Investigator-Initiated Clinical Trial Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of CS01 in Patients With Locally Advanced or Metastatic Solid Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Phase I: Incidence of DLT events during the observation period
研究概览
简要总结
This is an investigator-initiated clinical trial evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of CS01 in patients with locally advanced or metastatic solid tumors.
详细描述
Overall Design
- Trial Overview This trial is an Investigator-Initiated Trial (IIT) clinical study evaluating CS01 injection as monotherapy for locally advanced or metastatic solid tumors. A Safety and Efficacy Data Assessment Committee (SMC), jointly formed by the Sponsor and the investigators, will evaluate data from all treated subjects in the dose escalation phase to screen and determine the clinically recommended dose. The trial consists of two phases: Dose Escalation (Phase I) and Dose Expansion (Phase II). The first phase involves monotherapy dose escalation of CS01, and the second phase involves monotherapy dose expansion of CS01.
Phase I: Dose Escalation The Dose Escalation Phase will first be conducted in subjects with locally advanced or metastatic solid tumors. The monotherapy dose-escalation study of CS01 is designed with four planned dose groups: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg. It aims to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of CS01 monotherapy and to determine the maximum tolerated dose (MTD) (or minimum effective dose, MED) and the recommended Phase II dose (RP2D) for monotherapy.
Phase II: Dose Expansion The Dose Expansion Study will be conducted in potentially responsive populations identified during the Dose Escalation Phase (Phase I). Based on earlier findings, this phase aims to further validate the safety, efficacy, PK, PD, and biomarker profiles of CS01 injection as monotherapy at the RP2D in specific subjects with locally advanced or metastatic solid tumors. 2. Detailed Design Phase I: Dose Escalation This phase will utilize an accelerated titration design (for the first dose group only) and a "3+3" design. It will enroll approximately 10 patients with locally advanced or metastatic solid tumors who have failed standard treatment, are intolerant, or lack effective treatment options. The four planned dose groups are: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg. All patients will receive CS01 injection via intravenous infusion once every two weeks (Q2W), with every 4 weeks constituting one treatment cycle. Dose-Limiting Toxicity (DLT) assessments will be conducted at the end of the 4th week for each dose group. Antitumor efficacy assessments (based on RECIST v1.1 criteria) will be performed every 8 weeks. Safety data will be collected throughout the treatment period, and blood samples for PK, PD, immunogenicity, and biomarker analyses will also be collected.
Symptoms and signs of Cytokine Release Syndrome (CRS) will be closely monitored. CRS is defined as a supraphysiological response resulting from the activation or engagement of endogenous or infused T cells and/or other immune effector cells following the administration of any immunotherapeutic agent. The American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading for CRS is as follows:
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects must meet ALL of the following criteria for enrollment:
- •Age: 18 years or older (inclusive), male or female.
- •ECOG Performance Status: 0 to
- •Disease Characteristics:
- •Dose Escalation Phase: Subjects with histologically or cytologically confirmed unresectable or metastatic advanced solid tumors, who have failed standard treatment or are intolerant (disease progression, or intolerance to chemotherapy, targeted therapy, etc.), or who lack effective treatment options.
- •Dose Expansion Phase: Tumor types for which ≥1 instance of partial response (PR), or tumor-shrinking stable disease (SD), or biomarkers suggesting potential clinical benefit are observed during the dose escalation phase, as decided by the Safety and Efficacy Data Assessment Committee.
- •The subject must have at least one measurable lesion as defined by RECIST v1.
- •Agreement to provide tumor tissue specimens (optional).
- •o Note: For the dose escalation phase, tumor tissue samples equivalent to 4 FFPE unstained slides, or an equivalent amount of FFPE archived (within 2 years) or newly obtained tissue blocks are required. For the dose expansion phase, at least 4 and up to 9 FFPE unstained slides, or an equivalent amount of FFPE archived (within 2 years) or newly obtained tissue blocks are required. The FFPE biopsy must be from a surgical resection or core needle biopsy.
- •Life expectancy ≥ 3 months.
- •Recovery from toxicities of previous anti-tumor therapy to ≤ Grade 1 per CTCAE v5.0 (except for toxicities judged by the investigator to pose no safety risk, alopecia, or Grade 2 peripheral neuropathy judged irreversible). Immune-related adverse reactions must have completely resolved to baseline or Grade
- •Normal function of major organs, meeting the following laboratory criteria:
- •AST and ALT ≤ 2.5 × ULN; for subjects with liver metastases, AST and ALT ≤ 5 × ULN.
- •Total Bilirubin (TBil) ≤ 1.5 × ULN; for subjects with liver metastases or confirmed/suspected Gilbert's syndrome, TBil ≤ 3 × ULN.
- •Absolute Neutrophil Count (ANC) ≥ 1.5 × 10^9/L.
- •Platelets ≥ 100 × 10^9/L, with no transfusion within 28 days prior to the start of the study.
- •Hemoglobin ≥ 9.0 g/dL, with no transfusion within 14 days prior to the start of the study.
- •Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula).
- •International Normalized Ratio (INR) and Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN.
- •For female subjects of childbearing potential, a negative serum pregnancy test is required prior to the first dose of the investigational product.
- •Male or female subjects of childbearing potential (who have not undergone sterilization surgery or are not postmenopausal) must use highly effective contraception methods (such as oral contraceptives, intrauterine devices, sexual abstinence, or barrier methods combined with spermicide) during the study and continue for 6 months after the last dose.
- •The subject voluntarily agrees to join the study, signs the informed consent form, is able to understand the study procedures and methods, and is willing to strictly comply with the clinical trial protocol to complete the study.
排除标准
- •Subjects who meet ANY of the following criteria will be excluded from the study:
- •Previous treatment with anti-TNFR agonistic drugs.
- •Active autoimmune disease requiring systemic treatment within 12 months prior to the initiation of study treatment. This includes, but is not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis (Wegener's granulomatosis), Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Exceptions are made for the following:
- •Subjects with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone therapy are eligible.
- •Subjects with type 1 diabetes mellitus controlled on an insulin regimen are eligible.
- •Subjects with eczema, psoriasis, chronic lichen simplex, or vitiligo with dermatologic manifestations only (e.g., subjects with psoriatic arthritis are excluded) may be enrolled if they meet ALL of the following conditions:
- •i. The subject's rash covers <10% of body surface area. ii. The disease is well controlled at baseline, requiring only low-potency topical corticosteroids.
- •iii. There has been no acute exacerbation of the underlying condition within the past 12 months, or any acute exacerbation did not require treatment with psoralen plus ultraviolet A (PUVA) therapy, methotrexate, retinoids, biologics, oral calcineurin inhibitors, or high-potency/oral corticosteroids.
- •Subjects with a history of two or more primary synchronous or metachronous malignancies are excluded, except for cured carcinoma in situ or basal cell carcinoma. Other malignancies that have been stably treated for over 5 years prior to enrollment are allowed.
- •Within 4 weeks prior to the initiation of study treatment, subjects who have received the following treatments or medications:
- •Participation in another clinical trial involving an investigational drug (including investigational vaccines) or invasive investigational medical device, or current enrollment in an interventional investigational study.
- •Systemic anti-tumor therapy within 2 weeks prior to treatment initiation, or screening occurs within 5 half-lives of the previously administered drug (whichever is shorter).
- •Major surgery or significant trauma, or being in the recovery period which, in the investigator's judgment, may affect the trial, or having a planned surgery during the study period.
- •Chest radiotherapy or extensive field radiotherapy (defined as irradiation of >50% of pelvic bone marrow or equivalent) within 4 weeks, or palliative radiotherapy within 2 weeks prior to treatment initiation.
- •Administration of a live attenuated vaccine within 4 weeks prior to the first dose of study treatment, or expectation of requiring such a vaccine during the study or within 5 months after the last dose of study treatment.
- •Systemic treatment with corticosteroids (exceeding a dose equivalent to 10 mg prednisone per day) for more than 7 days, or other immunosuppressive agents, within 2 weeks prior to treatment initiation (use of inhaled or topical steroids, or adrenal replacement therapy at doses >10 mg prednisone equivalent is permitted in the absence of active autoimmune disease).
- •Primary central nervous system (CNS) tumors or symptomatic CNS metastases (subjects with leptomeningeal metastases are excluded regardless of symptoms). Exceptions are made for subjects with asymptomatic CNS metastases or symptomatic CNS metastases deemed stable by the investigator, provided they meet ALL the following criteria:
- •Clinical stability of neurological symptoms for ≥4 weeks prior to the first dose.
- •No evidence of CNS disease progression on contrast-enhanced brain MRI within 4 weeks prior to the first dose.
- •Discontinuation of anti-epileptic drugs for ≥2 weeks prior to the first dose.
- •Presence of uncontrolled pleural effusion, ascites, or pericardial effusion.
- •History of or current active interstitial lung disease.
- •Uncontrolled hypertension, defined as systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg despite optimal medical therapy.
- •Presence of clinically significant cardiovascular or cerebrovascular diseases, including:
- •Heart failure classified as New York Heart Association (NYHA) Class II-IV, congestive heart failure, or second-degree or higher heart block.
- •Myocardial infarction, unstable arrhythmia, or unstable angina occurring within the past 3 months.
- •Baseline QT interval corrected for heart rate (QTcF) >480 ms, or history of long QT syndrome (Note: Based on the average of three 12-lead ECGs at rest, using Fridericia's formula for correction).
- •Cerebral infarction occurring within the past 3 months.
- •Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) within the past 6 months.
- •Major vascular disease (e.g., aortic aneurysm requiring surgical intervention, any arterial thromboembolic event, or Grade 3 or higher venous thromboembolism per CTCAE v5.0) within 6 months prior to the first dose of study drug.
- •Thrombolytic therapy within 10 days prior to treatment initiation (except for maintaining venous catheter patency).
- •Any active infection requiring treatment, including but not limited to:
- •Active hepatitis B (HBsAg positive and HBV-DNA level above the lower limit of normal) or hepatitis C (HCV antibody positive and HCV-RNA quantitative test result above the lower limit of normal).
- •Known positive serology for human immunodeficiency virus (HIV).
- •Active tuberculosis.
- •History of allogeneic stem cell or solid organ transplantation.
- •Women who are pregnant or breastfeeding. Pregnancy is defined as the state of a female from conception until termination of the pregnancy, confirmed by a positive laboratory human chorionic gonadotropin (hCG) test within 7 days prior to study initiation.
- •Known or suspected inability to comply with the study protocol (e.g., due to alcoholism, drug dependency, or psychological disorders), or subjects who, in the opinion of the investigator, would be at risk by participating in this study; or the presence of any condition that, in the investigator's opinion, makes participation in this study not the best choice for the subject (e.g., compromises their health) or could affect, limit, or confound the protocol-specified assessments.
研究组 & 干预措施
0.03 mg/kg CS01
This phase will utilize an accelerated titration design (for the first dose group only) and a "3+3" design. It will enroll approximately 10 patients with locally advanced or metastatic solid tumors who have failed standard treatment, are intolerant, or lack effective treatment options. The four planned dose groups are: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg. All patients will receive CS01 injection via intravenous infusion once every two weeks (Q2W), with every 4 weeks constituting one treatment cycle. Dose-Limiting Toxicity (DLT) assessments will be conducted at the end of the 4th week for each dose group. Antitumor efficacy assessments (based on RECIST v1.1 criteria) will be performed every 8 weeks. Safety data will be collected throughout the treatment period, and blood samples for PK, PD, immunogenicity, and biomarker analyses will also be collected.
干预措施: CS01 (an anti-OX40 antibody) (Biological)
0.1 mg/kg CS01
This phase will utilize an accelerated titration design (for the first dose group only) and a "3+3" design. It will enroll approximately 10 patients with locally advanced or metastatic solid tumors who have failed standard treatment, are intolerant, or lack effective treatment options. The four planned dose groups are: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg. All patients will receive CS01 injection via intravenous infusion once every two weeks (Q2W), with every 4 weeks constituting one treatment cycle. Dose-Limiting Toxicity (DLT) assessments will be conducted at the end of the 4th week for each dose group. Antitumor efficacy assessments (based on RECIST v1.1 criteria) will be performed every 8 weeks. Safety data will be collected throughout the treatment period, and blood samples for PK, PD, immunogenicity, and biomarker analyses will also be collected.
干预措施: CS01 (an anti-OX40 antibody) (Biological)
0.3 mg/kg CS01
This phase will utilize an accelerated titration design (for the first dose group only) and a "3+3" design. It will enroll approximately 10 patients with locally advanced or metastatic solid tumors who have failed standard treatment, are intolerant, or lack effective treatment options. The four planned dose groups are: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg. All patients will receive CS01 injection via intravenous infusion once every two weeks (Q2W), with every 4 weeks constituting one treatment cycle. Dose-Limiting Toxicity (DLT) assessments will be conducted at the end of the 4th week for each dose group. Antitumor efficacy assessments (based on RECIST v1.1 criteria) will be performed every 8 weeks. Safety data will be collected throughout the treatment period, and blood samples for PK, PD, immunogenicity, and biomarker analyses will also be collected.
干预措施: CS01 (an anti-OX40 antibody) (Biological)
1 mg/kg CS01
This phase will utilize an accelerated titration design (for the first dose group only) and a "3+3" design. It will enroll approximately 10 patients with locally advanced or metastatic solid tumors who have failed standard treatment, are intolerant, or lack effective treatment options. The four planned dose groups are: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 1 mg/kg. All patients will receive CS01 injection via intravenous infusion once every two weeks (Q2W), with every 4 weeks constituting one treatment cycle. Dose-Limiting Toxicity (DLT) assessments will be conducted at the end of the 4th week for each dose group. Antitumor efficacy assessments (based on RECIST v1.1 criteria) will be performed every 8 weeks. Safety data will be collected throughout the treatment period, and blood samples for PK, PD, immunogenicity, and biomarker analyses will also be collected.
干预措施: CS01 (an anti-OX40 antibody) (Biological)
结局指标
主要结局
Phase I: Incidence of DLT events during the observation period
时间窗: From the day of the first dose of treatment to 28 days after the first dose of treatment, up to 28 days.
Phase I: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)
时间窗: Through study completion, an average of 2 year
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) (based on CTCAE v5.0), treatment interruptions and dose adjustments due to toxicity; changes from baseline in physical examinations, ECOG performance status, laboratory tests, electrocardiograms (ECG), and vital signs.
Phase I: Recommended Phase II Dose (RP2D) for CS01 injection monotherapy
时间窗: Through study completion, an average of 2 year
Phase II: Preliminary antitumor activity endpoint: Objective Response Rate (ORR)
时间窗: Through study completion, an average of 2 year
Preliminary antitumor activity endpoint: Objective Response Rate (ORR), defined as the proportion of subjects achieving a complete response (CR) or partial response (PR) as assessed by the investigator according to RECIST v1.1.
次要结局
- Phase I: Pharmacokinetics (PK): Cmax(Through study completion, an average of 2 year)
- Phase I: Pharmacokinetics (PK): elimination half-life (t½)(Through study completion, an average of 2 year)
- Phase I: Pharmacodynamics (PD): OX40 receptor occupancy.(5 weeks)
- Phase I: Immunogenicity: percentage of subjects positive for ADA(Through study completion, an average of 2 years)
- Phase I: Preliminary antitumor activity endpoint: ORR(Through study completion, an average of 2 year)
- Phase II: Incidence and severity of AEs and SAEs(Through study completion, an average of 2 year)
- Phase II: Progression-Free Survival (PFS)(Through study completion, an average of 2 years)
- Phase II: 12-month and 24-month overall survival rates(Through study completion, an average of 2 years)
- Phase II: Pharmacokinetics (PK): Cmax(Through study completion, an average of 2 years)
- Phase II: Pharmacokinetics (PK): elimination half-life (t½)(Through study completion, an average of 2 years)
- Phase II: Pharmacodynamics (PD): OX40 receptor occupancy.(5 weeks)
- Phase II: Immunogenicity: Immunogenicity: percentage of subjects positive for ADA(Through study completion, an average of 2 years)