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

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

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 Gynecologic Cancer, and obtain recommended doses and infusion patterns.

Study Overview

• Status: Recruiting
• Conditions: Gynecologic Cancer; 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): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Guantai Ni, M.D; Phone Number: 13705535528; Email: niguantai@yjsyy.com

Study Locations

• China
  • Anhui
    • Wuhu, Anhui, China
      • Recruiting
      • The First Affiliated Hospital of Wannan Medical College
      • Contact: Guantai Ni, MD; Phone Number: 13705535528; Email: niguantai@yjsyy.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Age ≥18 years old;
2. Advanced/metastatic gynecological tumor confirmed by histopathology or cytology (paraffin sections or fresh biopsy tumor tissue specimens) (CD70 positive tumor expression (CD70 positive tumor confirmed by histology or pathology (IHC 3+));
3. Failure or intolerance after standard treatment (disease progression or intolerance such as surgery, chemotherapy, radiotherapy, targeted therapy, etc.), and currently no effective treatment;
4. According to the RECIST version 1.1 standard, there is at least one measurable diameter and evaluable target lesion. Measurable lesions are defined as: extranodal lesions with CT scan diameter ≥10mm, lymph node lesions with CT scan diameter ≥15mm, scan layer thickness ≤ 5mm, and have not received local treatment;
5. ECOG 0 ~ 2 points ;
6. Expected survival time is more than 12 weeks;
7. No serious mental disorders;

8. The functions of important organs are basically normal:

   1. Hematopoietic function: neutral granules >1.0×109/L, platelet >75×109/L, hemoglobin >80g/L;
   2. Cardiac function: Echocardiography indicated cardiac ejection fraction ≥50%, and no obvious abnormality was found in electrocardiogram;
   3. Renal function: serum creatinine ≤2.0×ULN;
   4. Liver function: ALT and AST ≤2.0×ULN (patients with liver tumor infiltration can be relaxed to ≤3.0×ULN);
   5. Total bilirubin ≤2.0×ULN (Gilbert syndrome or liver tumor infiltration can be relaxed to ≤3.0×ULN);
   6. Blood oxygen saturation in non-oxygen state>92%.
9. Have the criteria for simple or intravenous blood collection, and no other contraindications for cell collection;
10. The subject agrees to use a reliable and effective contraceptive method for contraception (excluding safe period contraception) within 1 year from signing the informed consent to receiving the CAR T cell infusion;
11. The subject or his/her guardian agrees to participate in the clinical trial and signs the ICF, indicating that he/she understands the purpose and procedure of the clinical trial and is willing to participate in the study.

Exclusion Criteria:

1. Received anti-CD70 drug therapy before screening;
2. Active/symptomatic central nervous system metastasis or meningeal metastasis at the time of screening; Treated subjects with brain metastases can only be enrolled if no radiographically demonstrated progression is demonstrated ≥4 weeks after the end of treatment.

3. Received any of the following treatments prior to screening:

   1. Participated in other interventional clinical studies before screening, including: the time of last use of unmarketed new drugs less than 3 months from cell transfusion, or the time of last use of marketed drugs less than 5 half-lives from cell transfusion;
   2. Received anti-tumor therapy such as chemotherapy or targeted therapy within 2 weeks of preapheresis or at least 5 half-lives (whichever is shorter); Received systemic radiation within 4 weeks and local radiation within 2 weeks; Or received radioactive drugs (strontium, samarium) within 8 weeks prior to treatment.
   3. Systemic corticosteroid therapy with doses greater than 10mg/ day of prednisone (or equivalent doses of other corticosteroids) within 2 weeks of preapheresis (in the absence of active autoimmune disease, inhaled or topical steroid use and adrenocortical replacement with doses greater than 10mg/ day of prednisone efficacy dose are permitted);
   4. Received live attenuated vaccine within 4 weeks prior to screening;
4. There is an active or uncontrolled infection requiring systemic treatment within 1 week prior to screening;
5. Had malignancies other than the target tumor within 3 years prior to screening, except for malignancies that had received radical treatment and had no known active disease for ≥3 years prior to enrollment; Or adequately treated non-melanoma skin cancer with no evidence of disease;

6. Have any of the following heart conditions:

   1. New York Heart Association (NYHA) Stage III or IV congestive heart failure;
   2. Had myocardial infarction or coronary artery bypass grafting (CABG) within ≤6 months before enrollment;
   3. A history of clinically significant ventricular arrhythmia, or unexplained syncope (other than those caused by vasovagal or dehydration);
   4. History of severe non-ischemic 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 greater than the normal range; Hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus (HCV) RNA titer greater than the normal range; Positive for human immunodeficiency virus (HIV) antibodies; Syphilis positive; Cytomegalovirus (CMV) DNA test positive;
9. The subject has a history of venous embolism (e.g., pulmonary embolism) and currently requires anticoagulant therapy, or if: a. Bleeding with grade 3 to 4 persists for more than 30 days; b. have sequelae from venous embolism (e.g. persistent dyspnea and hypoxia); (Note: Participants who have venous embolism but do not meet the above criteria can participate in the test);
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, patients with blood pressure ≥150/90 MMHG at initial screening may receive antihypertensive treatment, if well controlled after treatment, And blood pressure < 150/90mmHg can be screened);
11. Women who are pregnant or breastfeeding, and male or female subjects who plan to have a family within 1 year after receiving CAR T cell transfusion;
12. Conditions deemed unsuitable for participation in the study by other researchers.

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
• Investigators: Principal Investigator: Guantai Ni, M.D, The First Affiliated Hospital of Wannan Medical College

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: January 11, 2024
• First Submitted That Met QC Criteria: January 11, 2024
• First Posted (Actual): January 22, 2024

Study Record Updates

• Last Update Posted (Actual): January 22, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: CAR-T; CD70
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Cervical Neoplasms
• Other Study ID Numbers: PBC061

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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