Study of Cord Blood-derived CAR NK Cells Targeting CD19/CD70 in Refractory/Relapsed B-cell Non-Hodgkin Lymphoma

To find the highest tolerable dose of dualCAR-NK19/70 (a type of cell therapy) that can be given to patients who have B-cell lymphoma that is relapsed or refractory.

Study Overview

• Status: Recruiting
• Conditions: Refractory or Relapsed B-cell Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: dualCAR-NK19/70 cell

Detailed Description

Primary Objectives:

--The primary objective is to determine the safety and identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of dualCAR-NK19/70 in patients with r/r B-cell lymphomas.

Hypothesis: DualCAR-NK19/70 will be safe, well-tolerated, and effective in patients with r/r B-cell lymphomas.

Secondary Objectives:

--The secondary objective is to determine the efficacy in adults with r/r LBCL and FL grade 3B treated at the MTD or RP2D of dualCAR-NK19/70. Although the clinical benefit of dualCAR-NK19/70 has not yet been established, the intent of offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be carefully monitored for tumor response and symptom relief in addition to safety and tolerability. Secondary endpoints include overall response rate (ORR; including CR + PR) and CR rate as defined by the Lugano Classification response criteria for malignant lymphoma, DOR, PFS, and OS.

Exploratory Objectives:

--The exploratory objectives are to assess the cellular kinetics and pharmacodynamic effects of dualCAR-NK19/70 and to evaluate biomarkers associated with response, resistance, and toxicity after administration of dualCAR-NK19/70 in blood and tumor samples.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: aibin Liang; Phone Number: 18601670600; Email: lab7182@tongji.edu.cn
• Study Contact Backup: Name: Ping Li; Phone Number: 13564181131; Email: lilyforever76@126.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200065
      • Recruiting
      • Shanghai Tongji Hospital, Tongji University School of Medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Voluntarily participate in the study and sign the informed consent;
2. Age 18-75, male and female;

3. Histologically confirmed diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), mantle cell lymphoma (MCL), and other Indolent B-cell NHL transforming types:

   （A） Relapsed or Refractory DLBCL and tFL after 2 lines Immunotherapy or chemotherapy ; （B） Definition of Refractory large B cell lymphoma (SCHOLAR - 1 Research Standard) : disease progression after more than 4 courses of standard Immunotherapy or chemotherapy; Or the time of disease stabilization ≤ 6 months; Or disease progression or recurrence within 12 months after autologous hematopoietic stem cell transplantation (auto-HSCT); （C） Relapsed or Refractory MCL must be 1 line with immune chemotherapy; BTK inhibitors are resistant or intolerant as 2-line therapy; （D） Relapsed or Refractory disease after chemotherapy including rituximab and anthracycline.

4. There was at least one measurable lesion with the longest diameter ≥ 1.5cm;
5. Estimated life expectancy of more than 12 weeks other than primary disease;
6. Previously confirmed diagnosis as CD19+ or CD70+ B-NHL.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 3.

8. Adequate reserve of organ function:

   （A） Serum alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤2.5 times the Upper Limit of Normal (ULN) for age; （B） A creatinine clearance (as estimated either by a direct urine collection or Cockcroft-Gault Equation) > 60mL/min; （C） Total bilirubin and alkaline phosphatase ≤1.5 times the Upper Limit of Normal (ULN) for age; （D） glomerular filtration rate > 50 ml/min （E） Cardiac ejection fraction (EF) ≥ 45% as determined by an echocardiogram (ECHO) or Multigated Radionuclide Angiography (MUGA); （F） Baseline oxygen saturation >92% on room air （G） Absolute neutrophil count > 1000/μL, Platelet count > 45,000/μL ,Hemoglobin > 80g/L;

9. Once previous autologous hematopoietic stem cell transplantation (auto-HSCT) is allowed;
10. For systemic therapy(Such as systemic chemotherapy, systemic radiotherapy and immunotherapy), at least 3 weeks，for Targeted drug therapy alone，at least 2 weeks，must have elapsed at the time of cell infusion;
11. Either having failed or Relapsed after CAR-T therapy at 3 months of assessment;
12. Subjects of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study until the follow-up period of the study. Women of childbearing potential must have a negative serum or urine pregnancy test.
13. The viral load of severe coronavirus disease 2019 (COVID-19) is undetectable per quantitative PCR and/or nucleic acid testing for two tests.

Exclusion Criteria:

1. Allergic to any of the components of cell products;
2. Previous or concurrent of other type of maligant tumors;
3. Acute GvHD or generalized chronic GvHD with grade II-IV (Glucksberg standard) after previous autologous hematopoietic stem cell transplantation (auto-HSCT); Or receiving of anti-GVHD therapy;
4. Known history of systemic gene therapy within the prior 3 months;
5. Active systemic fungal, viral, or bacterial infection (except for simple urinary tract infections and bacterial pharyngitis), however, Preventive treatment is permitted;
6. Known history of infection with hepatitis B (HBsAg positive, but HBV-DNA<1000 is not excluded) or hepatitis C virus (including virus carriers), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to HIV infection;
7. Class III or IV heart failure as defined by the New York Heart Association;
8. Persisting toxicities (>grade 1, except for clinically non-significant toxicities such as alopecia, fatigue, and anorexia) due to prior trerapy;
9. Known history of active seizures or presence of seizure activities or other central nervous system disease;
10. Have evidence of central nervous system lymphoma(CNS lymphoma) on CT or MRI;
11. Breast-feeding woman;
12. Any circumstances that possibly increase the risk of subjects or interfere with study results, which judged by investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Part 1 (dose escalation) and Part 2 (dose expansion); Part 1 (dose escalation) the dose of dualCAR-NK19/70 participants receive will depend on when you join this study. Up to 3 dose levels of dualCAR-NK19/70 will be tested. About 3-6 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level of dualCAR-NK19/70. Each new group will receive a higher dose of dualCAR-NK19/70 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of dualCAR-NK19/70 is found. Part 2 (dose expansion) Participants will receive dualCAR-NK19/70 at the recommended dose that was found in Part 1.

Drug: dualCAR-NK19/70 cell; Given by IV (vein); Other Names: CAR-NK cell

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence of dose limiting toxicity(DLTs)	To evaluate the safety,tolerabitility,and determine the recommended dosage of cord blood-derived CAR NK cells targeting CD19/CD70	up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate（ORR）	To determine the anti-tumor effectivity of CB dualCAR-NK19/70	6 months
Complete Remission Rate(CRR)	To determine the anti-tumor effectivity of CB dualCAR-NK19/70	3 months
Overall survival(OS)	To determine the anti-tumor effectivity of CB dualCAR-NK19/70	Up to 3 years
Duration of Response(DOR)	To determine the anti-tumor effectivity of CB dualCAR-NK19/70	Up to 3 years
progression-free survival(PFS)	To determine the anti-tumor effectivity of CB dualCAR-NK19/70	Up to 3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events	Type, frequency, and severity of adverse events,Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5	through study completion; an average of 1 year,up to 3 years
Exploratory Objectives	The exploratory objectives are to assess the cellular kinetics and pharmacodynamic effects of dualCAR-NK19/70 and to evaluate biomarkers associated with response, resistance, and toxicity after administration of dualCAR-NK19/70 in blood and tumor samples.	Up to 3 years

Collaborators and Investigators

• Sponsor: Aibin Liang，MD，Ph.D.
• Investigators: Study Chair: aibin Liang, Shanghai Tongji Hospital, Tongji University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2023
• Primary Completion (Anticipated): January 18, 2028
• Study Completion (Anticipated): January 18, 2029

Study Registration Dates

• First Submitted: March 25, 2023
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Estimate): May 4, 2023

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: April 24, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: B-cell Non-Hodgkin Lymphoma; CAR NK Cells Targeting CD19/CD70; Cord Blood-derived
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin
• Other Study ID Numbers: 2023-008

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