B-Lymphoid Malignancies, Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Non-hodgkin Lymphoma
Conditions
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
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.
Interventions
DRUGFludarabine
30 mg/m2 by vein on Days -5 to -3.
DRUGCyclophosphamide
300 mg/m2 by vein on Days -5 to -3.
DRUGMesna
300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.
BIOLOGICALiC9/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
DRUGAP1903
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.
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Events That Was Grade 3-4 Toxicities | 40 days | Toxicity is defined as a grade 3 or 4 within 40 days of NK cell infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate of Participants Analyzed | 30 days | 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: |
| Number of Participants Achieved an Objective Response | Up to 100 days after NK cell infusion | Number of participants that had Complete and Partial Response. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: 1x105 NK Cells /kg 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. | 3 |
| Group 2: 1x106 NK Cells /kg 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. | 6 |
| Group 3: 1x107 NK Cells /kg 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. | 23 |
| Group 4: 8x108 Flat NK Cell Dose 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. | 17 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Failed Requirements | 0 | 2 | 7 | 1 |
Baseline characteristics
| Characteristic | 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 |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 12 Participants | 8 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 11 Participants | 9 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 6 Participants | 21 Participants | 16 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 3 participants | 6 participants | 23 participants | 17 participants | 49 participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 8 Participants | 6 Participants | 18 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 15 Participants | 11 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 6 | 0 / 23 | 0 / 17 |
| other Total, other adverse events | 2 / 3 | 6 / 6 | 12 / 23 | 10 / 17 |
| serious Total, serious adverse events | 1 / 3 | 0 / 6 | 0 / 23 | 0 / 17 |
Outcome results
Primary
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.
Time frame: 40 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: 1x105 NK Cells /kg | Number of Events That Was Grade 3-4 Toxicities | Grade 3 - Toxicities | 4 events |
| Group 1: 1x105 NK Cells /kg | Number of Events That Was Grade 3-4 Toxicities | Grade 4 - Toxicities | 0 events |
| Group 2: 1x106 NK Cells /kg | Number of Events That Was Grade 3-4 Toxicities | Grade 4 - Toxicities | 0 events |
| Group 2: 1x106 NK Cells /kg | Number of Events That Was Grade 3-4 Toxicities | Grade 3 - Toxicities | 1 events |
| Group 3: 1x107 NK Cells /kg | Number of Events That Was Grade 3-4 Toxicities | Grade 3 - Toxicities | 22 events |
| Group 3: 1x107 NK Cells /kg | Number of Events That Was Grade 3-4 Toxicities | Grade 4 - Toxicities | 0 events |
| Group 4: 8x108 Flat NK Cell Dose | Number of Events That Was Grade 3-4 Toxicities | Grade 3 - Toxicities | 1 events |
| Group 4: 8x108 Flat NK Cell Dose | Number of Events That Was Grade 3-4 Toxicities | Grade 4 - Toxicities | 0 events |
Secondary
Number of Participants Achieved an Objective Response
Number of participants that had Complete and Partial Response.
Time frame: Up to 100 days after NK cell infusion
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: 1x105 NK Cells /kg | Number of Participants Achieved an Objective Response | Complete Response | 2 participants |
| Group 1: 1x105 NK Cells /kg | Number of Participants Achieved an Objective Response | Partial Response | 0 participants |
| Group 2: 1x106 NK Cells /kg | Number of Participants Achieved an Objective Response | Partial Response | 0 participants |
| Group 2: 1x106 NK Cells /kg | Number of Participants Achieved an Objective Response | Complete Response | 3 participants |
| Group 3: 1x107 NK Cells /kg | Number of Participants Achieved an Objective Response | Complete Response | 4 participants |
| Group 3: 1x107 NK Cells /kg | Number of Participants Achieved an Objective Response | Partial Response | 1 participants |
| Group 4: 8x108 Flat NK Cell Dose | Number of Participants Achieved an Objective Response | Complete Response | 5 participants |
| Group 4: 8x108 Flat NK Cell Dose | Number of Participants Achieved an Objective Response | Partial Response | 3 participants |
Secondary
Overall Response Rate of Participants Analyzed
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1: 1x105 NK Cells /kg | Overall Response Rate of Participants Analyzed | Partial Response | 0 participants |
| Group 1: 1x105 NK Cells /kg | Overall Response Rate of Participants Analyzed | Complete Response | 2 participants |
| Group 1: 1x105 NK Cells /kg | Overall Response Rate of Participants Analyzed | Progressive Disease | 1 participants |
| Group 1: 1x105 NK Cells /kg | Overall Response Rate of Participants Analyzed | Not Evaluable | 0 participants |
| Group 1: 1x105 NK Cells /kg | Overall Response Rate of Participants Analyzed | Stable Disease | 0 participants |
| Group 2: 1x106 NK Cells /kg | Overall Response Rate of Participants Analyzed | Partial Response | 0 participants |
| Group 2: 1x106 NK Cells /kg | Overall Response Rate of Participants Analyzed | Not Evaluable | 2 participants |
| Group 2: 1x106 NK Cells /kg | Overall Response Rate of Participants Analyzed | Progressive Disease | 1 participants |
| Group 2: 1x106 NK Cells /kg | Overall Response Rate of Participants Analyzed | Complete Response | 3 participants |
| Group 2: 1x106 NK Cells /kg | Overall Response Rate of Participants Analyzed | Stable Disease | 0 participants |
| Group 3: 1x107 NK Cells /kg | Overall Response Rate of Participants Analyzed | Stable Disease | 2 participants |
| Group 3: 1x107 NK Cells /kg | Overall Response Rate of Participants Analyzed | Complete Response | 3 participants |
| Group 3: 1x107 NK Cells /kg | Overall Response Rate of Participants Analyzed | Not Evaluable | 7 participants |
| Group 3: 1x107 NK Cells /kg | Overall Response Rate of Participants Analyzed | Partial Response | 5 participants |
| Group 3: 1x107 NK Cells /kg | Overall Response Rate of Participants Analyzed | Progressive Disease | 6 participants |
| Group 4: 8x108 Flat NK Cell Dose | Overall Response Rate of Participants Analyzed | Stable Disease | 5 participants |
| Group 4: 8x108 Flat NK Cell Dose | Overall Response Rate of Participants Analyzed | Complete Response | 5 participants |
| Group 4: 8x108 Flat NK Cell Dose | Overall Response Rate of Participants Analyzed | Partial Response | 3 participants |
| Group 4: 8x108 Flat NK Cell Dose | Overall Response Rate of Participants Analyzed | Progressive Disease | 2 participants |
| Group 4: 8x108 Flat NK Cell Dose | Overall Response Rate of Participants Analyzed | Not Evaluable | 2 participants |