)(Through study completion, an average of 1 year)
- Evaluation of immunogenicity of each antibody drug in the combinations(Up to 60 days following last dose)