Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] Dose Escalation Study for the Treatment of Advanced Solid Tumors: Phase 1 Clinical Trial
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 19
- 试验地点
- 1
- 主要终点
- Safety and Tolerability Assessment of CNSI-Fe(II)
研究概览
简要总结
This Phase I clinical trial aims to evaluate the safety, tolerability, pharmacokinetics (PK) profile and preliminary efficacy of intratumoral injection of Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] in patients with advanced solid tumors. The study also aims to observe dose-limiting toxicities (DLT) of CNSI-Fe(II) to determine the maximum tolerated dose (MTD) or the highest injectable dose in humans, providing dosing guidelines for future clinical studies. CNSI-Fe(II) shows promise as an innovative tumor therapeutic agent due to its unique properties of ferroptosis. The study primarily focuses on assessing the potential efficacy of CNSI-Fe(II) in patients with advanced solid tumors, particularly in patients with Kras mutation, e.g., pancreatic cancer patients.
详细描述
Indications: This study targets patients with advanced solid tumors who have either failed standard treatments (progression or intolerance) or lack available standard treatment options. Common tumor types include colorectal, pancreatic, breast, gastric, cervical, lung, head and neck, and prostate cancers.
Objectives: The primary goal is to assess the safety and tolerability of intratumoral injections of Carbon Nanoparticle Loaded Iron [CNSI-Fe(II)] in advanced solid tumor patients. This involves identifying dose-limiting toxicities (DLT) and determining the maximum tolerated dose (MTD) or highest injectable dose for subsequent clinical dosing decisions. Secondary objectives include evaluating the pharmacokinetics (PK) of CNSI-Fe(II) and its preliminary efficacy. Exploratory objectives is to understand the pharmacodynamics (PD) of CNSI-Fe(II), exploring the relationship between tumor size, injection dose, and drug concentration.
Participants: Up to 30 subjects will participate across 3 to 6 centers, with the final number dependent on dose group evaluations and tolerability.
Exit Criteria: Subjects may be withdrawn by researchers if they deviate from the protocol, impacting safety or efficacy assessment. Subjects can also voluntarily withdraw per guidelines, and their reasons will be documented. Efforts will be made to complete assessments for withdrawn cases.
Dose Selection: Based on animal toxicology and effective dose data, a starting dose of 0.5 mg/kg (escalating to 30 mg, 60 mg and 90 mg) is selected. Adjustments may occur if DLT is observed or MTD is not reached.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must meet all of the following criteria to be eligible:
- •Understand and voluntarily sign the informed consent form (ICF), demonstrating willingness and ability to comply with all trial requirements.
- •Male or female aged 18-80 years (inclusive) at the time of signing the ICF.
- •Histologically or cytologically confirmed advanced solid tumors with ineffective current standard therapy (disease progression after treatment or intolerable treatment) or lack of effective standard treatment options. Eligible tumor types include colorectal cancer, pancreatic cancer, breast cancer, gastric cancer, cervical cancer, lung cancer, head and neck cancer, bile duct cancer, kidney cancer, prostate cancer, vulvar cancer, etc. Note: Patients with advanced solid tumors experiencing disease progression due to the inability to receive standard treatment for any reason or those with tumor types insensitive to existing standard treatments (e.g., pancreatic cancer, undifferentiated thyroid cancer, and sarcomas) after receiving first-line standard treatment are also eligible.
- •Presence of at least one measurable lesion according to RECIST v1.1, which has not received radiation (except for lesions showing clear progression after radiation) or tissue biopsy within 7 days before the first dose.
- •Lesions amenable to injection, either directly or with assistance from medical imaging.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 7 days before the first dose.
- •Expected survival of ≥12 weeks.
- •Adverse drug reactions (ADR) caused by previous treatments have recovered to Grade 1 or lower (except for alopecia) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0 before screening.
- •Left ventricular ejection fraction (LVEF) ≥50%.
- •Within 7 days prior to the first dose, have adequate hematologic and end-organ function, with laboratory tests meeting the following criteria:
- •Hematology No use of granulocyte colony-stimulating factor (G-CSF) within 14 days prior to hematology laboratory tests, and absolute neutrophil count (ANC) ≥1.5×109/L; No platelet transfusion within 14 days prior to hematology laboratory tests, and platelet count (PLT) ≥90×109/L; No blood transfusion or use of erythropoietin within 14 days prior to hematology laboratory tests, and hemoglobin (Hb) ≥90 g/L;
- •Renal function Serum creatinine (Cr) ≤1.5×upper limit of normal (ULN) or calculated creatinine clearance (Ccr) ≥50 mL/min using the Cockcroft-Gault formula (only calculated if baseline Cr >1.5×ULN);
- •Hepatic function Total bilirubin (TBIL) ≤1.5×ULN (≤3.0×ULN for patients with Gilbert's syndrome or liver metastases);
- •Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤3×ULN, patients with confirmed liver or bone metastases must meet the following criteria:
- •Patients with confirmed liver metastases: AST and ALT ≤5×ULN; Patients with confirmed bone metastases: ALP ≤5×ULN; Serum albumin ≥2.8 g/dL;
- •Coagulation function International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤1.5×ULN; Note: For patients with injectable lesions in the skin and/or subcutaneous tissue who are receiving anticoagulant therapy, prolonged INR, PT and aPTT are allowed, as bleeding can be controlled by direct pressure application, as determined by the investigator.
- •Women of childbearing potential (WOCBP) must have a negative pregnancy test result within 7 days before the first dose and agree to use effective contraception or practice abstinence during the study treatment period and for 6 months after the end of the study treatment. In addition, female patients must be non-lactating and agree not to donate eggs during this period. Note: WOCBP refers to non-sterilized women who have experienced menarche but have not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and are not postmenopausal. Postmenopausal status is defined as continuous amenorrhea for ≥12 months in a woman over 45 years old without any other biological or physiological reasons. In addition, women under 55 years old must have serum follicle-stimulating hormone (FSH) levels >40 mIU/mL to be confirmed as postmenopausal. Hormone replacement therapy (HRT) can artificially suppress FSH levels in women and may require a washout period to return to physiological FSH levels. The recommended washout periods are as follows: vaginal hormone preparations (1 week), transdermal preparations (4 weeks), oral preparations (8 weeks), and other non-oral gastrointestinal preparations (up to 6 months). Postmenopausal status can be considered if the serum FSH level is >40 mIU/mL during the washout period.
- •Male patients must agree to use effective contraception or practice abstinence during the study treatment period and for 6 months after the end of the study treatment. In addition, male patients must agree not to donate sperm during this period.
排除标准
- •Patients meeting any of the following criteria cannot participate in this clinical study:
- •History of iron metabolism disorders (except for patients with iron-deficiency anemia), such as thalassemia or glucose-6-phosphate dehydrogenase deficiency.
- •History or current evidence of hollow organ perforation at the injection site.
- •History or current skin breakdown, redness, swelling, necrosis, or bleeding at the injection site that may affect the administration of the investigational drug.
- •Received radiotherapy or any antineoplastic therapy for the target lesion within 4 weeks before the first dose of the investigational drug or not reached 5 half-lives of the previous antineoplastic treatment [including but not limited to chemotherapy, targeted therapy, immunotherapy, National Medical Products Administration (NMPA) approved antineoplastic traditional Chinese medicine, and other traditional Chinese medicines with antitumor effects] before the first dose, whichever is shorter.
- •Undergone major surgical intervention, significant trauma, or have wounds or ulcers that have not healed within 4 weeks before the first dose.
- •Presence of life-threatening clinical manifestations of brain and central nervous system metastases at the time of enrollment.
- •Poorly controlled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg).
- •Uncontrolled tumor-related pain.
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once per month or more frequently).
- •History of other malignancies within 5 years before the start of study treatment, except for non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, stage I uterine cancer, cervical intraepithelial neoplasia, or stage 0 breast cancer after curative treatment.
- •Received live virus vaccines within 4 weeks before the start of study treatment. Note: Seasonal influenza vaccines administered by injection are usually inactivated, and their use is permitted. However, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
- •History of immunodeficiency diseases, including human immunodeficiency virus (HIV) positivity or acquired or congenital immunodeficiency diseases or organ transplantation.
- •Active hepatitis B virus (HBV) infection [positive for HBV surface antigen (HBsAg) or HBV core antibody (HBcAb) and HBV DNA quantification >500 IU/mL], hepatitis C virus (HCV) infection [positive for HCV antibody and HCV ribonucleic acid (RNA) measured by polymerase chain reaction (PCR) above the upper limit of normal (ULN)], or positive anti-human immunodeficiency virus antibody (Anti-HIV). Patients meeting any of these criteria are excluded.
- •Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral treatment within 4 weeks before the start of study treatment, excluding diagnostic procedures.
- •Severe cardiovascular diseases, including but not limited to acute coronary syndrome or history of coronary artery revascularization/stent placement/bypass grafting within the past 6 months, or New York Heart Association (NYHA) Class II-IV congestive heart failure (CHF), or history of NYHA Class III or IV CHF.
- •Active psychiatric disorders (e.g., schizophrenia, severe major depressive disorder, bipolar disorder, etc.).
- •Known allergies or intolerance to the active ingredient, excipients, or other iron supplements of the investigational drug.
- •Participated in other interventional clinical studies within 4 weeks before the start of the study treatment (from the first day after the last dose of the previous study, excluding interventions involving investigational drugs or medical devices).
- •Other conditions determined by the investigator that make the patient unsuitable for participation in this trial.
研究组 & 干预措施
CNSI-Fe(II) 30 mg
30 mg
CNSI-Fe(II) 30 mg: The trial comprises a treatment period, including the DLT evaluation period with a duration of 21 days, and a maintenance treatment period. If the subject completes DLT evaluation without intolerable toxicity, an additional dose may be administered based on the investigator's determination of the benefits outweighing the risks. The original protocol planned for three dose groups: 30 mg, 60 mg, and 90 mg. The protocol was amended on March 28, 2024, to add 120 mg and 150 mg dose groups. A single tumor lesion amenable to intratumoral injection will be selected, regardless of tumor size, number, or location. The drug should be administered at the dose specified for the current dose cohort. The injection volume should be adjusted based on the size of the injected lesion.
干预措施: CNSI-Fe(II) 30 mg (Drug)
CNSI-Fe(II) 60 mg
60 mg
CNSI-Fe(II) 60 mg: The trial comprises a treatment period, including the DLT evaluation period with a duration of 21 days, and a maintenance treatment period. If the subject completes DLT evaluation without intolerable toxicity, an dditional dose may be administered based aon the investigator's determination of the benefits outweighing the risks. The original protocol planned for three dose groups: 30 mg, 60 mg, and 90 mg. The protocol was amended on March 28, 2024, to add 120 mg and 150 mg dose groups. A single tumor lesion amenable to intratumoral injection will be selected, regardless of tumor size, number, or location. The drug should be administered at the dose specified for the current dose cohort. The injection volume should be adjusted based on the size of the injected lesion.
干预措施: CNSI-Fe(II) 60 mg (Drug)
CNSI-Fe(II) 90 mg
90 mg
CNSI-Fe(II) 90 mg: The trial comprises a treatment period, including the DLT evaluation period with a duration of 21 days, and a maintenance treatment period. If the subject completes DLT evaluation without intolerable toxicity, an additional dose may be administered based on the investigator's determination of the benefits outweighing the risks. The original protocol planned for three dose groups: 30 mg, 60 mg, and 90 mg. The protocol was amended on March 28, 2024, to add 120 mg and 150 mg dose groups. A single tumor lesion amenable to intratumoral injection will be selected, regardless of tumor size, number, or location. The drug should be administered at the dose specified for the current dose cohort. The injection volume should be adjusted based on the size of the injected lesion.
干预措施: CNSI-Fe(II) 90 mg (Drug)
CNSI-Fe(II) 120 mg
120 mg
CNSI-Fe(II) 120 mg: The dosing regimen is the same as that for the 30 mg, 60 mg, and 90 mg dose groups. Additionally, if a single lesion cannot accommodate the full corresponding dose of the investigational drug, additional lesions may be selected for simultaneous injection. When multiple lesions are injected, the drug distribution should be allocated proportionally according to the size of each lesion or determined based on the investigator's assessment of an appropriate distribution.
干预措施: CNSI-Fe(II) 120 mg (Drug)
CNSI-Fe(II) 150 mg
150 mg
CNSI-Fe(II) 150 mg: The dosing regimen is the same as that for the 30 mg, 60 mg, and 90 mg dose groups. Additionally, if a single lesion cannot accommodate the full corresponding dose of the investigational drug, additional lesions may be selected for simultaneous injection. When multiple lesions are injected, the drug distribution should be allocated proportionally according to the size of each lesion or determined based on the investigator's assessment of an appropriate distribution.
干预措施: CNSI-Fe(II) 150 mg (Drug)
结局指标
主要结局
Safety and Tolerability Assessment of CNSI-Fe(II)
时间窗: 21 days
This primary outcome measure is centered on the assessment of CNSI-Fe(II)'s safety and tolerability throughout the study. It encompasses the following assessments: Dose-Limiting Toxicity (DLT): This assessment involves the ongoing monitoring of adverse events, with a focus on determining their nature, severity, and frequency. Adverse events will be systematically categorized and reported according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Maximum Tolerated Dose (MTD): The MTD is a critical outcome measure representing the highest injectable dose in humans that can be safely administered without causing excessive adverse effects. The determination of MTD will be based on the careful observation and analysis of DLT data. The MTD was not determined in this Phase I study, and the MAD is 150mg. Units of Measure: DLT: Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0. MTD: Milligrams (mg) of CNSI-Fe(II).
次要结局
- PK Parameters Assessment: Cmax (ng/mL) Profile Assessment of CNSI-Fe(II) of First Dosage(72 h)
- PK Parameters Assessment: Tmax (h) Profile Assessment of CNSI-Fe(II) of First Dosage(72 h)
- PK Parameters Assessment: AUC (ng•h/mL) Profile Assessment of CNSI-Fe(II) of First Dosage(72 h)
- PK Parameters Assessment: t1/2 (h) Profile Assessment of CNSI-Fe(II) of First Dosage(72 h)
- Evaluated as CR (Complete Response) in the Preliminary Efficacy Assessment.(Observation period for a single dose is 21~28 days, the observation period for two doses is doubled.)
- Evaluated as PR (Partial Response) in the Preliminary Efficacy Assessment.(Observation period for a single dose is 21~28 days, the observation period for two doses is doubled.)
- Evaluated as SD (Stable Disease) in the Preliminary Efficacy Assessment.(Observation period for a single dose is 21~28 days, the observation period for two doses is doubled.)
- Evaluated as PD (Progressive Disease) in the Preliminary Efficacy Assessment.(Observation period for a single dose is 21~28 days, the observation period for two doses is doubled.)
- PK Parameters Assessment: Cmax (ng/mL) Profile Assessment of CNSI-Fe(II) of Second Dosage(72 h post second dosage (The second dosing occurs 22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Tmax (h) Profile Assessment of CNSI-Fe(II) of Second Dosage(72 h post second dosage (The second dosing occurs 22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: AUC (ng•h/mL) Profile Assessment of CNSI-Fe(II) of Second Dosage(72 h post second dosage (The second dosing occurs 22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 5 Min of First Dosage(at 5 min of a time frame of 72 h)
- PK Parameters Assessment: t1/2 (h) Profile Assessment of CNSI-Fe(II) of Second Dosage(72 h post second dosage (The second dosing occurs 22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 1 h Before First Dosage(at -1 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 10 Min of First Dosage(at 10 min of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 15 Min of First Dosage(at 15 min of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 30 Min of First Dosage(at 30 min of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 1 h of First Dosage(at 1 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 2 h of First Dosage(at 2 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 4 h of First Dosage(at 4 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 8 h of First Dosage(at 8 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 12 h of First Dosage(at 12 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 24 h of First Dosage(at 24 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 48 h of First Dosage(at 48 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 72 h of First Dosage(at 72 h of a time frame of 72 h)
- PK Parameters Assessment: Serum Iron Concentration at 1 h Before Second Dosage(1 h (of a time frame of 72 h) before second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 5 Min of Second Dosage(at 5 min (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 10 Min of Second Dosage(at 10 min (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 15 Min of Second Dosage(at 15 min (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 30 Min of Second Dosage(at 30 min (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 1 h of Second Dosage(at 1 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 2 h of Second Dosage(at 2 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 4 h of Second Dosage(at 4 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 8 h of Second Dosage(at 8 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 12 h of Second Dosage(at 12 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 24 h of Second Dosage(at 24 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 48 h of Second Dosage(at 48 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))
- PK Parameters Assessment: Serum Iron Concentration at 72 h of Second Dosage(at 72 h (of a time frame of 72 h) of second dosage (22~35 days after first dosing. For patient in 30 mg group, 23 days; for patients in 60 mg group, 26 and 22 days; for patients in 90 mg group, 23, 35 and 28 days; for patient in 120 mg group, 28 days.))