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

Locally Advanced or Metastatic Solid Tumors Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05137275
• Other study ID #: IBR854-03
• Status: Recruiting
• Phase: Early Phase 1
• Start date: November 24, 2021
• Est. completion date: May 2023

Study information

• Verified date: October 2022
• Source: Shanghai East Hospital
• Contact: Jin Li, PhD
• Phone: 13761222111
• Email: lijin[@]csco.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 (CAR-raNK) cells that target trophoblast glycoprotein (5T4) in patients with locally advanced or metastatic solid tumors.

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 information / eligibility

• Status: Recruiting
• Enrollment: 56
• Est. completion date: May 2023
• Est. primary completion date: April 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion criteria:

1. 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.

2. 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.

3. Eastern Cooperative Oncology Group (ECOG) score =1 and expected survival time > 3 months.

4. (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).

5. Organ function during screening should meet the following criteria:

6. 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

7. 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.

Exclusion Criteria:

1. 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.

2. Have participated in other clinical trials and received any unmarketedinvestigational drug or treatment within 4 weeks prior to first use of the study drug.

3. Any prior adoptive cellular immunotherapy.

4. 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.

5. 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).

6. 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.

7. 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.

8. Patients with active infection who currently require intravenous anti-infective therapy.

9. Active hepatitis b (HBsAg positive and hepatitis b virus (HBV) DNA

10. Patients with a known history of human immunodeficiency virus (HIV) infection, or other acquired, congenital immunodeficiency disease, or a history of organ transplantation.

11. 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).

12. 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 ?-? 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.

13. Previous or current interstitial lung disease (except local interstitial pneumonia induced by radiotherapy).

14. 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).

15. Cerebral parenchymal metastasis or meningeal metastasis with clinical symptoms were deemed unsuitable for inclusion by the investigator.

16. Had received immunotherapy and developed grade =3 immune-related adverse events (irAE).

17. The third interstitial effusion, which could not be controlled clinically, was judged by the investigator to be unsuitable for inclusion.

18. (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.

19. Pregnant or lactating women.

20. Have a history of alcohol or drug abuse.

21. Mental disorder or poor compliance.

22. The investigator considered that the subjects had a history of other serious systemic diseases or other reasons that made them unsuitable for the study.

Related Conditions & MeSH terms

• Locally Advanced or Metastatic Solid Tumors
• Neoplasms

Intervention

Biological:
• Anti-5T4 CAR-raNK Cells
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.

Locations

Country	Name	City	State
China	Shanghai East Hospital	Shanghai	Shanghai

Sponsors (2)

Lead Sponsor	Collaborator
Shanghai East Hospital	Imbioray (Hangzhou) Biomedicine Co., Ltd.

Country where clinical trial is conducted

China, 

References & Publications (9)

Franks SE, Wolfson B, Hodge JW. Natural Born Killers: NK Cells in Cancer Therapy. Cancers (Basel). 2020 Jul 31;12(8). pii: E2131. doi: 10.3390/cancers12082131. Review. — View Citation

Gras Navarro A, Björklund 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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Part B: Objective response rate (ORR)	To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells	Up to 1 year after infusion
Primary	Part B: Disease control rate (DCR)	To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells	Up to 1 year after infusion
Primary	Part B: Duration of remission (DOR)	To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells	Up to 1 year after infusion
Primary	Part B: Progression-free survival (PFS)	To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells	Up to 1 year after infusion
Primary	Part B: Overall survival (OS)	To determine the anti-tumor effectivity of Anti-5T4 CAR-raNK Cells	Up to 1 year after infusion
Secondary	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	From day1 to day 21
Secondary	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-1ß, IL-2, IL-4, IL-6, IL-10, IFN-?, TNF-a) concentration	From day1 to day 21
Secondary	Lymphocyte subtype	Blood samples will be collected at specified time points to analyze the lymphocyte subtypes (CD3, CD4, CD8, CD19, CD56).	From day1 to day 21
Secondary	Anti-CAR antibodies	Blood samples will be collected at specified time points to detect anti-CAR(anti-5T4 mAb) antibodies	From day1 to day 21