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

Study Overview
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Brief Summary
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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
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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: To assess the overall response rate (complete and partial response rates). To quantify persistence of infused allogeneic donor CAR-transduced CB-derived NK cells in the recipient. To conduct comprehensive immune reconstitution studies.

Official Title
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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

Conditions
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B-Lymphoid Malignancies, Acute Lymphocytic Leukemia, Chronic Lymphocytic Leukemia, Non-hodgkin Lymphoma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 7-80 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine + Cyclophosphamide + CAR-NK Cells<br>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<br>* 30 mg/m2 by vein on Days -5 to -3.<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* 300 mg/m2 by vein on Days -5 to -3.<br>* Other names: Neosar;Drug: Mesna<br>* 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.<br>* Other names: Mesnex;Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells<br>* Infusion of iC9/CAR.19/IL15-transduced CB-NK cells on Day 0 by vein. Starting dose: 10E5<br>* Other names: NK cells;Drug: AP1903<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 45 days | 
| Toxicity of Chimeric Antigen Receptors (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood Natural Liller (CB-NK) Cells in Patients with Relapsed/Refractory CD19+ B Lymphoid Malignancies | Toxicity defined as cytokine release storm (CRS) within 2 weeks of NK cell infusion requiring transfer to intensive care. | 2 weeks after NK cell infusion | 
| 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 | Efficacy defined as the patient being alive and in remission at day 30 post NK cell infusion. | 30 days after NK cell infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 100 days after NK cell infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, B-Lymphoid Malignancies, Relapsed/Refractory, Acute lymphocytic leukemia, ALL, Chronic lymphocytic leukemia, CLL, Non-Hodgkin lymphoma, (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