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CAR.CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood NK Cells, High-Dose Chemotherapy, and Stem Cell Transplant in Treating Participants With B-cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03579927
Recruitment Status : Not yet recruiting
First Posted : July 9, 2018
Last Update Posted : January 21, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE June 25, 2018
First Posted Date  ICMJE July 9, 2018
Last Update Posted Date January 21, 2019
Estimated Study Start Date  ICMJE February 2019
Estimated Primary Completion Date January 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Incidence of adverse events defined as graft failure, grade 3, 4 graft versus host disease, grade 3,4 cytokine release syndrome, grade 3, 4, neuro-toxicity, or death from any cause [ Time Frame: Up to 30 days within natural killer (NK) cell infusion ]
    Frequencies of toxicity will be summarized by dose. The relationships between toxicity and efficacy as functions of dose and other covariates will be assessed by fitting Bayesian regression models.
  • Complete response (CR) or partial response (PR) [ Time Frame: At day 30 post NK cell infusion ]
    Efficacy is defined as the patient being alive and in CR or PR at day 30 post NK cell infusion. Frequencies of efficacy will be summarized by dose. The relationships between toxicity and efficacy as functions of dose and other covariates will be assessed by fitting Bayesian regression models.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03579927 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 5, 2018)
  • Progression-free survival (PFS) time [ Time Frame: At day 100 ]
    Unadjusted distributions of the time-to-event outcome PFS will be estimated using the method of Kaplan and Meier. The relationship of PFS to prognostic covariates and NK cell dose level will be evaluated by Bayesian piecewise exponential survival regression.
  • Overall survival (OS) time [ Time Frame: At day 100 ]
    Unadjusted distributions of the time-to-event outcome OS will be estimated using the method of Kaplan and Meier. The relationship of OS to prognostic covariates and NK cell dose level will be evaluated by Bayesian piecewise exponential survival regression.
  • Response status [ Time Frame: 16 weeks ]
    Participants have a bone marrow aspiration and/or biopsy to check the status of the disease.
  • Number of chimeric antigen receptor (CAR) NK cells in blood by flow cytometry [ Time Frame: Up to 16 weeks post CAR NK cell infusion ]
    The number of CAR NK cells in blood by flow cytometry will be measured on days 3, 7, 14, 21, and at 4 weeks, 8 weeks, 12 weeks, and 16 weeks post CAR NK cell infusion. In addition to preliminary graphical analysis to assess possible patterns over time Bayesian longitudinal regression using a generalized Poisson regression model for the count at each time point as a function of patient baseline covariates, and random latent patient effects to induce within-patient correlation among each patient's vector of CAR NK cell counts.
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 CAR.CD19-CD28-zeta-2A-iCasp9-IL15-Transduced Cord Blood NK Cells, High-Dose Chemotherapy, and Stem Cell Transplant in Treating Participants With B-cell Lymphoma
Official Title  ICMJE Immunotherapy With Ex Vivo-Expanded Cord Blood-Derived CAR-NK Cells Combined With High-Dose Chemotherapy and Autologous Stem Cell Transplantation for B-Cell Lymphoma
Brief Summary This phase I/II trial studies the side effects and best dose of chimeric antigen receptor (CAR).CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood NK cells when given together with high-dose chemotherapy and stem cell transplant and to see how well they work in treating participants with B-cell lymphoma. Cord blood-derived CAR-NK cells may react against the B-cell lymphoma cells in the body, which may help to control the disease. Giving chemotherapy before a stem cell transplant may help kill any cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Detailed Description

PRIMARY OBJECTIVES:

I. To establish the safety and relative efficacy of CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood natural killer (CB-NK) cells in patients with B cell non-Hodgkin lymphoma (NHL) undergoing high dose chemotherapy and autologous stem cell transplantation.

SECONDARY OBJECTIVES:

I. To estimate the relapse-free survival (RFS). II. To estimate the overall survival (OS). III. To quantify the persistence of infused CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells in the recipient.

OUTLINE: This is a phase I, dose-escalation study of CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells followed by a phase II study.

Participants receive rituximab intravenously (IV) over 3 hours on days -14 and -8, carmustine IV over 2 hours on day -13, etoposide IV over 3 hours twice daily (BID) on days -12 to -9, cytarabine IV over 1 hour BID on days -12 to -9, melphalan IV over 30 minutes on day -8, CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells IV over 1 hour on day -5. Participants undergo autologous stem cell transplantation (ASCT) on day 0. Beginning day 0, participants receive filgrastim subcutaneously (SC) once daily (QD) until evidence of an absolute neutrophil count (ANC) of 0.5 x 10^9/L per 3 consecutive days.

After completion of study treatment, participants are followed for up to 15 years.

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
  • CD19 Positive
  • Mantle Cell Lymphoma
  • Recurrent Diffuse Large B-Cell Lymphoma
  • Recurrent Follicular Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Diffuse Large B-Cell Lymphoma
  • Refractory Follicular Lymphoma
Intervention  ICMJE
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
    Undergo ASCT
    Other Names:
    • Autologous Hematopoietic Cell Transplantation
    • autologous stem cell transplantation
  • Drug: Carmustine
    Given IV
    Other Names:
    • BCNU
    • Becenum
    • Becenun
    • BiCNU
    • Bis(chloroethyl) Nitrosourea
    • Bis-Chloronitrosourea
    • Carmubris
    • Carmustin
    • Carmustinum
    • FDA 0345
    • Gliadel
    • N,N'-Bis(2-chloroethyl)-N-nitrosourea
    • Nitrourean
    • Nitrumon
    • SK 27702
    • SRI 1720
    • WR-139021
  • Drug: Cytarabine
    Given IV
    Other Names:
    • .beta.-Cytosine arabinoside
    • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
    • 1-.beta.-D-Arabinofuranosylcytosine
    • 1-Beta-D-arabinofuranosyl-4-amino-2(1H)pyrimidinone
    • 1-Beta-D-arabinofuranosylcytosine
    • 1.beta.-D-Arabinofuranosylcytosine
    • 2(1H)-Pyrimidinone, 4-Amino-1-beta-D-arabinofuranosyl-
    • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
    • Alexan
    • Ara-C
    • ARA-cell
    • Arabine
    • Arabinofuranosylcytosine
    • Arabinosylcytosine
    • Aracytidine
    • Aracytin
    • Aracytine
    • Beta-cytosine Arabinoside
    • CHX-3311
    • Cytarabinum
    • Cytarbel
    • Cytosar
    • Cytosine Arabinoside
    • Cytosine-.beta.-arabinoside
    • Cytosine-beta-arabinoside
    • Erpalfa
    • Starasid
    • Tarabine PFS
    • U 19920
    • U-19920
    • Udicil
    • WR-28453
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Biological: Filgrastim
    Given SC
    Other Names:
    • FILGRASTIM, LICENSE HOLDER UNSPECIFIED
    • G-CSF
    • Neupogen
    • r-metHuG-CSF
    • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    • rG-CSF
    • Tevagrastim
  • Drug: Melphalan
    Given IV
    Other Names:
    • Alanine Nitrogen Mustard
    • CB-3025
    • L-PAM
    • L-Phenylalanine Mustard
    • L-sarcolysin
    • L-Sarcolysin Phenylalanine mustard
    • L-Sarcolysine
    • Melphalanum
    • Phenylalanine Mustard
    • Phenylalanine nitrogen mustard
    • Sarcoclorin
    • Sarkolysin
    • WR-19813
  • Biological: Rituximab
    Given IV
    Other Names:
    • ABP 798
    • BI 695500
    • C2B8 Monoclonal Antibody
    • Chimeric Anti-CD20 Antibody
    • CT-P10
    • IDEC-102
    • IDEC-C2B8
    • IDEC-C2B8 Monoclonal Antibody
    • MabThera
    • Monoclonal Antibody IDEC-C2B8
    • PF-05280586
    • Rituxan
    • Rituximab Biosimilar ABP 798
    • Rituximab Biosimilar BI 695500
    • Rituximab Biosimilar CT-P10
    • Rituximab Biosimilar GB241
    • Rituximab Biosimilar IBI301
    • Rituximab Biosimilar PF-05280586
    • Rituximab Biosimilar RTXM83
    • Rituximab Biosimilar SAIT101
    • RTXM83
  • Biological: Umbilical Cord Blood-derived Natural Killer Cells
    Given CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells IV
    Other Names:
    • Cord Blood NK Cells
    • Umbilical Cord Blood-derived NK Cells
Study Arms  ICMJE Experimental: Treatment (CAR transduced CB-NK cells, chemotherapy, ASCT)
Participants receive rituximab IV over 3 hours on days -14 and -8, carmustine IV over 2 hours on day -13, etoposide IV over 3 hours BID on days -12 to -9, cytarabine IV over 1 hour BID on days -12 to -9, melphalan IV over 30 minutes on day -8, CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells IV over 1 hour on day -5. Participants undergo ASCT on day 0. Beginning day 0, participants receive filgrastim SC QD until evidence of an ANC of 0.5 x 10^9/L per 3 consecutive days.
Interventions:
  • Procedure: Autologous Hematopoietic Stem Cell Transplantation
  • Drug: Carmustine
  • Drug: Cytarabine
  • Drug: Etoposide
  • Biological: Filgrastim
  • Drug: Melphalan
  • Biological: Rituximab
  • Biological: Umbilical Cord Blood-derived Natural Killer Cells
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 Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 5, 2018)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2020
Estimated Primary Completion Date January 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age 18-70.
  2. Patients with B-cell lymphoma who are candidates to autologous stem-cell transplantation, including: 1. Primary refractory or relapsed diffuse large B-cell lymphoma in response to salvage treatment. 2. Primary refractory or relapsed follicular lymphoma or other indolent B-cell histology in response to salvage treatment. 3. Chemosensitive mantle-cell lymphoma in first or later line of treatment. 4. Patients with B cell lymphoma (all CD19+ NHL) with progressive or refractory disease who would otherwise not be candidates for autologous stem cell transplantation.
  3. Adequate organ function: Renal: Creatinine clearance (as estimated by Cockcroft Gault) >/= 60 cc/min. 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. Cardiac: Cardiac ejection fraction >/= 50%, no evidence of pericardial effusion as determined by an ECHO, and no clinically significant ECG findings. Pulmonary: No clinically significant pleural effusion, Baseline oxygen saturation > 92% on room air.
  4. Patients must have a cord blood unit available which is matched with the patient at 4, 5, or 6/6 HLA class I (serological) and II (molecular) antigens.
  5. Availability of autologous peripheral blood stem cell graft, containing at least 6.0 x 10^6 CD34+ cells/kg.
  6. Performance status < 2 (ECOG).
  7. Negative Beta HCG in woman with child-bearing potential.
  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. Primary CNS lymphoma.
  2. Grade >/= 3 non-hematologic toxicity from prior therapy that has not resolved to </= G1.
  3. Prior whole brain irradiation.
  4. Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/= 10,000 copies/mL, or >/= 2,000 IU/mL).
  5. Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
  6. Active infection requiring parenteral antibiotics.
  7. HIV infection.
  8. Radiation therapy in the month prior to enroll.
  9. 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.
  10. Concomitant use of other investigational agents.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katy Rezvani 713-792-8750 krezvani@mdanderson.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03579927
Other Study ID Numbers  ICMJE 2017-0295
NCI-2018-01111 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0295 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
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 National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Katy Rezvani M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date January 2019

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