First in Human Study of YB1-X7 Injection

Официальное название

An Open-Label, Dose-Escalation Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics, and Preliminary Efficacy of YB1-X7 Injection in Subjects with Advanced Solid Tumors

Обзор

This clinical trial is an open-label, dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetic, and preliminary efficacy of YB1-X7 injection in subjects with advanced solid tumors. YB1-X7 injection is an attenuated Salmonella-based tumor therapy. It selectively accumulates in hypoxic tumor regions while being rapidly cleared from normal organs. After proliferating in the tumor microenvironment, YB1-X7 invades tumor cells and releases its therapeutic payload, leading to tumor cell death and tumor regression. Conditions：To treat subjects with advanced and/or metastatic solid tumors who do not to respond to conventional standard treatment or who lack effective standard treatment.

Подробное описание

YB1-X7 is a genetically engineered attenuated Salmonella enterica strain. It has been further optimized based on the attenuated model of VNP20009 while inserting an anaerobic-targeting enrichment system, transforming YB1-X7 into a nutrient-deficient strain under aerobic conditions. This modification allows YB1-X7 to selective proliferation in hypoxic tumor regions while being cleared in normal oxygenated tissues, thereby achieving selective enrichment in tumor.

Additionally, YB1-X7 carries plasmids encoding the drug protein. Upon reaching the tumor region, YB1-X7 invades tumor cells, expressing and releasing drug protein, leading to tumor cell death and tumor regression.

This study is divided into two parts based on the route of administration:

Part 1: Subjects receiving intratumoral injection (IT). Part 2: Subjects receiving intravenous infusion (IV).

Both administration routes will have three dose cohorts (low, medium, and high dose) following the standard 3+3 dose-escalation design, with single-dose multiple administrations in an escalating dose scheme.

Each subject will receive only one administration method (IT or IV) and be assigned to only one dose cohort, completing the full treatment regimen for that dose level.

YB1-X7 injection will be administrated in 28-days cycles (once weekly for 3 weeks followed by 1-week rest).

For Subjects receiving intratumoral injection, superficial lesions can be injected directly, while deep-seated lesions may require ultrasound, CT, or endoscopic guidance for precise administration.

Вмешательства

• Препарат YB1-X7 Injection (IT)
  Intratumoral injection
• Препарат YB1-X7 Injection (IV)
  Intravenous infusion

Первичные конечные точки

• Incidence of dose limiting toxicity (DLTs) [Срок оценки: Up to 28 days post first dose.]
• Adverse events (AEs) [Срок оценки: From receiving study drug and throughout the study, until 28 days after the last dosing]
• Serious adverse events(SAEs) [Срок оценки: From receiving study drug and throughout the study, until 28 days after the last dosing.]

Вторичные конечные точки (11)

• YB1-X7 level in blood for PK analysis [Срок оценки: Before the first administration up to 28 days after the last dosing.]
• Immunogenicity (anti-drug antibodies) [Срок оценки: Before the first administration up to 28 days after the last dosing.]
• YB1-X7 level in blood for bacterial shedding. [Срок оценки: Before the first administration up to 28 days after the last dosing.]
• YB1-X7 shedding level analysis in urine, saliva, faeces using qPCR [Срок оценки: Before the first administration up to 28 days after the last dosing.]
• Cytokines [Срок оценки: Before the first administration up to 28 days after the last dosing.]
• Objective Response Rate (ORR) [Срок оценки: From signing the informed consent form until 28 days after the last dose.]
• Progression Free Survival (PFS) [Срок оценки: From signing the informed consent form until 28 days after the last dose.]
• ime to Progression (TTP) [Срок оценки: From signing the informed consent form until 28 days after the last dose.]
• Duration of Response (DOR) [Срок оценки: From signing the informed consent form until 28 days after the last dose.]
• Overall Survival (OS) [Срок оценки: 1 year]
• ECOG Performance Status Before and After Treatment [Срок оценки: From baseline to week 12]

Критерии участия

Критерии включения

• Age ≥18 years, no gender limitatlon
• Subjects with advanced or metastatic solid tumors confirmed by pathological histology.
• Subjects with advanced malignant solid tumors for whom standard treatment has failed or no other effective standard treatment available.
• At least one measurable solid tumor by RECIST 1.1.
• Subjects assigned to intratumoral injection must have at least one tumor that is suitable for biopsy or intratumoral injection.
• Life expectancy must be at least 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status score 0-1.
• Male and female subjects of childbearing potential should take effective contraceptive measures.

① Fertile women and men must agree to use acceptable contraceptive methods from the start of informed consent until at least 6 months after the last administration.

• Laboratory blood test results during the screen period:

(1)No blood cell growth factors received within 14 days prior to testing.

① Absolute neutrophil count (ANC)≥1.5×109/L.

② Platelets≥90×109/L. Hemoglobin ≥90 g/L (blood transfusion is allowed to correct). (2) Serum albumin >30 g/L, total bilirubin <1.5×ULN, ALT and AST <2.5×ULN; for subjects with liver metastasis, ALT and AST <5×ULN; creatinine clearance ≥50 mL/min (Cockcroft-Gault formula) or Cr <1.5×ULN; (3) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) <1.5×ULN.

10\. Subjects understand the study and willing to sign the informed consent form.

Критерии исключения

1.Pregnant or breastfeeding women. Subjects known to have a history of abuse of psychiatric drugs, alcoholism, or drug use.

3.Subjects who have previously undergone oncolytic bacteria treatment. 4.Subjects planning to surgery, radiation therapy, or other local treatments for target lesions during the study.

5.Subjects known to be allergic to the study drug or any of its excipients. 6.Subjects allergic or intolerant to antibiotics sensitive to Salmonella, such as amikacin cefpirome, ciprofloxacin,cefotaxime,meropenem.

7.Subjects currently using antibiotics. 8.Subjects who have not recovered fom adverse reactions of prior treatments (treatment-related toxicity grade≤2, except for hair loss, pigmentation, and other tolerable events determined by the investigator).

9.Subjects with active auto-immune diseases or prior diseases with recurrence potential (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for clinically stable autoimmune thyroiditis.

10.Subjects with active or uncontrolled infections or unexplained fever≥38.5℃, including but not limited to bacterial infections, tuberculosis, herpes virus infections syphilis infections.

11.Subjects who underwent major surgery within 3 months prior to the first dose of the study drug (except for biopsies for diagnostic purposes).

12.Subjects who have received any anti-tumor treatment within 28 days or 5 half-lives prior to the first dose of the study drug, including chemotherapy, cell therapy, gene therapy, immunotherapy,biological agents, hormone therapy, targeted therapy, tumor drug embolization therapy.

13.Subjects who received radiation therapy within 28 days prior to the first dose of the study drug (except for local radiation therapy for pain relief).

14.Subjects who receive (live attenuated) virus vaccines: within 28 days prior to the first dose of the study drug, or during the study period or within 60 days after the last dose of the study drug.

Subjects who have used immunosuppressive drugs within 14 days prior to the first dose of the study drug (i.e., prednisone≥10 mg/day, dexamethasone≥1.5 mg/day), except for corticosteroid nasal sprays and inhaled corticosteroids or physiological doses of systemic corticosteroids (i.e., prednisone not exceeding 10 mg/day)or equivalent physiologica doses of other corticosteroids.

16\. Subjects with known, uncontrolled, or symptomatic active central nervous system conditions.

17\. Subjects with existing clinical symptoms or pooely controlled heart disease:

• New York Heart Association (NYHA) class ≥II;
• Unstable angina;
• Myocardial infarction within the past year; Subjects with clinically significant supraventricular or ventricular arrhythmias needing treatment or intervention; Medicaion uncontrolled hypertension or hypotension (determined by the investigator); Subjects with valvular heart disease or mitral valve prolapse, aortic valve disease; Severe myocardial diseases. 18.Subjects known to have peripheral thromboembolic vascular diseases, aneurysms, or arterial/venous malformations.

19.Subjects Known allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

20.Subjects who are positive for Treponema pallidum antibodies, individuals with human immunodeficiency virus (HIV) infection, or known acquired immunodeficiency syndrome (AIDS).

21.Subjects with active hepatitis B (HBsAg positive and/or HBcAb positive with HBV-DNA ≥2000 IU/mL or requiring antiviral treatment), or those who test positive for hepatitis C virus (HCV) antibodies; or subjects co-infection with hepatitis B and C.

22.Other reasons unsuitable for the study as determined by the investigator.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT06889675 · ZXK24-D1-P001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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