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Locally Advanced or Metastatic Solid TumorsEarly Phase 1NCT05137275

Study of Anti-5T4 CAR-raNK Cell Therapy in Locally Advanced or Metastatic Solid Tumors

A Early Phase 1 study testing Anti-5T4 CAR-raNK Cells in people with Locally Advanced or Metastatic Solid Tumors, run by Shanghai East Hospital at 1 site in China.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 80 years
What is being tested?
Anti-5T4 CAR-raNK Cells
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
56 participants
Where
1 siteChina
Study dates
24 Nov 2021to May 2023
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Subjects volunteer to participate in this clinical study, are fully aware of the study and have signed the Informed Consent Form (ICF). Subjects are willing to follow and able to complete all trial procedures.
  • Age: adult at the age of 18-80 (both inclusive), female or male. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not eligible for standard therapy at this stage; Part B: Patients with specific primary tumor types, including:
  • Cohort 1: Non-small cell lung cancer with disease progression or intolerance after at least two systemic therapies; For patients with known epidermal growth factor receptor (EGFR)-sensitive mutations, anaplastic lymphoma kinase (ALK) gene fusion, or other driver gene positivity, progression must be followed by appropriate targeted therapy.
  • Cohort 2: Breast cancer, negative for progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor-2 (HER2), treated with at least one systemic chemotherapy agent.
  • Cohort 3: Colorectal cancer with disease progression or intolerance after at least two systemic therapies.
  • Cohort 4: Mesothelioma with disease progression or intolerance after at least two systemic therapies.
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  • Cohort 5: Other tumors with high expression of antigen 5T4.
  • Eastern Cooperative Oncology Group (ECOG) score ≤1 and expected survival time > 3 months.
  • (Part A) According to RECIST v1.1, there is at least one assessable tumor lesion; (Part B) According to RECIST v1.1, there is at least one measurable tumor lesion (a lesion within the field of previous radiation cannot be targeted unless there is radiographic evidence of progression or persistence after 3 months of radiation).
  • Organ function during screening should meet the following criteria:
  • Hematologic system (no blood transfusion or hematopoietic stimulator treatment within 14 days)
  • Absolute neutrophil count (ANC) ≥1.5×109/L
  • Platelet (PLT) ≥75×109/L
  • Hemoglobin (Hb) ≥85g/L
  • Hepatic function
  • Total bilirubin (TBIL) ≤1.5×ULN
  • Alanine aminotransferase (ALT) ≤3×ULN;
  • Patients with liver metastasis or liver cancer: ≤5×ULN
  • Aspartate aminotransferase (AST) ≤3×ULN;
  • Patients with liver metastasis or liver cancer: ≤5×ULN Renal function
  • Creatinine (Cr) ≤1.5× ULN
  • Creatinine clearance (Ccr) (to be calculated only when Cr > 1.5× ULN) > -50ml/min/1.73m2 (Cockcroft-Gault formula) Coagulation function
  • Activated partial thrombin time (APTT) ≤1.5×ULN
  • International normalized ratio (INR) ≤1.5×ULN
  • Subjects of reproductive age and their partners should agree to have no family planning and to use effective contraceptive methods (hormonal or barrier methods or abstinence, etc.) for 6 months from signing the ICF until the last dose of the study drug is administered; women of reproductive age must have a negative serological pregnancy test 7 days prior to their first use of the study drug.

Who cannot join

  • 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.
  • Have participated in other clinical trials and received any unmarketedinvestigational drug or treatment within 4 weeks prior to first use of the study drug.
  • 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.
  • 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).
  • 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.
  • 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.
  • Patients with active infection who currently require intravenous anti-infective therapy.
  • Active hepatitis b (HBsAg positive and hepatitis b virus (HBV) DNA
  • Patients with a known history of human immunodeficiency virus (HIV) infection, or other acquired, congenital immunodeficiency disease, or a history of organ transplantation.
  • 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).
  • 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.
  • Previous or current interstitial lung disease (except local interstitial pneumonia induced by radiotherapy).
  • 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).
  • Cerebral parenchymal metastasis or meningeal metastasis with clinical symptoms were deemed unsuitable for inclusion by the investigator.
  • Had received immunotherapy and developed grade ≥3 immune-related adverse events (irAE).
  • The third interstitial effusion, which could not be controlled clinically, was judged by the investigator to be unsuitable for inclusion.
  • (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.
  • Pregnant or lactating women.
  • Have a history of alcohol or drug abuse.
  • Mental disorder or poor compliance.
  • The investigator considered that the subjects had a history of other serious systemic diseases or other reasons that made them unsuitable for the study.

Trial locations and contacts

1 site in 1 country.

Jin Li, PhD contact

13761222111

lijin@csco.org.cn

China1 site, 1 recruiting

  • Shanghai East Hospital

    Shanghai, Shanghai Municipality

    Recruiting

Other trials in China

About this study

Official title: Dose Escalation and Extension Study to Evaluate the Safety, Tolerability, and Initial Efficacy of Anti-5T4 CAR-raNK Cell Therapy in Locally Advanced or Metastatic Solid Tumors

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.

Read the 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.

Being tested
Anti-5T4 CAR-raNK Cells

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Anti-5T4 CAR-raNK CellsBiological

    In the 3+3 dose escalation study, the minimum initial dose is 3.0×10^9 cells and then escalate to 6.0× 10^9 and 9.0× 10^9 cells. Every 21 days is one cycle, and intravenous infusion is performed on day 1 and day 3\8 of each cycle. In dose extension study, the initial dose will be determined by RP2D determined by the results of dose escalation study, and the other intervention methods are consistent.

Study groups in NCT05137275
Study groupRoleWhat they receive
Anti-5T4 CAR-raNK CellsExperimentalNot described
Receives: Biological: Anti-5T4 CAR-raNK Cells

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Part A: Incidence of dose limiting toxicity (DLTs)

    To evaluate the safety, tolerability, and determine the RP2D of Anti-5T4 CAR-raNK Cells

    Measured: From day1 to day 21

  2. Part A: Number of Adverse Events (AEs)

    To evaluate the safety of Anti-5T4 CAR-raNK Cells

    Measured: From day 1 to day 90 after the last dose

  3. Part B: Objective response rate (ORR)

    To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells

    Measured: Up to 1 year after infusion

  4. Part B: Disease control rate (DCR)

    To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells

    Measured: Up to 1 year after infusion

  5. Part B: Duration of remission (DOR)

    To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells

    Measured: Up to 1 year after infusion

  6. Part B: Progression-free survival (PFS)

    To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells

    Measured: Up to 1 year after infusion

  7. Part B: Overall survival (OS)

    To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells

    Measured: Up to 1 year after infusion

Secondary outcomes (4)

  1. The number of CAR-raNK cells

    Blood samples will be collected at specified time points to detect the number of CAR raNK cells in peripheral blood

    Measured: From day1 to day 21

  2. Cytokine release

    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

    Measured: From day1 to day 21

  3. Lymphocyte subtype

    Blood samples will be collected at specified time points to analyze the lymphocyte subtypes (CD3, CD4, CD8, CD19, CD56).

    Measured: From day1 to day 21

  4. Anti-CAR antibodies

    Blood samples will be collected at specified time points to detect anti-CAR(anti-5T4 mAb) antibodies

    Measured: From day1 to day 21

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Nov 2021
  2. Study start24 Nov 2021
  3. Primary completionApr 2023 (estimated)
  4. Study completionMay 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential
Masking
None (open label)
Enrolment
56 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05137275
Sponsor's protocol ID
IBR854-03
Status last verified
Oct 2022
First submitted
11 Nov 2021
Last updated
27 Oct 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Gras Navarro A, Bjorklund AT, Chekenya M. Therapeutic potential and challenges of natural killer cells in treatment of solid tumors. Front Immunol. 2015 Apr 29;6:202. doi: 10.3389/fimmu.2015.00202. eCollection 2015.

    PubMed 25972872

  • Franks SE, Wolfson B, Hodge JW. Natural Born Killers: NK Cells in Cancer Therapy. Cancers (Basel). 2020 Jul 31;12(8):2131. doi: 10.3390/cancers12082131.

    PubMed 32751977

  • Griffiths RW, Gilham DE, Dangoor A, Ramani V, Clarke NW, Stern PL, Hawkins RE. Expression of the 5T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy. Br J Cancer. 2005 Sep 19;93(6):670-7. doi: 10.1038/sj.bjc.6602776.

    PubMed 16222313

  • Shaw DM, Embleton MJ, Westwater C, Ryan MG, Myers KA, Kingsman SM, Carroll MW, Stern PL. Isolation of a high affinity scFv from a monoclonal antibody recognising the oncofoetal antigen 5T4. Biochim Biophys Acta. 2000 Dec 15;1524(2-3):238-46. doi: 10.1016/s0304-4165(00)00165-3.

    PubMed 11113573

  • Redchenko I, Harrop R, Ryan MG, Hawkins RE, Carroll MW. Identification of a major histocompatibility complex class I-restricted T-cell epitope in the tumour-associated antigen, 5T4. Immunology. 2006 May;118(1):50-7. doi: 10.1111/j.1365-2567.2006.02338.x.

    PubMed 16630022

  • Stern PL, Harrop R. 5T4 oncofoetal antigen: an attractive target for immune intervention in cancer. Cancer Immunol Immunother. 2017 Apr;66(4):415-426. doi: 10.1007/s00262-016-1917-3. Epub 2016 Oct 18.

    PubMed 27757559

  • Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, Nassif Kerbauy L, Overman B, Thall P, Kaplan M, Nandivada V, Kaur I, Nunez Cortes A, Cao K, Daher M, Hosing C, Cohen EN, Kebriaei P, Mehta R, Neelapu S, Nieto Y, Wang M, Wierda W, Keating M, Champlin R, Shpall EJ, Rezvani K. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607.

    PubMed 32023374

  • Xia H, Wang Y, Sun HL, Gao LY, Cao Y, Zaongo SD, Zeng RN, Wu H, Zhang MJ, Ma P. Safety and efficacy of allogeneic natural killer cell immunotherapy on human immunodeficiency virus type 1 immunological non-responders: a brief report. Chin Med J (Engl). 2020 Dec 5;133(23):2803-2807. doi: 10.1097/CM9.0000000000001189.

    PubMed 33273328

  • Nagai K, Harada Y, Harada H, Yanagihara K, Yonemitsu Y, Miyazaki Y. Highly Activated Ex Vivo-expanded Natural Killer Cells in Patients With Solid Tumors in a Phase I/IIa Clinical Study. Anticancer Res. 2020 Oct;40(10):5687-5700. doi: 10.21873/anticanres.14583.

    PubMed 32988894

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Anti-5T4 CAR-raNK Cells in people with Locally Advanced or Metastatic Solid Tumors, run by Shanghai East Hospital at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 25 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 27 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Jin Li, PhD (13761222111, lijin@csco.org.cn), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part A: Incidence of dose limiting toxicity (DLTs) (time frame: From day1 to day 21). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05137275, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2022.

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