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Iron

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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. Three dose groups are planned \[based on Fe(II)\]: 30 mg, 60 mg, and 90 mg. A single tumor lesion amenable to intratumoral injection will be selected, regardless of tumor size, number, or location. The corresponding dose will be administered by intratumoral injection, with the injection volume determined according to the size of the injection lesion.

CNSI-Fe(II) 30 mg

CNSI-Fe(II) 60 mg

CNSI-Fe(II) 90 mg

Xiaohai Tang, PhD & MD

Yan Zhao, Bachelor's

Yongsheng Wang, PhD & MD

Huashan Shi, PhD & MD

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.

This Phase 1 clinical trial employs a dose escalation design for the investigation of Carbon Nanoparticle-Loaded Iron \[CNSI-Fe(II)\] in the treatment of advanced solid tumors. The study follows a "Sequential" Study Model and consists of unique arms for each dose level(30mg, 60mg, and 90mg), using the traditional "3+3 method" for dose escalation.

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

Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] Dose Escalation Study for the Treatment of Advanced Solid Tumors: Phase 1 Clinical Trial

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.

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).

This secondary outcome measure focuses on assessing the pharmacokinetic (PK) profile of CNSI-Fe(II) in patients with advanced solid tumors.

Assessment Details:

PK Parameters Assessment: This assessment involves the analysis of the drug's absorption, distribution, metabolism, and excretion (ADME) in patients. It will provide insights into how CNSI-Fe(II) behaves in the human body. The first assessed parameter is maximum plasma concentration (Cmax).

Units of Measure:

Cmax: Nanograms per milliliter (ng/mL)

This secondary outcome measure focuses on assessing the pharmacokinetic (PK) profile of CNSI-Fe(II) in patients with advanced solid tumors.

Assessment Details:

PK Parameters Assessment: This assessment involves the analysis of the drug's absorption, distribution, metabolism, and excretion (ADME) in patients. It will provide insights into how CNSI-Fe(II) behaves in the human body. The second assessed parameter is time to maximum plasma concentration (Tmax).

Units of Measure:

Tmax: Hours (h)

This secondary outcome measure focuses on assessing the pharmacokinetic (PK) profile of CNSI-Fe(II) in patients with advanced solid tumors.

Assessment Details:

PK Parameters Assessment: This assessment involves the analysis of the drug's absorption, distribution, metabolism, and excretion (ADME) in patients. It will provide insights into how CNSI-Fe(II) behaves in the human body. The third assessed parameter is area under the concentration-time curve (AUC).

Units of Measure:

AUC: Nanograms per hour per milliliter (ng•h/mL)

This secondary outcome measure focuses on assessing the pharmacokinetic (PK) profile of CNSI-Fe(II) in patients with advanced solid tumors.

Assessment Details:

PK Parameters Assessment: This assessment involves the analysis of the drug's absorption, distribution, metabolism, and excretion (ADME) in patients. It will provide insights into how CNSI-Fe(II) behaves in the human body. The fourth assessed parameter is elimination half-life (t1/2).

Units of Measure:

t1/2: Hours (h)

Sichuan Enray Pharmaceutical Sciences Company

Sarcoma

Neoplasms, Glandular and Epithelial

Carcinoma

Neoplasms by Histologic Type

Neoplasms, Connective and Soft Tissue

Soft Tissue Sarcoma

Malignant Mesenchymoma

Antineoplastic Agents

Interleukin-12

NHS-IL12 escalating doses on a 4 week schedule (Completed).

NHS-IL12 escalating doses on a 2 week schedule

NHS-IL12 expansion group on a 4 week schedule (Completed).

NHS-IL12 is an investigational agent supplied to investigators by the manufacturer EMD Serono, Inc.

NHS-IL-12

James L Gulley, M.D.

Background:

- The experimental drug NHS-IL12 may help the immune system become more active and kill cancer cells that have not responded to standard treatments. NHS-IL12 has been designed to cause less severe side effects than other anticancer drugs, and may be more effective. More research is needed to test NHS-IL12 in people who have solid tumors that have not responded to treatment.

Objectives:

- To test the safety and effectiveness of NHS-IL12 as a treatment for solid tumors which have not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age with solid tumors that have not responded to standard treatments.

Design:

* Participants will be screened with a medical history, physical exam, blood and urine tests, and imaging studies.
* Participants will receive NHS-IL12 injection every 4 weeks, and will stay in the hospital for at least one day to be monitored with frequent blood tests.
* Participants will have periodic blood samples taken before treatment and during the first week after treatment for the first two cycles. They will then have blood samples taken before treatment for the rest of the cycles.

Background:

* Interleukin-12 (IL-12) is a proinflammatory cytokine produced by activated phagocytes and dendritic cells (DCs) that plays a critical role in regulating the transition from innate to adaptive immunity.
* IL-12 has shown some promising clinical activity in phase I trials, including stabilization of disease in renal cancer patients with partial regression of a metastatic lesion, but has not proceeded further in clinical development due to toxicity.
* The NHS-IL12 concept is a strategy to reduce the toxicity associated with systemic administration of recombinant human IL-12 by selectively targeting delivery to tumors. The NHS-IL12 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and doublestranded DNA. Thus, NHS-IL12 targets delivery to regions of tumor necrosis where DNA has become exposed.

Objectives:

-To determine the dose-limiting toxicities (DLTs) and Maximum Tolerated Dose (MTD) of NHS-IL12 administered subcutaneously every 4 weeks and subcutaneously every 2 weeks in participants with metastatic or locally advanced solid epithelial or mesenchymal tumors.

Eligibility:

* Adults with histologically or cytologically proven metastatic or locally advanced solid epithelial or mesenchymal tumors, except unstable brain metastases, for which standard curative or palliative measures do not exist or are no longer effective.
* Adequate organ function as defined by liver, kidney, and hematologic laboratory testing.
* Participants with acquired immune defects, systemic autoimmune disease, history of organ transplant, history of chronic infections, or history of active inflammatory bowel disease will be excluded.

Design:

* With amendment D, this is a phase I, open-label, dose-escalation study designed to assess the safety, tolerability, PK, and biological and clinical activity of NHS-IL12. Goals are to determine the MTD of every 4-week doses at a starting dose level of 2 mcg/kg of NHS IL12 and to define the biologically optimal treatment schedule.
* Participants will be enrolled in cohorts of 3 to 6 participants using a standard 3+3 approach until MTD is reached.
* The trial will include a planned schedule-optimization amendment with up to 12 participants at each of the 2 dose levels that are of greater biologic interest (MTD and dose below MTD), which will be submitted as soon as a clear biological response (changes in circulating cytokine levels) is measured in at least 3 participants at a given dose level. With amendment L, a cohort will be enrolled evaluating NHS-IL12 at 12 mcg/kg every 2 weeks with dose escalation to 16.8 mcg/kg every 2 weeks if 0 of 3 or 1 of 6 DLTS are observed.
* With a maximum accrual ceiling of 83 participants, this study will be completed within 1year, enrolling up to 2-3 participants per month.

NHS-IL12 for Solid Tumors

First In-Human Phase I Trial of NHS-IL12 in Patients With Metastatic Solid Tumors

Determination of safety, immune response and pharmacokinetic parameters

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] in the Treatment of Advanced Solid Tumor	NCT06048367	Advanced Solid ... Lung Cancer Pancreas Cancer Breast Cancer Thyroid Cancer Colorectal Canc... Cervical Cancer Ovarian Cancer Vulva Cancer	CNSI-Fe(II) 30 ... CNSI-Fe(II) 60 ... CNSI-Fe(II) 90 ...	18 Years - 75 Years	Sichuan Enray Pharmaceutical Sciences Company
NHS-IL12 for Solid Tumors	NCT01417546	Epithelial Neop... Epithelial Tumo... Malignant Mesen...	NHS-IL-12	18 Years -	National Institutes of Health Clinical Center (CC)
NHS-IL12 for Solid Tumors	NCT01417546	Epithelial Neop... Epithelial Tumo... Malignant Mesen...	NHS-IL-12	18 Years -	National Institutes of Health Clinical Center (CC)
Carbon Nanoparticle-Loaded Iron [CNSI-Fe(II)] in the Treatment of Advanced Solid Tumor	NCT06048367	Advanced Solid ... Lung Cancer Pancreas Cancer Breast Cancer Thyroid Cancer Colorectal Canc... Cervical Cancer Ovarian Cancer Vulva Cancer	CNSI-Fe(II) 30 ... CNSI-Fe(II) 60 ... CNSI-Fe(II) 90 ...	18 Years - 75 Years	Sichuan Enray Pharmaceutical Sciences Company
NHS-IL12 for Solid Tumors	NCT01417546	Epithelial Neop... Epithelial Tumo... Malignant Mesen...	NHS-IL-12	18 Years -	National Institutes of Health Clinical Center (CC)

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