A Clinical Research About CD70-targeted CAR-T in the Treatment of CD70-positive Advanced/Metastatic Solid Tumors

A Phase I Clinical Study to Assess the Safety and Efficacy of CD70-targeted CAR-T in the Treatment of CD70-positive Advanced/Metastatic Solid Tumors

This is a single-center, double-arm, open-label study. this study plans to evaluate the safety and efficacy of CD70-targeting CAR-T cells in the treatment of CD70-positive advanced/metastatic solid tumors, and obtain recommended doses and infusion patterns.

Study Overview

• Status: Recruiting
• Conditions: Renal Cell Carcinoma; Ovarian Cancer; Metastatic Cancer; Cervix Cancer; Advanced Cancer
• Intervention / Treatment: Biological: CD70 CAR-T cells; Biological: CD70 CAR-T cells

Detailed Description

The research designs to follow 2 groups：Intravenous infusion group and Intraperitoneal injection group；each group sets up 2 phases,the first phase is dose discovery phase to obtain recommended doses,the second phase is dose expansion phase to verify the safety in the recommended doses. In the discovery phase,each group puts up 4 dose groups, adopting a dose-escalating 3+3 design, and plan to recruit about 12 subjects with CD70-positive advanced/metastatic solid tumors.In the dose expansion phase,each group will choose one or two dose groups to verify the safety and efficacy at this dose,and plan to recruit about 6 subjects in each dose group.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Fei Li, M.D; Phone Number: 13970038386; Email: 691058841@qq.com

Study Locations

• China
  • Jiangxi
    • Nanchang, Jiangxi, China
      • Recruiting
      • The First Affiliated Hospital Of Nanchang University
      • Contact: Fei Li, MD; Phone Number: 13970038386; Email: 691058841@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥18 years old, male or female;
2. Advanced/metastatic solid tumor confirmed by histopathology or cytology (paraffin section or fresh biopsy tumor tissue specimen) (positive tumor CD70 expression (tumor CD70 positive (IHC 3+) confirmed by histology or pathology)) ;
3. At least after TKI/PARPi, anti-vascular drug treatment is ineffective, there is no available standard treatment plan or standard treatment fails or intolerable (disease progression or intolerance such as surgery, chemotherapy, radiotherapy, targeted therapy, etc.), There is currently no effective treatment;
4. Measurable and evaluable lesions defined by RECIST version 1.1: Measurable disease is defined as at least one lesion that can be accurately measured on at least one level (long diameter needs to be recorded); ), when measured by magnetic resonance imaging (MRI), each lesion must be >10mm, The lymph node must be >15mm in the short axis;
5. ECOG 0-2 points (Appendix 2);
6. The expected survival time is more than 12 weeks;
7. No serious mental disorder;

8. The functions of important organs are basically normal:

   1. Hematopoietic function: neutrophils 1.0×109/L, platelets 75×109/L, hemoglobin 80g/L;
   2. Cardiac function: echocardiography showed cardiac ejection fraction ≥50%, and no obvious abnormality was found on electrocardiogram;
   3. Renal function: serum creatinine≤2.0×ULN;
   4. Liver function: ALT and AST ≤2.0×ULN (for patients with liver tumor infiltration, it can be relaxed to ≤3.0×ULN);
   5. Total bilirubin ≤2.0×ULN (Gilbert syndrome or combined liver tumor infiltration can be relaxed to ≤3.0×ULN);
   6. Oxygen saturation > 92% in non-oxygen state.
9. Have apheresis or venous blood collection standards, and have no other contraindications for cell collection;
10. Subjects agree to use reliable and effective contraceptive methods for contraception within 1 year after signing the informed consent form to receiving CAR-T cell infusion (excluding rhythm contraception);
11. Subjects or their guardians agree to participate in this clinical trial and sign the ICF, indicating that they understand the purpose and procedures of this clinical trial and are willing to participate in the research.

Exclusion Criteria:

1. Received anti-CD70 drug treatment before screening;
2. Active/symptomatic central nervous system metastases or meningeal metastases at the time of screening; subjects with brain metastases who have been treated must be confirmed to have no imaging evidence of progression ≥ 4 weeks after the end of treatment before they can be enrolled;

3. Received any of the following treatments before screening:

   1. Participated in other interventional clinical studies before screening, including: the last use of unmarketed new drugs is less than 3 months before cell reinfusion, or the last use of marketed drugs is less than 5 half-lives from cell reinfusion;
   2. Received anti-tumor therapy such as chemotherapy and targeted therapy within 2 weeks or at least 5 half-lives (whichever is shorter) before apheresis;
   3. Received systemic corticosteroid therapy at doses greater than 10 mg/day prednisone (or equivalent doses of other corticosteroids) within 2 weeks prior to apheresis (inhalation or topical allowed in the absence of active autoimmune disease Use steroids and adrenal corticosteroid replacement at doses greater than 10 mg/day of prednisone);
   4. Received live attenuated vaccine within 4 weeks before screening;
4. Active infection or uncontrollable infection requiring systemic treatment within 1 week before screening;
5. Malignant tumors other than the target tumor within 3 years before screening, except for the following: malignant tumors that have received radical treatment, and no known active disease within ≥ 3 years before enrollment; or Treated non-melanoma skin cancer with no evidence of disease;

6. Suffering from any of the following heart diseases:

   1. New York Heart Association (NYHA) stage III or IV congestive heart failure;
   2. Myocardial infarction or coronary artery bypass grafting (CABG) within 6 months before enrollment;
   3. Clinically significant ventricular arrhythmia, or a history of unexplained syncope (except those caused by vasovagal or dehydration);
   4. History of severe nonischemic cardiomyopathy.
7. Known to have active or uncontrolled autoimmune diseases, such as Crohns disease, rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, etc.;
8. Hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) positive and peripheral blood hepatitis B virus (HBV) DNA titer detection is greater than the normal range; hepatitis C virus (HCV) antibody positive and peripheral blood type C Hepatitis virus (HCV) RNA titer detection greater than normal range Human immunodeficiency virus (HIV) antibody positive; syphilis positive test; cytomegalovirus (CMV) DNA test positive;
9. The subject has experienced venous thromboembolic events (for example: pulmonary embolism) and still needs anticoagulation therapy, or meets the following conditions: a. Bleeding with grades 3 to 4 for more than 30 days; b. There are venous Sequelae caused by embolism (such as persistent dyspnea and hypoxia); Arterial embolism but those who do not meet the above conditions can participate in the trial);
10. Poorly controlled hypertension, defined as systolic blood pressure ≥150mmHg and/or diastolic blood pressure ≥90mmHg (blood pressure values are measured based on the average of 3 readings at least 2 minutes apart, blood pressure ≥150/90mmHg at initial screening Receive antihypertensive treatment, if the treatment is well controlled and blood pressure is less than 150/90mmHg, screening can be performed);
11. Women who are pregnant or breastfeeding, and male or female subjects who plan to have children within 1 year after receiving CAR-T cell reinfusion;
12. Other investigators deem it unsuitable to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous of CD70-targeted CAR-T; Infusion of CD70-targeted CAR-T cells by dose of 1-10x10^6 cells/kg	Biological: CD70 CAR-T cells; After lymphodepletion with Fludarabine and Cyclophosphamide,CAR T cells were transfused intravenically; Biological: CD70 CAR-T cells; After lymphodepletion with Fludarabine and Cyclophosphamide,CAR T cells were injected intraperitoneally
Experimental: intraperitoneal injection of CD70-targeted CAR-T; Infusion of CD70-targeted CAR-T cells by dose of 1-10x10^6 cells/kg	Biological: CD70 CAR-T cells; After lymphodepletion with Fludarabine and Cyclophosphamide,CAR T cells were transfused intravenically; Biological: CD70 CAR-T cells; After lymphodepletion with Fludarabine and Cyclophosphamide,CAR T cells were injected intraperitoneally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse events after CD70 CAR-T cells infusion [Safety and Tolerability]	Therapy-related adverse events were recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0)	28 days
Obtain the maximum tolerated dose of CD70 CAR-T cells[Safety and Tolerability]	Dose-limiting toxicity after cell infusion	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CMAX of CD70 CAR-T cells [Cell dynamics]	CMAX is defined as the highest concentration of CD70 CAR-T cells expanded in peripheral blood	3 months
TMAX of CD70 CAR-T cells[Cell dynamics]	TMAX is defined as the time to reach the highest concentration	3 months
AUCS of CD70 CAR-T cells [Cell dynamics]	AUCS is defined as the area under the curve in 90 days	3 months
Disease control rate of CAR-T cell preparations in CD70 positive advanced malignancies [Effectiveness]	Disease control rate: The proportion of subjects who achieved CR, PR, SD after CAR-T infusion accounted for all treated subjects (Assessed based on RECIST criteria)，the minimum value is 0%，maximum value is 100%, and higher scores mean a better outcome.	3 months
Objective response rate (ORR) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	Objective response rate includes：The proportion of subjects who achieved CR, PR after CAR-T infusion accounted for all treated subjects (Assessed based on RECIST criteria)，the minimum value is 0%，maximum value is 100%, and higher scores mean a better outcome.	3 months
Duration of Response (DOR) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	DOR will be assessed from the first assessment of CR/PR/SD to the first assessment of recurrence or progression of the disease or death from any cause	2 years
Pharmacodynamics of CD70 CAR-T cells[Cell dynamics]	Concentration levels of CAR-T-related serum cytokines such as CRP, IL-6, ferritin at each time point，which measured by Chemiluminescence method	3 months
Progress-free survival(PFS) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	PFS will be assessed from the first CD70-CAR-T cell infusion to death from any cause or the first assessment of progression(Assessed based on RECIST criteria)	2 years
Overall survival(OS)of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	OS will be assessed from the first CD70-CAR-T cell infusion to death from any cause (Assessed based on RECIST criteria)	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The correlation between CD70 positive rate and safety	assessment the correlation between CD70 positive rate and the incidence of CRA and ICANS	2 years
Correlation between CD70 positive rate and efficacy	assessment the correlation between CD70 positive rate and the disease control rate，Disease control rate: including CR, PR and SD	2 years
Duration of Response (DOR) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	DOR will be assessed from the first assessment of CR/PR/SD to the first assessment of recurrence or progression of the disease or death from any cause (Assessed by investigators based on IRECIST criteria)	2 years
Overall survival(OS)of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	OS will be assessed from the first CD70-CAR-T cell infusion to death from any cause (Assessed by investigators based on IRECIST criteria)	2 years
Progress-free survival(PFS) of CD70 CAR-T treatment in patients with CD70-positive advanced malignancies[Effectiveness]	PFS will be assessed from the first CD70-CAR-T cell infusion to death from any cause or the first assessment of progression (Assessed by investigators based on IRECIST criteria)	2 years

Collaborators and Investigators

• Sponsor: Chongqing Precision Biotech Co., Ltd
• Collaborators: The First Affiliated Hospital of Nanchang University
• Investigators: Principal Investigator: Fei Li, M.D, The First Affiliated Hospital Of Nanchang University

Study record dates

Study Major Dates

• Study Start (Estimated): November 30, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: August 18, 2023
• First Submitted That Met QC Criteria: August 23, 2023
• First Posted (Actual): August 25, 2023

Study Record Updates

• Last Update Posted (Actual): November 8, 2023
• Last Update Submitted That Met QC Criteria: November 6, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: CAR-T; CD70
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Carcinoma, Renal Cell; Uterine Cervical Neoplasms
• Other Study ID Numbers: PBC052

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No