Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT03056339 |
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Recruitment Status :
Completed
First Posted : February 17, 2017
Results First Posted : March 25, 2024
Last Update Posted : March 25, 2024
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| B-Lymphoid Malignancies Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Non-hodgkin Lymphoma | Drug: Fludarabine Drug: Cyclophosphamide Drug: Mesna Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells Drug: AP1903 | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 49 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | June 21, 2017 |
| Actual Primary Completion Date : | March 6, 2023 |
| Actual Study Completion Date : | March 6, 2023 |
| Arm | Intervention/treatment |
|---|---|
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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:
Drug: Cyclophosphamide 300 mg/m2 by vein on Days -5 to -3.
Other Names:
Drug: Mesna 300 mg/m2 by vein on Days -5 to -3 before and after the cyclophosphamide dose.
Other Name: 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 Name: 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. |
- Number of Events That Was Grade 3-4 Toxicities [ Time Frame: 40 days ]Toxicity is defined as a grade 3 or 4 within 40 days of NK cell infusion.
- Overall Response Rate of Participants Analyzed [ Time Frame: 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 [ Time Frame: Up to 100 days after NK cell infusion ]Number of participants that had Complete and Partial Response.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 7 Years to 80 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03056339
| United States, Texas | |
| University of Texas MD Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Loretta Nastoupil, MD | M.D. Anderson Cancer Center |
Documents provided by M.D. Anderson Cancer Center:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| 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 Posted: | February 17, 2017 Key Record Dates |
| Results First Posted: | March 25, 2024 |
| Last Update Posted: | March 25, 2024 |
| Last Verified: | March 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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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 |
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Leukemia Neoplasms Lymphoma, Non-Hodgkin Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma Neoplasms by Histologic Type Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Hematologic Diseases Leukemia, B-Cell Chronic Disease |
Disease Attributes Pathologic Processes Cyclophosphamide Fludarabine Fludarabine phosphate Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Myeloablative Agonists Antimetabolites, Antineoplastic |