Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] in the Treatment of Advanced Solid Tumor

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.

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 24 subjects will participate across 2 to 4 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Exit Criteria: Subjects may be withdrawn by researchers if they deviate from the protocol, impacting safety or efficacy assessment.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 Efforts will be made to complete assessments for withdrawn cases.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.

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:

1. Grade 3 cardiac toxicity lasting more than 3 days after optimal treatment or Grade 4 cardiac toxicity.
2. Grade 3 liver toxicity (for subjects with liver or bone metastasis and baseline liver enzyme ALT, AST, or ALP at Grade 2, ALT, AST, or ALP \>10×ULN) lasting more than 3 days after optimal treatment or Grade 4 liver toxicity.
3. Any Grade 3 non-hematological toxicity (excluding laboratory abnormalities) lasting more than 3 days after optimal treatment, except for Grade 3 nausea, Grade 3 vomiting, or Grade 3 diarrhea.
4. Any Grade 4 non-hematological toxicity (excluding laboratory abnormalities).
5. Any Grade 3 or 4 non-hematological laboratory abnormality if it requires medical intervention, leads to hospitalization, or persists at Grade 3 or above for 7 days or more after discontinuation of the drug.

Other:

1. Any Grade 5 toxicity.
2. Other toxicities requiring early termination of CNSI-Fe(II) treatment as decided by the investigator and sponsor.

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.

Eligibility Criteria:
Inclusion Criteria:

* Patients must meet all of the following criteria to be eligible:

  1. Understand and voluntarily sign the informed consent form (ICF), demonstrating willingness and ability to comply with all trial requirements.
  2. Male or female aged 18-75 years (inclusive) at the time of signing the ICF.
  3. 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.
  4. 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.
  5. Lesions amenable to injection, either directly or with assistance from medical imaging.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 7 days before the first dose.
  7. Expected survival of ≥12 weeks.
  8. 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.
  9. Left ventricular ejection fraction (LVEF) ≥50%.
  10. Adequate hematologic, renal, hepatic, and coagulation function within 7 days before the first dose.
  11. 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.
  12. 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:

  1. History of iron metabolism disorders (except for patients with iron-deficiency anemia), such as thalassemia or glucose-6-phosphate dehydrogenase deficiency.
  2. History of local skin breakdown, redness, necrosis, bleeding, or signs of perforation at the injection site or presence of perforation in hollow organs.
  3. 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.
  4. Undergone major surgical intervention, significant trauma, or have wounds or ulcers that have not healed within 4 weeks before the first dose.
  5. Presence of life-threatening clinical manifestations of brain and central nervous system metastases at the time of enrollment.
  6. Poorly controlled hypertension (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg).
  7. Uncontrolled tumor-related pain.
  8. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once per month or more frequently).
  9. 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.
  10. 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.
  11. History of immunodeficiency diseases, including human immunodeficiency virus (HIV) positivity or acquired or congenital immunodeficiency diseases or organ transplantation.
  12. 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.
  13. Severe chronic or active infections requiring systemic antibacterial, antifungal, or antiviral treatment within 4 weeks before the start of study treatment, excluding diagnostic procedures.
  14. 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.
  15. Active psychiatric disorders (e.g., schizophrenia, severe major depressive disorder, bipolar disorder, etc.).
  16. Known allergies or intolerance to the active ingredient, excipients, or other iron supplements of the investigational drug.
  17. 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).
  18. Other conditions determined by the investigator that make the patient unsuitable for participation in this trial.