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

This study is currently recruiting participants.
Verified October 2017 by M.D. Anderson Cancer Center
Sponsor:
ClinicalTrials.gov Identifier:
NCT03056339
First Posted: February 17, 2017
Last Update Posted: October 31, 2017
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Bellicum Pharmaceuticals
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
  Purpose
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.

Condition Intervention 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

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • 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.

  • 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 [ Time Frame: 2 weeks after NK cell infusion ]
    Toxicity defined as cytokine release storm (CRS) within 2 weeks of NK cell infusion requiring transfer to intensive care.

  • 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:
  • 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.


Estimated Enrollment: 36
Actual Study Start Date: June 21, 2017
Estimated Study Completion Date: June 2022
Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)
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 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.

  Hide Detailed Description

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:

Participant may be taking part in this study for up to 15 years. Participation on the study will be over after the long-term follow-up visits described below.

Tests Before Study Drug Administration:

Before participant receives 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 participant receives study drugs:

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

Study Drug Administration:

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

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

On Days -5, -4, and -3, participant will receive fludarabine by vein over 1 hour and cyclophosphamide by vein over 3 hours. Participant 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, participant will rest.

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

If participant has graft-versus-host disease (GvHD) or cytokine release syndrome after the NK cell infusion, participant 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 +7, participant will have a physical exam.

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:

°Participant 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 participants 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.

Participant will have blood tests performed to check to make sure participant does 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 participant does not have the RCR infection, the rest of participant's 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 participant's 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 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 participants will take part in this study. All will be enrolled at MD Anderson.

  Eligibility

Information from the National Library of Medicine

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:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
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 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. 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. 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.
  Contacts and Locations
Information from the National Library of Medicine

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


Contacts
Contact: Katy Rezvani, MD, PHD 713-792-8750 CR_Study_Registration@mdanderson.org
Contact: Bethany Overman, RN,BSN,CPN 713-745-4567

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Clinical Research Operations       CR_Study_Registration@mdanderson.org   
Sponsors and Collaborators
M.D. Anderson Cancer Center
Bellicum Pharmaceuticals
Investigators
Principal Investigator: Katy Rezvani, MD, PHD M.D. Anderson Cancer Center
  More Information

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03056339     History of Changes
Other Study ID Numbers: 2016-0641
First Submitted: February 14, 2017
First Posted: February 17, 2017
Last Update Posted: October 31, 2017
Last Verified: October 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
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

Additional relevant MeSH terms:
Leukemia
Neoplasms
Lymphoma, Non-Hodgkin
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Lymphoma
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Vidarabine
Mesna
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
Antimetabolites
Antiviral Agents