An Exploratory Clinical Trial of Autologous Humanized Anti-cluster of Differentiation Antigen 19/20(CD19/CD20) Dual Specific CAR-T Cells Injection

NCT ID: NCT04486872

Last Updated: 2020-08-26

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-25
• Study Completion Date: 2022-06-25

Brief Summary

This is a single-arm, open-label, dose escalation, phase I study, aiming to evaluate the safety and efficacy of Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific Chimeric Antigen Receptor (CAR) T-cells in patient with relapsed or refractory diffuse B cell lymphoma.

Detailed Description

CD19 CAR-T cell therapy has made breakthroughs in the treatment of B cell lymphoma and leukemia, but 30% of patients still have antigen escape, which may be related to variants in tumor cells and the expansion of CD19-negative tumor cells after treatment with CD19 CAR-T cells. CD19/CD20 bispecific CAR-T cell targeting multiple antigens can attack tumor cells while overcoming tumor antigen escape caused by a single target, maximizing efficacy and duration of treatment, and can also solve the problem of uneven distribution or low expression of single target on the tumor surface.

Conditions

Diffuse Large B Cell Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

anti-CD19 and anti-CD20 dual specific CAR-T Cells

Group Type: EXPERIMENTAL

Autologous humanized anti-CD19 and anti-CD20 dual specific CAR-T Cells

Intervention Type: BIOLOGICAL

Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells injection. Within 3 to 5 days after the pretreatment, the subjects received a single A-02 reinfusion, the infusion dose of each group of subjects 1.00 × 10\^6/kg, 3.00 × 10\^6/kg or 5.00 × 10\^6/kg (if applicable), it is recommended to complete the infusion within 30 min after cell recovery.

Interventions

Autologous humanized anti-CD19 and anti-CD20 dual specific CAR-T Cells

Autologous Humanized Anti-CD19 and Anti-CD20 Dual Specific CAR-T Cells injection. Within 3 to 5 days after the pretreatment, the subjects received a single A-02 reinfusion, the infusion dose of each group of subjects 1.00 × 10\^6/kg, 3.00 × 10\^6/kg or 5.00 × 10\^6/kg (if applicable), it is recommended to complete the infusion within 30 min after cell recovery.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

1. The subject or her/his legally guardian(s) must sign the informed consent form approved by the Institutional Ethics Committee (IEC) prior to any screening procedures;

2. Subjects aged 18 years or older with relapsed or refractory DLBCL (including primary mediastinal large B-cell lymphoma and transformed follicular lymphoma), of which refractory is defined as:

• Have no response to the recent treatment including:

• The best response to the treatment regimen is progressive disease (PD) ,or;
• stable disease(SD) which maintained less than 6 months after the last treatment, or;
• not suitable for autologous hematopoietic stem cell transplantation (ASCT), or ASCT refractory, including:

• progressive disease after ASCT or relapse within 12 months (relapse must be confirmed by biopsy), or;
• If remedial treatment is given after ASCT, the subject must have no response or relapse after the last treatment.

3. Subjects who have previously received ≥2 lines treatment, and at least including:

• Anti-CD20 monoclonal antibody(rituximab), unless the CD20 negative;
• A chemotherapy regimen containing anthracyclines;
• The DLBCL patients who transformed from follicular lymphoma must have previously received chemotherapy for follicular lymphoma and have developed chemotherapy-refractory diseases after transform to DLBCL.

4. Confirmation for either CD19 or CD20 positivity using immunohistochemistry or flow cytometry(accepting the previous results from the a third-level grade A hospitals before the collection of peripheral blood mononuclear cells or peripheral blood. For CD20 positive only, the investigator needs to determine whether the treatment benefit);

5. According to the preliminary assessment of Hodgkin's lymphoma and non-Hodgkin's lymphoma, staging and response assessment recommendations (2014 version), there is at least one measurable lesion at baseline;

6. If the subject has received a single target in the past, such as CD19-CAR cell therapy, it must be confirmed that the disease has progressed or relapsed after treatment and is at least 1 month from the planned single collection period

7. Life expectancy ≥12 weeks;

8. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening;

9. Adequate organ function:

• Renal function defined as:

• A serum creatinine of ≤1.5 × Upper Limit of Normal(ULN), or;
• Estimated Glomerular Filtration Rate (eGFR) ≥60 ml/min/1.73m2；[eGFR=186×（age）-0.203×SCr-1.154（mg/dl）， female ×0.742 on the basis of the calculation results]；
• Liver function defined as:

• Alanine aminotransferase (ALT)≤ 5 × Upper Limit of Normal(ULN) for age, and;
• Total bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN.
• Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and blood oxygen saturation > 91% on room air;

10. Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA);

11. Adequate bone marrow reserve without transfusions defined as:

• Absolute neutrophil count (ANC) >1×10^9 /L；
• Absolute lymphocyte count (ALC) ≥0.3×10^9 /L；
• Platelets ≥50×10^9 /L;
• Hemoglobin > 8.0 g/dl;

12. Subjects who use the following drugs should meet the following criteria:

• Steroids: Therapeutic doses of steroids must be stopped 2 weeks prior to A-02 infusion. However, the following physiological replacement doses of steroids are allowed: < 6 - 12 mg/m2/day hydrocortisone or equivalent;
• Immunosuppression: Any immunosuppressive medication must be stopped ≥ 4 weeks prior to sign the informed consent form;
• Anti-proliferative therapy other than pretreatment chemotherapy within 2 weeks of A-02 infusion;
• CD20 antibody-related treatment must be discontinued within 4 weeks of A-02 infusion or 5 half-lives (whichever is longer);
• CNS disease prophylaxis must be stopped > 1 week prior to A-02 infusion (e.g. intrathecal methotrexate);

13. The investigator judged that the subject recovered from the toxicity of the previous anti-tumor treatment to grade 1 or below (except for special grade 2 or below toxicity that cannot be recovered in a short period of time, such as hair loss), suitable for pretreatment. Chemotherapy and treatment of CAR-T cells;

14. Women of child-bearing potential and all male subjects must agree to use highly effective methods of contraception for at least 12 months following A-02 infusion and until CAR-T cells are no longer present by Polymerase chain reaction(PCR) on two consecutive tests.

Exclusion Criteria

Subjects who meet any of the following criteria will not be enrolled:

1. Subjects who have received any CD19/CD20 dual-target cell therapy products before signing the informed consent form;

2. Subjects with detectable cerebrospinal fluid malignant cells or brain metastases, or with a history of central nervous system (CNS) lymphoma or primary CNS lymphoma;

3. Subjects with current or previous history of central nervous system disease, such as seizures, cerebral ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease involving the central nervous system;

4. Subjects who have previously received allogeneic hematopoietic stem cell transplantation (HSCT); or suitable and consenting to Autologous hematopoietic stem cell transplantation (ASCT);

5. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of A-02 infusion;

6. Investigational medicinal product within the last 30 days prior to sign the informed consent form;

7. Subjects with active hepatitis B（defined as hepatitis B surface antigen positive, or hepatitis B core antibody positive with hepatitis B virus DNA detection value > 1000 copies/ml）or hepatitis C(HCV RNA positive);

8. Subjects positive for HIV antibody or treponema pallidum antibody;

9. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to A-02 infusion);

10. Unstable angina and/or myocardial infarction within 6 months prior to sign the informed consent form;

11. Previous or concurrent malignancy with the following exceptions:

• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to sign the informed consent form);
• In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to sign the informed consent form;
• A primary malignancy which has been completely resected and in complete remission for ≥ 5 years;

12. Pregnant or nursing women (women of childbearing age were tested positive for pregnancy during screening period);

13. Subjects with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyotrophic Lateral Sclerosis);

14. Other conditions that the investigator thinks he/she should not be included in this clinical trial, such as poor compliance.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

First Affiliated Hospital of Zhejiang University

OTHER

Sponsor Role: lead

Responsible Party

shentu jianzhong

Prof

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

First Affiliated Hospital of Zhejiang University

Hangzhou, Zhejiang, China

Site Status: RECRUITING

Countries

China

Central Contacts

Jie Jin, Prof

Role: CONTACT

jiej0503@163.com

13505716779

Jianzhong Shentu, Prof

Role: CONTACT

stjz@zju.edu.cn

13957111817

Facility Contacts

Jie Jin, Prof

Role: primary

jiej0503@163.com

13505716779

Jianzhong Shentu, Prof

Role: backup

stjz@zju.edu.cn

13957111817

References

Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Reference Type: DERIVED

PMID: 34515338 (View on PubMed)

Other Identifiers

A-02 POC-01

Identifier Type: -

Identifier Source: org_study_id