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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.
Full description
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Exit Criteria: Subjects may be withdrawn by researchers if they deviate from the protocol, impacting safety or efficacy assessment.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 Efforts will be made to complete assessments for withdrawn cases.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.
As of March 28, 2024, only one case of DLT occurred in the 90 mg dose group among the 30 mg, 60 mg, and 90 mg dose groups, demonstrating favorable safety and tolerability. The study has successfully passed the SRC meeting, allowing for further dose exploration at 120 mg, 150 mg, and potentially higher doses. Therefore, this protocol is hereby revised.
Study Design: This open-label Phase I trial assesses CNSI-Fe(II) intratumoral injections in advanced solid tumor patients. The study includes screening, treatment (with DLT evaluation), and follow-up phases.
Dose Escalation: The "3+3 method" guides dose escalation. Enrollment occurs in dose groups; dose escalation decisions are based on DLT occurrence.
DLT Evaluation: DLTs are defined using toxicity criteria, assessed during the first cycle (21 days). Escalation decisions depend on DLT occurrence.
DLT is defined as toxicities that are considered definitely or possibly related to the investigational drug CNSI-Fe(II) and occur within the first cycle (21 days) after the first dose. This includes Grade 4 hematological toxicity, Grade 3 hematological toxicity lasting >7 days after optimal treatment, Grade 3 thrombocytopenia with bleeding or requiring platelet transfusion, and Grade 3 neutropenia with fever.
Non-hematological toxicity:
Other:
Besides evaluating the safety and tolerability of CNSI-Fe(II), this study will also preliminarily assess the efficacy of CNSI-Fe(II) in patients with advanced solid tumors. The investigator will evaluate CNSI-Fe(II)'s efficacy based on imaging examinations (computed tomography [CT], positron emission tomography [PET]/CT, or magnetic resonance imaging [MRI]), following the revised RECIST v1.1 criteria. Baseline imaging evaluations will be conducted within 28 days before the first treatment in the study. Subsequent tumor assessments will be performed for all subjects in the study at weeks 3-4 and, for those entering the maintenance phase, at weeks 7-8. Confirmation will be required for subjects achieving a complete response (CR) or partial response (PR) at least 4 weeks after the initial response. Baseline evaluations must include chest, abdomen, pelvis, skull (to exclude brain metastases), and other suspected tumor sites. Subsequent evaluations should reassess all measurable and evaluable lesions identified at baseline, including chest, abdomen, pelvis, and other suspected tumor sites. The imaging methods used for efficacy evaluation during the study must be consistent with the baseline imaging evaluation.
Medicinal Products: The study uses CNSI-Fe(II) consisting of a nanoparticle carbon dispersion injection and injectable ferrous sulfate.
Preparation of CNSI-Fe(II): Take one vial of injectable ferrous sulfate, keeping the aluminum cap and rubber stopper tightly closed and removing only the plastic outer cap of the aluminum-plastic combination cap. Slowly draw an appropriate amount of nanoparticle carbon dispersion injection using a suitable syringe and inject it into the vial containing ferrous sulfate, ensuring the solution is thoroughly mixed. The preparation of CNSI-Fe(II) should be done under aseptic conditions, avoiding exposure to air. It should be prepared and used at room temperature within 6 hours.
Dosing: Dosing varies per phase and dose group, ensuring administration within the target tumor.
PK and PD Analysis: Concentration-time curves, AUC, Cmax, Tmax, and PD marker levels are assessed using descriptive statistics.
Statistical Analysis: Descriptive statistics are employed for demographic, safety, efficacy, and PK/PD data. No formal hypothesis testing is planned.
Study Duration: The study will continue from the approval of the study by the Ethics Committee (EC) until the expected sample size is reached, subject to actual circumstances. The study is anticipated to end 28 days after the last subject has received a maximum of two doses of the study drug. After the study is completed, subjects who continue to achieve Complete Response (CR) or Partial Response (PR) and are determined by the investigator to still benefit from the treatment can continue to receive the study drug as a gift until disease progression, intolerable toxicity, or the investigator determines it is not appropriate to continue the study drug or the sponsor terminates the study.
Enrollment
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Inclusion criteria
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.
Exclusion criteria
Patients meeting any of the following criteria cannot participate in this clinical study:
Primary purpose
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19 participants in 5 patient groups
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Central trial contact
Yan Zhao, Bachelor's; Xiaohai Tang, PhD & MD
Data sourced from clinicaltrials.gov
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