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

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ClinicalTrials.gov Identifier: NCT03056339
Recruitment Status : Recruiting
First Posted : February 17, 2017
Last Update Posted : July 3, 2019
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE February 14, 2017
First Posted Date  ICMJE February 17, 2017
Last Update Posted Date July 3, 2019
Actual Study Start Date  ICMJE June 21, 2017
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2017)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 14, 2017)
  • 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 killer (CB-NK) cells in patients with relapsed/refractory CD19+ B lymphoid malignancies [ Time Frame: 2 weeks after NK cell infusion ]
    Toxicity defined ascytokine 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.
Change History Complete list of historical versions of study NCT03056339 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 14, 2017)
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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells for B Lymphoid Malignancies
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • B-Lymphoid Malignancies
  • Acute Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • Non-hodgkin Lymphoma
Intervention  ICMJE
  • 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.
Study Arms  ICMJE 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.

Interventions:
  • Drug: Fludarabine
  • Drug: Cyclophosphamide
  • Drug: Mesna
  • Biological: iC9/CAR.19/IL15-Transduced CB-NK Cells
  • Drug: AP1903
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 14, 2017)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2022
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 7 Years to 80 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katy Rezvani, MD, PHD 713-792-8750 krezvani@mdanderson.org
Contact: Bethany Overman, RN,BSN,CPN 713-745-4567
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03056339
Other Study ID Numbers  ICMJE 2016-0641
NCI-2018-01221 ( Registry Identifier: NCI CTRP )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Katy Rezvani, MD, PHD M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP