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

NCT05137275 | Unknown Early Phase 1

• 1 other identifier: IBR854-03
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

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.

Conditions

Locally Advanced or Metastatic Solid Tumors

Outcome Measures

Primary Outcomes (7)

• Part A: Incidence of dose limiting toxicity (DLTs)

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

  From day1 to day 21

• Part A: Number of Adverse Events (AEs)

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

  From day 1 to day 90 after the last dose

• Part B: Objective response rate (ORR)

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

  Up to 1 year after infusion

• Part B: Disease control rate (DCR)

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

  Up to 1 year after infusion

• Part B: Duration of remission (DOR)

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

  Up to 1 year after infusion

• Part B: Progression-free survival (PFS)

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

  Up to 1 year after infusion

• Part B: Overall survival (OS)

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

  Up to 1 year after infusion

Secondary Outcomes (4)

• The number of CAR-raNK cells

  From day1 to day 21

• Cytokine release

  From day1 to day 21

• Lymphocyte subtype

  From day1 to day 21

• Anti-CAR antibodies

  From day1 to day 21

Study Arms (1)

Anti-5T4 CAR-raNK Cells

EXPERIMENTAL

Biological: Anti-5T4 CAR-raNK Cells

Interventions

Anti-5T4 CAR-raNK Cells BIOLOGICAL

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.

Anti-5T4 CAR-raNK Cells

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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.
• 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:

Sponsors & Collaborators

• Shanghai East Hospital: lead
• Imbioray (Hangzhou) Biomedicine Co., Ltd.: collaborator

Study Sites (1)

Shanghai East Hospital

Shanghai, Shanghai Municipality, China

RECRUITING

Related Publications (9)

• 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.

  PMID: 25972872 BACKGROUND

• 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.

  PMID: 32751977 BACKGROUND

• 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.

  PMID: 16222313 BACKGROUND

• 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.

  PMID: 11113573 BACKGROUND

• 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.

  PMID: 16630022 BACKGROUND

• 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.

  PMID: 27757559 BACKGROUND

• 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.

  PMID: 32023374 BACKGROUND

• 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.

  PMID: 33273328 BACKGROUND

• 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.

  PMID: 32988894 BACKGROUND

Study Officials

• Jin Li, PhD

  Shanghai East Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jin Li, PhD

CONTACT

13761222111; lijin@csco.org.cn

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director

Study Record Dates

• First Submitted: November 11, 2021
• First Posted: November 30, 2021
• Study Start: November 24, 2021
• Primary Completion: April 1, 2023
• Study Completion: May 1, 2023
• Last Updated: October 27, 2022

Record last verified: 2022-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)