Carbon Nanoparticle-Loaded Iron in the Treatment of Advanced Solid Tumor

A Phase Ib/IIa Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, and Preliminary Efficacy of Intratumoral Injection of Carbon Nanoparticle-Loaded Iron Suspension Injection [CNSI-Fe(II)] With Multiple Administrations in Subjects With Advanced Solid Tumors

Independently developed by Sichuan Yingrui Pharmaceutical Technology Co., Ltd., CNSI-Fe is an innovative anti-cancer drug with Fe2+ as the active ingredient, which exerts anti-tumor effects by regulating the ferroptosis pathway. CNSI-Fe intratumoral injection has the following three effects: 1. Nanocarbon can increase the content of hydrogen peroxide in tumor cells and tumor microenvironment, and is a reactive oxygen species that catalyzes hydrogen peroxide through the Fenton reaction of iron ions to produce "ferroptosis", which complements each other; 2. The adsorption of Fe2+ by nanocarbon can help Fe2+ better enter the cell, thereby exerting anti-tumor effects; 3. The lesion localization and lymphatic tracing functions of nanocarbon are retained. The combination of the regulatory mechanism of ferroptosis and the characteristics of nanocarbon particles has increased the advantages of new nanopharmaceuticals in cancer prevention and treatment.

At present, CNSI-Fe has carried out a first-in-human phase I clinical trial of dose escalation in subjects with advanced solid tumors in China, and has conducted safety and efficacy exploration in four dose groups, including: 30 mg, 60 mg, 90 mg, and 120 mg, and the overall safety and tolerability of the 16 subjects enrolled have been good, no obvious liver and kidney impairment and hematologic toxicity have been observed, and only one subject in the 90 mg dose group has a dose-limiting toxicity (DLT) event; Partial response (PR) was observed in 1 subject (30 mg group), complete tumor response (CR) was observed in 1 subject (60 mg group), and stable tumor (SD) was observed in 11 subjects (including 1 in the 30 mg group, 2 in the 60 mg group, 5 in the 90 mg group, and 3 in the 120 mg group), and the disease control rate (DCR) of the trial treatment was 87%. This Phase I clinical study is planned to continue dose exploration at 150 mg or higher.

Therefore, based on the results of the Phase I clinical trial obtained, it is planned to conduct this Phase Ib/IIa clinical study in subjects with advanced solid tumors in China to further evaluate the safety, tolerability, pharmacokinetic (PK) characteristics and preliminary efficacy of CNSI-Fe intratumoral injection and multiple administration, so as to provide a basis for clinical development in the later stage.

Ib：Trial period: including screening period, treatment period and follow-up period.

Screening period: -28~-1 days, it is confirmed that the subjects meet the inclusion criteria and do not meet the exclusion criteria.

Treatment period: Subjects who were successfully screened received CNSI-Fe intratumoral injection according to the protocol plan, administered once every two weeks, for a total of 4 doses.

CNSI-Fe intratumoral injection selects 1~3 suitable lesions to complete the corresponding dose of study drug injection (no more than 3 lesions). If the target lesion that has been injected intratumorally reaches CR or disappears and shrinks to the point where intratumoral injection is not possible, it is up to the investigator to judge whether the injection of the lesion can be stopped, and whether a new lesion can be selected for injection. After the completion of 4 doses, the investigator will judge according to the subject's situation, and if the benefit of the subject outweighs the risk, the number of doses can be appropriately increased.

During the study period, safety checks were performed within 7 days before each dose and two weeks after the last dose. The tumor efficacy evaluation will be carried out within 3 days before the third dose, 3~4 weeks after the fourth dose, and every 6 weeks thereafter (if disease progression is suspected, it can be checked in advance). Subjects who are evaluated for CR or PR for the first time need to be confirmed after 4~5 weeks, and the tumor evaluation after the original plan of 6 weeks does not need to be carried out, and the next tumor evaluation will be carried out according to the original planned time. Samples were collected according to the established visit time points in the protocol flow chart.

No other investigational products, drugs, or therapies for the purpose of treating tumors other than CNSI-Fe may be used. Supportive care measures used to control symptoms caused by the subject's malignancy are permitted.

Subjects in the treatment period who terminate treatment early for any reason, or withdraw from the study before completing safety follow-up, are required to complete the end-of-treatment/end-of-study (EOT/EOS) visit as soon as possible within 7 days of early termination/early withdrawal from the study (results of the examination after the last treatment of the previous 7 days can be accepted).

Follow-up period: Subjects who have received at least one CNSI-Fe treatment will enter a follow-up period after discontinuation of study drug treatment, which includes safety follow-up and efficacy follow-up. (1) Safety follow-up: A safety follow-up is required 28 days (±3 days) after the end of the last medication. (2) Disease progression as assessed by the investigator based on RECIST v1.1 and no new anti-tumor therapy has been initiated, subjects are required to be followed up for disease progression every 6 weeks at a frequency until disease progression as assessed by the investigator based on RECIST v1.1, initiation of new anti-tumor therapy, death, loss to follow-up, withdrawal of informed consent, or the end of this study, whichever occurs first.

Criteria for the evaluation of local efficacy of CNSI-Fe: The revised RECIST v1.1 is based on RECIST v1.1 with appropriate modifications, and since CNSI-Fe is a local intratumoral injection, only the selection method of target lesions has been changed as a criterion for evaluating the efficacy of locally injected lesions. The changes in the revised RECIST v1.1 are as follows:

1. Lesions treated with local injection are defined as target lesions, and lesions not treated by local injection are defined as non-target lesions;
2. The tumor shrinkage effect at each evaluation time point was determined based on the evaluation of local injection treatment lesions;
3. The tumor shrinkage effect of the target lesion is the tumor shrinkage effect of the lesion treated by local injection.

IIa：Phase IIa tentatively plans to develop three advanced solid tumor cohorts, each with about 10 subjects. After the completion of the Phase Ib multi-dose dose exploration phase, the specific design of the cohort expansion phase (such as cohort number, sample size, etc.) will be determined. Based on the existing data on safety, PK characteristics and preliminary efficacy, the sponsor and investigator will select the target tumor type for the Phase IIa cohort expansion study.

Based on the clinical efficacy data obtained, the target tumor types to be explored in the Phase IIa study and the initiation of each arm may be adjusted. During the study, the sponsor and the investigator will analyze the study data in a timely manner and determine whether to stop a study cohort, increase the study cohort or change the dosing regimen based on the safety and efficacy data of the existing subjects.

Inclusion Criteria:

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

1. Understand and voluntarily sign the written informed consent form (ICF), be willing and able to comply with all trial requirements;

2. Male or female aged 18~80 years old (including cut-off value) at the time of signing the ICF;

3. Stage Ib: patients with advanced solid tumors confirmed by histology or cytology, and the current standard therapy is ineffective (disease progression after treatment or treatment is not tolerated) or there is no effective standard treatment, such as soft tissue sarcoma, refractory thyroid cancer, colorectal cancer, pancreatic cancer, breast cancer, gastric cancer, cervical cancer, lung cancer, head and neck cancer, liver cancer, bile duct cancer, kidney cancer, prostate cancer, vulvar cancer, etc.; Note: Subjects with advanced solid tumors whose disease progresses due to no standard therapy for any reason, or advanced solid tumors whose disease has progressed after receiving the first course of standard therapy for tumor types that are not sensitive to existing standard therapies (e.g., pancreatic cancer, undifferentiated thyroid cancer, sarcoma, etc.) can be included.

4. At least one measurable lesion according to RESICT v1.1 and the lesion has not previously undergone radiotherapy (unless the lesion has clearly progressed after radiotherapy) and has not undergone a tissue biopsy within 7 days prior to screening;

5. Have injectable lesions (such as direct injection or assisted injection by medical imaging instruments), which are judged by the investigator to be suitable for repeated intratumoral injection;

6. The ECOG score within 7 days before the first dose is 0~1 points;

7. Expected survival ≥ 3 months;

8. Adverse drug reactions (ADRs) caused by prior therapy have recovered to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria grade 1 and below before screening (alopecia, grade 2 or below peripheral neurotoxicity, etc., except for toxicities judged by the investigator to be of low safety risk);

9. Left ventricular ejection fraction (LVEF) ≥50%;

10. Within 7 days prior to the first dose, adequate hematologic and end-organ function with laboratory tests meeting the following criteria:

    haematology No treatment with granulocyte colony-stimulating factor (G-CSF) within 14 days prior to hematology laboratory tests, and absolute neutrophil count (ANC) ≥ 1.5×109/L; Have not been treated with platelet transfusion or interleukin-11 (IL-11) or recombinant human thrombopoietin injection before hematological laboratory examination, and the platelet count (PLT) ≥ 90×109/L; No blood transfusion or erythropoietin within 14 days prior to hematology laboratory tests, and hemoglobin (Hb) ≥ 90 g/L; Kidney function Serum creatinine (Cr) ≤ 1.5× upper limit of normal (ULN) or 50 mL/min (Cr only) calculated using the Cockcroft-Gault formula (Cr) 50 mL/min (Cr ≥> only). 1.5 Calculate Ccr when ×ULN); Liver function TBIL ≤ 1.5× ULN (3.0 ≤× ULN for subjects with Gilbert's syndrome or liver metastases);

    AST, ALT, and ALP≤3×ULN, and subjects with confirmed liver metastases or bone metastases must meet the following conditions:

    Subjects with confirmed liver metastases: AST and ALT≤5×ULN; Subjects with confirmed bone metastases: ALP≤5×ULN; serum albumin≥ 2.8 g/dL; Coagulation function International normalized ratio (INR) or prothrombin time (PT) and aPTT ≤1.5×ULN; Note: Subjects receiving anticoagulant medication are allowed to prolong their INR, PT and aPTT if the injected lesion is in the skin and/or subcutaneous, because excessive bleeding can be controlled by applying direct pressure, at the discretion of the investigator; Subjects receiving anticoagulant therapy are advised to discontinue anticoagulant medication for at least 1 week before deep lesion injection, at the discretion of the investigator.

11. Female subjects of childbearing potential (WOCBP) who must have a negative serum pregnancy test result within 7 days prior to the first dose of study drug and a commitment to adequate and effective contraception or abstinence during treatment with study drug and for 6 months after the end of study drug treatment. In addition, female subjects must be non-lactating.

    Note: WOCBP is defined as non-postmenopausal women who have experienced menarche but have not yet undergone sterilization surgery (hysterectomy or bilateral salpingectomy). Postmenopausal is defined as meeting any of the following conditions: (1) prior bilateral oophorectomy; (2) Age≥ 60 years old; (3) Age < 60 years and have been out of menstruation for 12 months or more without chemotherapy and taking tamoxifen, toremifene and ovarian function suppression therapy; (4) If taking tamoxifen or toremiaphene and < age 60 years, FSH and plasma estradiol levels must be in the postmenopausal range.

    Hormone replacement therapy (HRT) may artificially suppress FSH levels in women and may require a washout period to return to physiological FSH levels. The duration of the washout period is one of the effects of the HRT type. The following washout period duration is recommended as a guideline, and the investigator should judge the results of the serum FSH level on his own.

    vaginal hormonal preparations (drug rings, creams, gels) for at least 1 week; transdermal preparation for at least 4 weeks; Oral preparation for at least 8 weeks; Other parenteral preparations may require a washout period of up to 6 months. If the serum FSH level > 40 mIU/mL during the washout period, a postmenopausal woman may be considered.

12. Male subjects commit to adequate and effective contraception or abstinence during study drug treatment and for 6 months after the end of study drug treatment. In addition, male subjects 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. Previous or current diseases with abnormal iron metabolism (except for subjects with iron deficiency anemia), such as thalassemia, fava bean disease (erythrocyte glucose-6-phosphate dehydrogenase deficiency), etc.;
2. Signs of perforation of hollow viscera at the previous or current injection site;
3. Previous or current injection site with local skin breakdown, redness, swelling, necrosis, bleeding, etc., which affects the injection of study drugs;
4. Systemic chemotherapy, targeted therapy, anti-tumor biologic therapy, or immunotherapy within 3 weeks prior to the first dose of study drug; Prior radiotherapy within 14 days prior to the first dose of study drug (with the exception of central nervous system [CNS] radiotherapy, which requires a washout period of ≥ 28 days); Received traditional Chinese medicine with anti-tumor indications within 2 weeks before the first dose of the study drug;
5. Major surgery within 4 weeks prior to the first dose of study drug or unhealed wounds, ulcers, or fractures (except for minor surgeries performed within 1 week and full recovery);
6. Untreated or with active brain metastases, spinal cord compression, carcinomatous meningitis, or other evidence that the subject's brain or spinal cord metastases have not been controlled (except for those who have been treated and have stable symptoms, have been stable for at least 4 weeks before the first dose on imaging tests, and have no evidence of cerebral edema, and do not require glucocorticoid therapy);
7. Uncontrolled or poorly controlled hypertension (e.g., systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg);
8. Uncontrolled tumor-related pain;
9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once/month or more often);
10. Active malignancy within 5 years prior to the first dose of study treatment, with the exception of non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ or stage I uterine cancer, cervical carcinoma in situ, or carcinoma in situ of the breast that has received curative therapy;
11. Vaccination with a live virus vaccine within 4 weeks prior to the first dose of study treatment; Note: Seasonal influenza vaccines for injection are usually inactivated influenza vaccines and are permitted; However, intranasal influenza vaccine is a live attenuated vaccine and is not allowed.
12. Those with a history of immunodeficiency, including human immunodeficiency virus (HIV) positive or other acquired, congenital immunodeficiency diseases, or a history of organ transplantation;
13. Active hepatitis B virus (HBV) infection (HBV DNA quantification >500 IU/mL), hepatitis C virus (HCV) infection (HCV antibody positive and polymerase chain reaction [PCR] of HCV ribonucleic acid [RNA] exceeds ULN), positive anti-human immunodeficiency virus antibody (Anti-HIV). Those who meet any of the above items;
14. Severe chronic or active infection (including tuberculosis infection, etc.) requiring systemic antibacterial, antifungal or antiviral therapy prior to the start of study treatment; Note: Subjects with viral hepatitis are allowed to receive antiviral therapy.
15. History of severe cardiac insufficiency, stroke, or transient ischemic attack (TIA) within 6 months prior to enrollment. History of ventricular tachycardia or torsade de pointes. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG. Has clinically significant cardiac disease, including acute myocardial infarction, Class III or IV congestive heart failure (New York Heart Association classification, see Appendix 5 for details), unstable angina, or cardiac arrhythmia requiring treatment that occurred within 6 months prior to the first dose of study treatment. Note: Subjects with arrhythmias who are receiving anti-arrhythmic drugs and have a controlled heart rate rhythm on screening ECG can be enrolled.
16. Have an active psychiatric disorder (schizophrenia, major depressive disorder, bipolar disorder, etc.);
17. Subjects who are known to be allergic or intolerant to the active ingredient or excipient of the study drug;
18. Have participated in other interventional clinical studies within 3 weeks prior to the start of study treatment administration (calculated from the first day after the last dose of the previous study, except for those who have not used interventional drugs or investigational medical devices);
19. Other conditions judged by the investigator to be unsuitable for participation in this trial