Clinical Trials /

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

NCT03056339

Description:

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
  • Official Title: Dose Escalation Study Phase I/II of Umbilical Cord Blood-Derived CAR-Engineered NK Cells in Conjunction With Lymphodepleting Chemotherapy in Patients With Relapsed/Refractory B-Lymphoid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2016-0641
  • SECONDARY ID: NCI-2018-01221
  • NCT ID: NCT03056339

Conditions

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

Interventions

DrugSynonymsArms
FludarabineFludarabine phosphate, FludaraFludarabine + Cyclophosphamide + CAR-NK Cells
CyclophosphamideCytoxan, NeosarFludarabine + Cyclophosphamide + CAR-NK Cells
MesnaMesnexFludarabine + Cyclophosphamide + CAR-NK Cells
iC9/CAR.19/IL15-Transduced CB-NK CellsNK cellsFludarabine + Cyclophosphamide + CAR-NK Cells
AP1903Fludarabine + Cyclophosphamide + CAR-NK Cells

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Fludarabine + Cyclophosphamide + CAR-NK CellsExperimentalOn 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.
  • Fludarabine
  • Cyclophosphamide
  • Mesna
  • iC9/CAR.19/IL15-Transduced CB-NK Cells
  • AP1903

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.
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:7 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Optimal NK Cell Dose Level 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
Time Frame:45 days
Safety Issue:
Description:Dose-finding done using the sequentially adaptive phase I-II EffTox trade-off-based design. Toxicity is defined as a grade 3 or 4 GVHD within 45 days of NK cell infusion.

Secondary Outcome Measures

Measure:Response 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
Time Frame:100 days after NK cell infusion
Safety Issue:
Description:Unadjusted distributions of the time-to-event outcomes estimated using the method of Kaplan and Meier and their relationship to prognostic covariates and NK cell dose level evaluated by Bayesian piecewise exponential survival regression.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial 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

Last Updated

July 1, 2019