Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies

NCT ID: NCT03056339

Last Updated: 2024-03-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 49 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-21
• Study Completion Date: 2023-03-06

Brief Summary

If you are reading and signing this form on behalf of a potential participant, please note: Any time the words "you," "your," "I," or "me" appear, it is meant to apply to the potential participant.

The goal of this clinical research study is to learn if giving genetically changed immune cells, called CAR-NK cells, after chemotherapy will improve the disease in stem cell transplant patients with relapsed (has returned) and/or refractory (has not responded to treatment) B-cell lymphoma or leukemia. Also, researchers want to find the highest tolerable dose of CAR-NK cells to give to patients with relapsed or refractory B-cell lymphoma or leukemia. The safety of this treatment will also be studied.

This is an investigational study. The making of and infusion of genetically changed NK cells and the drug AP1903 (if you receive it, explained below) are not FDA approved or commercially available for use in this type of disease. They are currently being used for research purposes only. The chemotherapy drugs in this study (fludarabine, cyclophosphamide, and mesna) are commercially available and FDA approved.

Up to 36 patients will take part in this study. All will be enrolled at MD Anderson.

Detailed Description

Objectives:

Primary objective:

To determine the safety and relative efficacy of Chimeric antigen receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood natural killer (CB-NK) cells in patients with relapsed/refractory CD19+ B lymphoid malignancies.

Secondary Objectives:

1. To assess the overall response rate (complete and partial response rates).

2. To quantify persistence of infused allogeneic donor CAR-transduced CB-derived NK cells in the recipient.

3. To conduct comprehensive immune reconstitution studies.

Conditions

B-Lymphoid Malignancies; Acute Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; Non-hodgkin Lymphoma

Study Design

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

Study Groups

Fludarabine + Cyclophosphamide + CAR-NK Cells

On Days -5, -4, and -3, participants receive Fludarabine and Cyclophosphamide. Participants also receive Mesna before and after the cyclophosphamide dose.

On Day 0, participants receive genetically modified NK cells as a cell infusion.

If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they receive AP1903 by vein and possibly steroids by mouth or by vein.

Group Type: EXPERIMENTAL

Fludarabine

Intervention Type: DRUG

30 mg/m2 by vein on Days -5 to -3.

Cyclophosphamide

Intervention Type: DRUG

300 mg/m2 by vein on Days -5 to -3.

Mesna

Intervention Type: DRUG

300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.

iC9/CAR.19/IL15-Transduced CB-NK Cells

Intervention Type: BIOLOGICAL

Infusion of iC9/CAR.19/IL15-transduced CB-NK cells on Day 0 by vein.

Starting dose: 10E5

AP1903

Intervention Type: DRUG

If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they will receive AP1903 0.4 mg/kg administered as an intravenous infusion.

Interventions

Fludarabine

30 mg/m2 by vein on Days -5 to -3.

Intervention Type: DRUG

Cyclophosphamide

300 mg/m2 by vein on Days -5 to -3.

Intervention Type: DRUG

Mesna

300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.

Intervention Type: DRUG

iC9/CAR.19/IL15-Transduced CB-NK Cells

Infusion of iC9/CAR.19/IL15-transduced CB-NK cells on Day 0 by vein.

Starting dose: 10E5

Intervention Type: BIOLOGICAL

AP1903

If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, they will receive AP1903 0.4 mg/kg administered as an intravenous infusion.

Intervention Type: DRUG

Other Intervention Names

Fludarabine phosphate; Fludara; Cytoxan; Neosar; Mesnex; NK cells

Eligibility Criteria

Inclusion Criteria

1. Patients with history of CD 19 positive B-lymphoid malignancies (ALL, CLL, NHL) who have received at least 2 lines of standard chemoimmunotherapy or targeted therapy and have persistent disease.

2. Patients with ALL, CLL, NHL with relapsed disease following standard therapy or a stem cell transplant.

3. Patients at least 3 weeks from last cytotoxic chemotherapy at the time of starting lymphodepleting chemotherapy. Patients may continue tyrosine kinase inhibitors or other targeted therapies until at least two weeks prior to administration of lymphodepleting chemotherapy.

4. Karnofsky/Lansky Performance Scale > 70.

5. Adequate organ function: a. Renal: Creatinine clearance (as estimated by Cockcroft Gault) >/= 60 cc/min. b. Hepatic: ALT/AST </= 2.5 x ULN or </= 5 x ULN if documented liver metastases, Total bilirubin </= 1.5 mg/dL, except in subjects with Gilbert's Syndrome in whom total bilirubin must be </= 3.0 mg/dL. c. Cardiac: Cardiac ejection fraction >/= 50%, no evidence of pericardial effusion as determined by an ECHO or MUGA, and no clinically significant ECG findings. d. Pulmonary: No clinically significant pleural effusion, baseline oxygen saturation > 92% on room air.

6. Able to provide written informed consent.

7. 7-80 years of age.

8. All participants who are able to have children must practice effective birth control while on study. Acceptable forms of birth control for female patients include: hormonal birth control, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence, for the length of the study. If the participant is a female and becomes pregnant or suspects pregnancy, she must immediately notify her doctor. If the participant becomes pregnant during this study, she will be taken off this study. Men who are able to have children must use effective birth control while on the study. If the male participant fathers a child or suspects that he has fathered a child while on the study, he must immediately notify his doctor.

9. Signed consent to long-term follow-up protocol PA17-0483.

Exclusion Criteria

1. Positive beta HCG in female of child-bearing potential defined as not postmenopausal for 24 months or no previous surgical sterilization or lactating females.

2. Known positive serology for HIV.

3. Presence of Grade 3 or greater toxicity from the previous treatment.

4. Presence of fungal, bacterial, viral, or other infection requiring IV antimicrobials for management. Note: Simple UTI and uncomplicated bacterial pharyngitis are permitted if responding to active treatment.

5. Presence of active neurological disorder(s).

6. Concomitant use of other investigational agents.

• Minimum Eligible Age: 7 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

M.D. Anderson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Loretta Nastoupil, MD

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

Locations

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Countries

United States

References

Marin D, Li Y, Basar R, Rafei H, Daher M, Dou J, Mohanty V, Dede M, Nieto Y, Uprety N, Acharya S, Liu E, Wilson J, Banerjee P, Macapinlac HA, Ganesh C, Thall PF, Bassett R, Ammari M, Rao S, Cao K, Shanley M, Kaplan M, Hosing C, Kebriaei P, Nastoupil LJ, Flowers CR, Moseley SM, Lin P, Ang S, Popat UR, Qazilbash MH, Champlin RE, Chen K, Shpall EJ, Rezvani K. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat Med. 2024 Mar;30(3):772-784. doi: 10.1038/s41591-023-02785-8. Epub 2024 Jan 18.

Reference Type: DERIVED

PMID: 38238616 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32023374 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.mdanderson.org

MD Anderson Cancer Center

Other Identifiers

NCI-2018-01221

Identifier Type: REGISTRY

Identifier Source: secondary_id

2016-0641

Identifier Type: -

Identifier Source: org_study_id