Study of Anti-5T4 CAR-raNK Cell Therapy in Locally Advanced or Metastatic Solid Tumors
- Conditions
- Locally Advanced or Metastatic Solid Tumors
- Interventions
- Biological: Anti-5T4 CAR-raNK Cells
- Registration Number
- NCT05137275
- Lead Sponsor
- Shanghai East Hospital
- Brief Summary
This study is a multicenter, open-label, investigator-initiated trial (IIT), divided into dose escalation (Part A) and dose extension (Part B) phases to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacokinetics (PD) and initial efficacy of conjugated antibody redirecting ready-to-use allogeneic NK (CAR-raNK) cells that target trophoblast glycoprotein (5T4) in patients with locally advanced or metastatic solid tumors.
- Detailed Description
Part A is a dose escalation study to evaluate maximum toxic dose (MTD) and/or recommended phase II dose (RP2D) which adopts the 3+3 dose escalation design protocol. The dose is respectively 3.0×10\^9 live cells, 6.0×10\^9 live cells and 9.0×10\^9 live cells (if the safety of dose group with 9.0×10\^9 live cells is still good, the Safety Monitoring Committee (SMC) will co-decide whether to continue the dose escalation and the specific dose based on the obtained data on safety, efficacy, and PK). The 3.0×10\^9 live cell dose group is given on days 1 and 3 of each cycle (21 days), and the follow-up dose group is given on days 1 and 8 of each cycle (21 days).3-6 subjects will be enrolled at every dose level. The first and second subjects in the same group shall be enrolled at an interval of at least 7 days, for the purpose of ensuring their safety. Only when the dose-limiting toxicity (DLT) of all subjects in the previous dose group was observed can the enrollment of the next dose group get started.
Part B is the dose extension study. After recommended phase II dose (RP2D) is determined in Part A, the SMC will discuss whether to conduct the Part B study. This stage will be carried out in different tumor types with high expression of 5T4 antigen, and 6 to 10 subjects will be enrolled in each tumor type, and all subjects will receive anti-5T4 CAR-raNK cell therapy at RP2D level. Every 21 days is one cycle, and the administration is performed on day 1 and day 8 of each cycle.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 56
Not provided
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Have received systemic antitumor therapy, including chemotherapy, immunotherapy, and radical radiotherapy, within 4 weeks prior to their first use of the study drug. The following special cases should be assessed separately:
- The time of the last treatment of nitrosourea or mitomycin C is less than 6 weeks before the first use of the study drug;
- The time of last treatment of fluorouracil and small-molecule targeted drugs is less than 2 weeks or 5 half-lives of the drug (whichever was longer) after the first use of the study drug;
- The time of the last treatment of the traditional Chinese medicine with anti-tumor indications was less than 2 weeks after the first use of the study drug.
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Have participated in other clinical trials and received any unmarketedinvestigational drug or treatment within 4 weeks prior to first use of the study drug.
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Any prior adoptive cellular immunotherapy.
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Have undergone major organ surgery (excluding needle biopsy) or had significant trauma within 4 weeks prior to their first use of the study drug, or required elective surgery during the study period.
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Have received systemic glucocorticoids (prednisone> 10 mg/ day or an equivalent dose of another drug of the same class) or other immunosuppressants within 14 days prior to initial use of the study drug. The exceptions are: local, ocular, intraarticular, intranasal, and inhaled glucocorticoids; short-term use of glucocorticoids for prophylaxis (e.g., to prevent contrast allergy).
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Have received live, attenuated, adenovirus, or messenger ribonucleic acid (mRNA) vaccines within 4 weeks prior to initial use of the study drug, or plan to receive these vaccines during the study period.
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Have used immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferon, etc., within 14 days prior to their first use of study drugs.
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Patients with active infection who currently require intravenous anti-infective therapy.
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Active hepatitis b (HBsAg positive and hepatitis b virus (HBV) DNA
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Patients with a known history of human immunodeficiency virus (HIV) infection, or other acquired, congenital immunodeficiency disease, or a history of organ transplantation.
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Have active autoimmune diseases or have had autoimmune diseases that are likely to recur (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, vasculitis, psoriasis, etc.). Except in the following cases: type 1 diabetes that was well controlled with hormone replacement therapy, hypothyroidism, skin conditions that did not require systemic therapy (e.g., vitiligo), and other conditions that were well controlled and that the investigator determined were less likely to recur (e.g., childhood asthma in remission).
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Have a history of serious cardiovascular and cerebrovascular diseases, including but not limited to:
- There are serious cardiac rhythm or conduction abnormalities, such as ventricular arrhythmia, and Ⅱ-Ⅲ degree atrioventricular block, which need clinical intervention;
- The mean QT interval (QTcF) corrected by Fridericia method was > 480ms;
- Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other grade 3 or above cardiovascular and cerebrovascular events occurring within 6 months before the first administration;
- Patients with heart failure or left ventricular ejection fraction (LVEF) < 50% in the New York Heart Association (NYHA) classification ≥II;
- Hypertension beyond clinical control.
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Previous or current interstitial lung disease (except local interstitial pneumonia induced by radiotherapy).
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Adverse effects of previous antineoplastic therapy have not returned to CTCAE grade 5.0 ≤1 (except for toxicity that the investigator determined to be of no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stabilized by hormone replacement therapy).
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Cerebral parenchymal metastasis or meningeal metastasis with clinical symptoms were deemed unsuitable for inclusion by the investigator.
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Had received immunotherapy and developed grade ≥3 immune-related adverse events (irAE).
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The third interstitial effusion, which could not be controlled clinically, was judged by the investigator to be unsuitable for inclusion.
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(Extension phase) had other malignant tumors in the past 5 years, excluding skin basal cell carcinoma, ductal carcinoma in situ and cervical carcinoma in situ with a radical surgery.
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Pregnant or lactating women.
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Have a history of alcohol or drug abuse.
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Mental disorder or poor compliance.
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The investigator considered that the subjects had a history of other serious systemic diseases or other reasons that made them unsuitable for the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Anti-5T4 CAR-raNK Cells Anti-5T4 CAR-raNK Cells -
- Primary Outcome Measures
Name Time Method Part B: Duration of remission (DOR) Up to 1 year after infusion To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells
Part A: Incidence of dose limiting toxicity (DLTs) From day1 to day 21 To evaluate the safety, tolerability, and determine the RP2D of Anti-5T4 CAR-raNK Cells
Part B: Disease control rate (DCR) Up to 1 year after infusion To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells
Part B: Progression-free survival (PFS) Up to 1 year after infusion To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells
Part A: Number of Adverse Events (AEs) From day 1 to day 90 after the last dose To evaluate the safety of Anti-5T4 CAR-raNK Cells
Part B: Objective response rate (ORR) Up to 1 year after infusion To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells
Part B: Overall survival (OS) Up to 1 year after infusion To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells
- Secondary Outcome Measures
Name Time Method Cytokine release From day1 to day 21 Blood samples will be collected at specified time points to detect serum Blood samples will be collected at specified time points to detect the cytokine (IL-1β, IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α) concentration
Anti-CAR antibodies From day1 to day 21 Blood samples will be collected at specified time points to detect anti-CAR(anti-5T4 mAb) antibodies
The number of CAR-raNK cells From day1 to day 21 Blood samples will be collected at specified time points to detect the number of CAR raNK cells in peripheral blood
Lymphocyte subtype From day1 to day 21 Blood samples will be collected at specified time points to analyze the lymphocyte subtypes (CD3, CD4, CD8, CD19, CD56).
Trial Locations
- Locations (1)
Shanghai East Hospital
🇨🇳Shanghai, Shanghai, China