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History of Changes for Study: NCT03056339
Umbilical & CB Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
Latest version (submitted August 1, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 February 14, 2017 None (earliest Version on record)
2 April 20, 2017 Study Status and Contacts/Locations
3 June 13, 2017 Outcome Measures, Study Status, Eligibility, Study Description and Study Identification
4 June 21, 2017 Recruitment Status, Study Status and Contacts/Locations
5 July 7, 2017 Study Status
6 August 16, 2017 Study Status and Contacts/Locations
7 October 25, 2017 Study Status
8 October 26, 2017 Study Status
9 October 27, 2017 Study Status
10 December 5, 2017 Eligibility, Study Description, Study Status and Study Identification
11 December 6, 2017 Study Description and Study Status
12 December 27, 2017 Study Status
13 June 21, 2018 Study Status, Eligibility, Study Description and Study Identification
14 July 6, 2018 Contacts/Locations and Study Status
15 July 17, 2018 Sponsor/Collaborators and Study Status
16 August 1, 2018 Study Status
17 October 3, 2018 Study Status
18 November 21, 2018 Eligibility, Study Description and Study Status
19 December 11, 2018 Study Status
20 January 24, 2019 Study Status
21 March 20, 2019 Study Status
22 April 1, 2019 Study Status
23 May 1, 2019 Study Status
24 May 15, 2019 Study Status
25 May 16, 2019 Study Status
26 June 17, 2019 Study Status
27 June 21, 2019 Study Status
28 July 1, 2019 Study Status
29 April 13, 2020 Study Status
30 June 17, 2020 Contacts/Locations and Study Status
31 July 6, 2020 Study Status
32 July 15, 2021 Contacts/Locations and Study Status
33 November 18, 2021 Recruitment Status, Contacts/Locations and Study Status
34 August 1, 2022 Study Status, References and Study Identification
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Study NCT03056339
Submitted Date:  February 14, 2017 (v1)

Open or close this module Study Identification
Unique Protocol ID: 2016-0641
Brief Title: Umbilical & CB Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
Official Title: Dose Escalation Study Phase I/II of Umbilical and Cord Blood-Derived CAR-Engineered NK Cells in Conjunction in Patients With Relapsed/Refractory B-Lymphoid Malignancies
Secondary IDs:
Open or close this module Study Status
Record Verification: February 2017
Overall Status: Not yet recruiting
Study Start: May 2017
Primary Completion: May 2022 [Anticipated]
Study Completion: May 2022 [Anticipated]
First Submitted: February 14, 2017
First Submitted that
Met QC Criteria:
February 14, 2017
First Posted: February 17, 2017 [Actual]
Last Update Submitted that
Met QC Criteria:
February 14, 2017
Last Update Posted: February 17, 2017 [Actual]
Open or close this module Sponsor/Collaborators
Sponsor: M.D. Anderson Cancer Center
Responsible Party: Sponsor
Collaborators: Bellicum Pharmaceuticals
Open or close this module Oversight
U.S. FDA-regulated Drug: Yes
U.S. FDA-regulated Device: No
Data Monitoring: No
Open or close this module Study Description
Brief Summary: The goal of this clinical research study is to learn if giving genetically changed immune cells, called 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.
Detailed Description:

Gene Transfer:

The process of changing the DNA (the genetic material in cells) of NK cells is called "gene transfer." NK cells will be separated out from frozen cord blood using a machine. Researchers then perform a gene transfer to change the NK cells' DNA, and then inject the genetically changed NK cells into the body of the patient receiving the transplant.

Length of Study Participation You may be taking part in this study for up to 15 years. Your participation on the study will be over after the long-term follow-up visits described below.

Tests Before Study Drug Administration:

Before you receive study drugs, blood (about 4 tablespoons) will be drawn for research tests. This blood will be used as a baseline to study the immune system before starting treatment.

Within 7 days before you receive study drugs:

  • You will have a physical exam.
  • Blood (about 4 tablespoons) will be drawn for routine tests. If you can become pregnant, part of the blood will be used for a pregnancy test.

Study Drug Administration:

You will receive fludarabine and cyclophosphamide to help prepare your body for CAR-NK infusion. These drugs may kill some cancer cells, but that is not the main goal for their use. The day you receive the CAR-NK cells is called Day 0. The days before you receive your CAR-NK cells are called minus days. The days after you receive the CAR-NK cells are called plus days.

On Day -6, you will be admitted to the hospital and given fluids by vein to hydrate you.

On Days -5, -4, and -3, you will receive fludarabine by vein over 1 hour and cyclophosphamide by vein over 3 hours. You will also receive mesna by vein over before and after the cyclophosphamide dose to lower the risk of side effects to the bladder caused by cyclophosphamide.

On Days -2 and -1, you will rest.

On Day 0, you will receive the genetically modified NK cells as a cell infusion by vein.

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

GvHD occurs when donor cells attack the cells of the person receiving them. Cytokine release syndrome (CRS) occurs when a large amount of proteins are released into the blood. The risks of GvHD and CRS, some of which are serious, are described in greater detail below.

Study Tests After the NK Infusion:

On Day +2 and then at Weeks 1, 2, 3, 4, 8, 12, and 16:

°Blood (about 5 tablespoons) will be drawn for routine tests, for chimerism tests (to see how well the transplant has taken), and for research tests.

During Weeks 1, 3, 4, and 16:

°You will have a bone marrow aspiration and biopsy to check the status of the disease and for research tests. To collect a bone marrow aspiration/biopsy, an area of the hip is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.

Long-Term Follow-Up:

For safety reasons, the FDA requires that patients who receive infusions of CAR-NK cells treated with a gene transfer procedure must have long-term follow-up yearly for at least 15 years after receiving the gene transfer.

You will have blood tests performed to check to make sure you do not have a type of infection called the replication-competent retrovirus (RCR). For this test, blood (up to 4 teaspoons each time) will be drawn about 1, 3, and 6 months after the NK cell infusion, then again every 6 months for 5 years, and then once a year after that for 10 years.

If the RCR test results during the first year after the NK cell infusion show that you do not have the RCR infection, the rest of your leftover blood samples (left over from RCR testing in Years 2-15) will be stored at Bellicum Pharmaceuticals for safety reasons. This is so researchers can study any changes in your blood (related to RCR) that may arise in Years 2-15.

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.

Open or close this module Conditions
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
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 1/Phase 2
Interventional Study Model: Single Group Assignment
Number of Arms: 1
Masking: None (Open Label)
Allocation: N/A
Enrollment: 36 [Anticipated]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: 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.

Drug: Fludarabine
30 mg/m2 by vein on Days -5 to -3.
Other Names:
  • Fludarabine phosphate
  • Fludara
Drug: Cyclophosphamide
300 mg/m2 by vein on Days -5 to -3.
Other Names:
  • Cytoxan
  • Neosar
Drug: Mesna
300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.
Other Names:
  • Mesnex
Biological: 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

Other Names:
  • NK cells
Drug: 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.
Open or close this module Outcome Measures
Primary Outcome Measures:
1. 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 ]

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.
2. Toxicity 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: 2 weeks after NK cell infusion ]

Toxicity defined ascytokine release storm (CRS) within 2 weeks of NK cell infusion requiring transfer to intensive care.
3. 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
[ Time Frame: 30 days after NK cell infusion ]

Efficacy defined as the patient being alive and in remission at day 30 post NK cell infusion.
Secondary Outcome Measures:
1. 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 ]

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.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age: 65 Years
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Patients with history of 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. Patients may continue tyrosine kinase inhibitors or other targeted therapies until at least two weeks prior to administration of lymphodepleting chemotherapy.
  4. Karnofsky Performance Scale > 70.
  5. Adequate hepatic function, as defined by SGPT < 3 X upper limit of normal; serum bilirubin and alkaline phosphatase < 2 X upper limit of normal, or considered not clinically significant by the study doctor or designee, serum creatinine of </= 2 mg/dl.
  6. Able to provide written informed consent.
  7. 18-65 years of age.
  8. Availability of a CB unit matched with the patient at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens.
  9. 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.

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. Concomitant use of other investigational agents.
Open or close this module Contacts/Locations
Central Contact Person: Katy Rezvani, MD, PHD
Telephone: 713-792-8750
Study Officials: Katy Rezvani, MD, PHD
Principal Investigator
M.D. Anderson Cancer Center
Locations: United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links: Description: University of Texas MD Anderson Cancer Center Website
Available IPD/Information:

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