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

NCT03056339 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 2016-0641NCI-2018-01221
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

B-Lymphoid Malignancies; Relapsed/Refractory; Acute lymphocytic leukemia; ALL; Chronic lymphocytic leukemia; CLL; Non-Hodgkin lymphoma; NHL; (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood natural killer cells; CB-NK cells; Fludarabine; Fludarabine phosphate; Fludara; Cyclophosphamide; Cytoxan; Neosar; AP1903; Mesna; Mesnex

Outcome Measures

Primary Outcomes (1)

• Number of Events That Was Grade 3-4 Toxicities

  Toxicity is defined as a grade 3 or 4 within 40 days of NK cell infusion.

  40 days

Secondary Outcomes (2)

• Overall Response Rate of Participants Analyzed

  30 days

• Number of Participants Achieved an Objective Response

  Up to 100 days after NK cell infusion

Study Arms (1)

Fludarabine + Cyclophosphamide + CAR-NK Cells

EXPERIMENTAL

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.

Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells; Drug: AP1903

Interventions

Fludarabine DRUG

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

Also known as: Fludarabine phosphate, Fludara

Fludarabine + Cyclophosphamide + CAR-NK Cells

Cyclophosphamide DRUG

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

Also known as: Cytoxan, Neosar

Fludarabine + Cyclophosphamide + CAR-NK Cells

Mesna DRUG

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

Also known as: Mesnex

Fludarabine + Cyclophosphamide + CAR-NK Cells

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

Infusion of iC9/CAR.19/IL15-transduced CB-NK cells on Day 0 by vein. Starting dose: 10E5

Also known as: NK cells

Fludarabine + Cyclophosphamide + CAR-NK Cells

AP1903 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.

Fludarabine + Cyclophosphamide + CAR-NK Cells

Eligibility Criteria

• Age: 7 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Patients with ALL, CLL, NHL with relapsed disease following standard therapy or a stem cell transplant.
• 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.
• Karnofsky/Lansky Performance Scale \> 70.
• 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.
• Able to provide written informed consent.
• years of age.
• 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.
• Signed consent to long-term follow-up protocol PA17-0483.

You may not qualify if:

• Positive beta HCG in female of child-bearing potential defined as not postmenopausal for 24 months or no previous surgical sterilization or lactating females.
• Known positive serology for HIV.
• Presence of Grade 3 or greater toxicity from the previous treatment.
• 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.
• Presence of active neurological disorder(s).
• Concomitant use of other investigational agents.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (2)

• 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.

  PMID: 38238616 DERIVED

• 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.

  PMID: 32023374 DERIVED

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Recurrence

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide; Mesna; AP 1903 reagent

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphoma

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids

Results Point of Contact

• Title: Dr. Loretta Nastoupil, M.D. / Stem Cell Transplantation and Cellular Therapy Department
• Organization: The University of Texas MD Anderson Cancer Center

lnastoupil@mdanderson.org

713-792-2860

Study Officials

• Loretta Nastoupil, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 14, 2017
• First Posted: February 17, 2017
• Study Start: June 21, 2017
• Primary Completion: March 6, 2023
• Study Completion: March 6, 2023
• Last Updated: March 25, 2024
• Results First Posted: March 25, 2024

Record last verified: 2024-03

Locations

US (1)