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

• ClinicalTrials.gov Identifier: NCT03056339
• Recruitment Status: Completed
• First Posted: February 17, 2017
• Results First Posted: March 25, 2024
• Last Update Posted: March 25, 2024
• Sponsor: M.D. Anderson Cancer Center
• Information provided by (Responsible Party): M.D. Anderson Cancer Center

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: B-Lymphoid Malignancies; Acute Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; Non-hodgkin Lymphoma
• Interventions: Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells; Drug: AP1903
• Enrollment: 49

Participant Flow

Recruitment Details	Recruitment period: June 2017 to May 2021. All participants were registered at The University of Texas MD Anderson Cancer Center.
Pre-assignment Details	Patient accession #3 and #21 are the same patient. The patient was taken off protocol and re-consented for a second infusion. Patient was only evaluated in regards to safety and efficacy as 1 subject.

Arm/Group Title	Group 1: 1x105 NK Cells /kg	Group 2: 1x106 NK Cells /kg	Group 3: 1x107 NK Cells /kg	Group 4: 8x108 Flat NK Cell Dose
Arm/Group Description	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 106 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 107 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 108 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.
Period Title: Overall Study
Started	3	6	23	17
Completed	3	4	16	16
Not Completed	0	2	7	1
Reason Not Completed
Failed Requirements	0	2	7	1

Baseline Characteristics

Arm/Group Title		Group 1: 1x105 NK Cells /kg	Group 2: 1x106 NK Cells /kg	Group 3: 1x107 NK Cells /kg	Group 4: 8x108 Flat NK Cell Dose	Total
Arm/Group Description		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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 106 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 107 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 108 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.	Total of all reporting groups
Overall Number of Baseline Participants		3	6	23	17	49
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	6 participants	23 participants	17 participants	49 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	3 100.0%	5 83.3%	11 47.8%	9 52.9%	28 57.1%
	>=65 years	0 0.0%	1 16.7%	12 52.2%	8 47.1%	21 42.9%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	6 participants	23 participants	17 participants	49 participants
	Female	1 33.3%	3 50.0%	8 34.8%	6 35.3%	18 36.7%
	Male	2 66.7%	3 50.0%	15 65.2%	11 64.7%	31 63.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	6 participants	23 participants	17 participants	49 participants
	Hispanic or Latino	0 0.0%	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Not Hispanic or Latino	2 66.7%	6 100.0%	21 91.3%	16 94.1%	45 91.8%
	Unknown or Not Reported	1 33.3%	0 0.0%	2 8.7%	1 5.9%	4 8.2%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	3 participants	6 participants	23 participants	17 participants	49 participants
		3	6	23	17	49

Outcome Measures

1. Primary Outcome

Title	Number of Events That Was Grade 3-4 Toxicities
Description	Toxicity is defined as a grade 3 or 4 within 40 days of NK cell infusion.
Time Frame	40 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1: 1x105 NK Cells /kg	Group 2: 1x106 NK Cells /kg	Group 3: 1x107 NK Cells /kg	Group 4: 8x108 Flat NK Cell Dose
Arm/Group Description:	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 106 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 107 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 108 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.
Overall Number of Participants Analyzed	3	6	23	17
Measure Type: Number; Unit of Measure: events
Grade 3 - Toxicities	4	1	22	1
Grade 4 - Toxicities	0	0	0	0

2. Secondary Outcome

Title	Overall Response Rate of Participants Analyzed
Description	Participants response was defined as partial or complete response by Efftox assessment below.; Acute lymphoblastic leukemia: Complete response will be defined as bone marrow with < 5% blasts, the absence of circulating blasts, and no extramedullary sites of disease (as assessed by means of computed tomography or positron-emission tomography), regardless of cell-count recovery.; CLL: Response will be defined based on the NCI-WG/IWCLL 2008 criteria, Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia. Lymphomas: Response will be defined based on the Lugano criteria- Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma:
Time Frame	30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1: 1x105 NK Cells /kg	Group 2: 1x106 NK Cells /kg	Group 3: 1x107 NK Cells /kg	Group 4: 8x108 Flat NK Cell Dose
Arm/Group Description:	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 106 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 107 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 108 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.
Overall Number of Participants Analyzed	3	6	23	17
Measure Type: Number; Unit of Measure: participants
Complete Response	2	3	3	5
Partial Response	0	0	5	3
Progressive Disease	1	1	6	2
Not Evaluable	0	2	7	2
Stable Disease	0	0	2	5

3. Secondary Outcome

Title	Number of Participants Achieved an Objective Response
Description	Number of participants that had Complete and Partial Response.
Time Frame	Up to 100 days after NK cell infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1: 1x105 NK Cells /kg	Group 2: 1x106 NK Cells /kg	Group 3: 1x107 NK Cells /kg	Group 4: 8x108 Flat NK Cell Dose
Arm/Group Description:	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 106 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 107 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.	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 108 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.
Overall Number of Participants Analyzed	3	6	23	17
Measure Type: Number; Unit of Measure: participants
Complete Response	2	3	4	5
Partial Response	0	0	1	3

Adverse Events

Time Frame	Adverse events were collected from the time of infusion up to 40 days.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Group 1: 1x105 NK Cells /kg		Group 2: 1x106 NK Cells /kg		Group 3: 1x107 NK Cells /kg		Group 4: 8x108 Flat NK Cell Dose
Arm/Group Description	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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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 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.		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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 106 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.		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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 107 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.		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. Fludarabine: 30 mg/m2 by vein on Days -5 to -3. Cyclophosphamide: 300 mg/m2 by vein on Days -5 to -3. Mesna: 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose. 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: 108 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.
All-Cause Mortality
	Group 1: 1x105 NK Cells /kg		Group 2: 1x106 NK Cells /kg		Group 3: 1x107 NK Cells /kg		Group 4: 8x108 Flat NK Cell Dose
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/3 (0.00%)		0/6 (0.00%)		0/23 (0.00%)		0/17 (0.00%)
Serious Adverse Events
	Group 1: 1x105 NK Cells /kg		Group 2: 1x106 NK Cells /kg		Group 3: 1x107 NK Cells /kg		Group 4: 8x108 Flat NK Cell Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.33%)		0/6 (0.00%)		0/23 (0.00%)		0/17 (0.00%)
General disorders
General disorders and administration site conditions † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	0/23 (0.00%)	0	0/17 (0.00%)	0
1 Term from vocabulary, CTCAE 4.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Group 1: 1x105 NK Cells /kg		Group 2: 1x106 NK Cells /kg		Group 3: 1x107 NK Cells /kg		Group 4: 8x108 Flat NK Cell Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.67%)		6/6 (100.00%)		12/23 (52.17%)		10/17 (58.82%)
Blood and lymphatic system disorders
Anemia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	2/17 (11.76%)	2
Blood and lymphatic system disorders - (Other) † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Cardiac disorders
Abdominal Pain † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	2/17 (11.76%)	2
Atrial flutter † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Cardiac disorders - (Other), specify † 1	1/3 (33.33%)	1	1/6 (16.67%)	1	4/23 (17.39%)	4	1/17 (5.88%)	1
Chest pain † 1	0/3 (0.00%)	0	1/6 (16.67%)	1	0/23 (0.00%)	0	1/17 (5.88%)	1
Dizziness † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	2/17 (11.76%)	2
Fatigue † 1	2/3 (66.67%)	2	0/6 (0.00%)	0	10/23 (43.48%)	10	10/17 (58.82%)	10
Hypertension † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	4/17 (23.53%)	5
Pleural effusion † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Sinus tachycardia † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	2/23 (8.70%)	2	0/17 (0.00%)	0
Ventricular tachycardia † 1	0/3 (0.00%)	0	1/6 (16.67%)	1	0/23 (0.00%)	0	0/17 (0.00%)	0
Ear and labyrinth disorders
Hearing impaired † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Endocrine disorders
Hypothyroidism † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	1/17 (5.88%)	1
Gastrointestinal disorders
Constipation † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	5/23 (21.74%)	5	4/17 (23.53%)	4
Diarrhea † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	6/17 (35.29%)	6
Dry mouth † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Dysphagia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Hemorrhoids † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	2/17 (11.76%)	2
Ileus † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Nausea † 1	1/3 (33.33%)	1	2/6 (33.33%)	2	12/23 (52.17%)	12	7/17 (41.18%)	7
General disorders
Chills † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	2/17 (11.76%)	2
Fever † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	8/23 (34.78%)	8	1/17 (5.88%)	1
Gastrointestinal disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	2/17 (11.76%)	2
General disorders and administration site conditions † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	1/23 (4.35%)	1	4/17 (23.53%)	4
Pain † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	2/17 (11.76%)	2
Hepatobiliary disorders
Cholecystitis † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Encephalopathy † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Portal vein thrombosis † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Immune system disorders
Allergic reaction † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	0/23 (0.00%)	0	0/17 (0.00%)	0
Arthralgia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Dyspnea † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	2/17 (11.76%)	2
Immune system disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	3/23 (13.04%)	3	2/17 (11.76%)	2
Infections and infestations
Infections and infestations † 1	2/3 (66.67%)	2	3/6 (50.00%)	3	4/23 (17.39%)	4	1/17 (5.88%)	1
Urinary tract infection † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	0/23 (0.00%)	0	0/17 (0.00%)	0
Injury, poisoning and procedural complications
Back pain † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	1/17 (5.88%)	1
Injury, poisoning and procedural complications † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	4/23 (17.39%)	4	0/17 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	1/3 (33.33%)	1	1/6 (16.67%)	1	0/23 (0.00%)	0	3/17 (17.65%)	3
Alkaline phosphatase increased † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	1/23 (4.35%)	1	2/17 (11.76%)	2
Aspartate aminotransferase increased † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	3/17 (17.65%)	3
Blood bilirubin increased † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	1/23 (4.35%)	1	1/17 (5.88%)	1
Blood and lymphatic system disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Creatinine increased † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	4/17 (23.53%)	4
Investigations - (Other) † 1	2/3 (66.67%)	2	6/6 (100.00%)	8	3/23 (13.04%)	3	1/17 (5.88%)	1
Weight gain † 1	0/3 (0.00%)	0	1/6 (16.67%)	1	0/23 (0.00%)	0	0/17 (0.00%)	0
Metabolism and nutrition disorders
Hyperglycemia † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	0/23 (0.00%)	0	0/17 (0.00%)	0
Hyperuricemia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Hypoalbuminemia † 1	0/3 (0.00%)	0	2/6 (33.33%)	2	0/23 (0.00%)	0	0/17 (0.00%)	0
Hypocalcemia † 1	0/3 (0.00%)	0	1/6 (16.67%)	1	0/23 (0.00%)	0	0/17 (0.00%)	0
Hypomagnesemia † 1	0/3 (0.00%)	0	1/6 (16.67%)	1	0/23 (0.00%)	0	0/17 (0.00%)	0
Hyponatremia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Metabolism and nutrition disorders - (Other) † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	0/17 (0.00%)	0
Vomiting † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	3/17 (17.65%)	3
Musculoskeletal and connective tissue disorders
Anorexia † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	1/23 (4.35%)	1	2/17 (11.76%)	2
Generalized muscle weakness † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	0/17 (0.00%)	0
Musculoskeletal and connective tissue disorder † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	1/17 (5.88%)	1
Myalgia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	0/17 (0.00%)	0
Neck pain † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Pain in extremity † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Nervous system disorders
Headache † 1	2/3 (66.67%)	2	0/6 (0.00%)	0	0/23 (0.00%)	0	4/17 (23.53%)	4
Nervous system disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	2/17 (11.76%)	2
Paresthesia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Presyncope † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	0/17 (0.00%)	0
Stroke † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Syncope † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Psychiatric disorders
Anxiety † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	3/23 (13.04%)	3	2/17 (11.76%)	2
Confusion † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	2/23 (8.70%)	2	0/17 (0.00%)	0
Depression † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	2/17 (11.76%)	2
Insomnia † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	5/23 (21.74%)	5	2/17 (11.76%)	2
Renal and urinary disorders
Acute kidney injury † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	0/23 (0.00%)	0	0/17 (0.00%)	0
Cystitis noninfective † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Reproductive system and breast disorders
Prostatic obstruction † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Prostatic pain † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Cough † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Nasal congestion † 1	1/3 (33.33%)	1	0/6 (0.00%)	0	0/23 (0.00%)	0	0/17 (0.00%)	0
Pulmonary edema † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Respiratory, thoracic and mediastinal disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	10/23 (43.48%)	10	0/17 (0.00%)	0
Sore throat † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	0/23 (0.00%)	0	1/17 (5.88%)	1
Skin and subcutaneous tissue disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	4/23 (17.39%)	4	1/17 (5.88%)	1
Vascular disorders
Hematoma † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	1/23 (4.35%)	1	0/17 (0.00%)	0
Hypotension † 1	0/3 (0.00%)	0	1/6 (16.67%)	1	4/23 (17.39%)	4	1/17 (5.88%)	1
Vascular disorders † 1	0/3 (0.00%)	0	0/6 (0.00%)	0	4/23 (17.39%)	4	0/17 (0.00%)	0
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Loretta Nastoupil, M.D. / Stem Cell Transplantation and Cellular Therapy Department
• Organization: The University of Texas MD Anderson Cancer Center
• Phone: 713-792-2860
• EMail: lnastoupil@mdanderson.org

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT03056339
• Other Study ID Numbers: 2016-0641; NCI-2018-01221 ( Registry Identifier: NCI CTRP-Clinical Trials Reporting Registry )
• First Submitted: February 14, 2017
• First Posted: February 17, 2017
• Results First Submitted: September 22, 2023
• Results First Posted: March 25, 2024
• Last Update Posted: March 25, 2024