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Recruitment Status : Withdrawn (Lack of Funding)
First Posted : July 9, 2018
Last Update Posted : January 29, 2020
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|Condition or disease||Intervention/treatment||Phase|
|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||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||Phase 1 Phase 2|
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.
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 :||Interventional (Clinical Trial)|
|Actual Enrollment :||0 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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|
|Actual Study Start Date :||October 3, 2019|
|Actual Primary Completion Date :||October 3, 2019|
|Actual Study Completion Date :||October 3, 2019|
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.
Procedure: Autologous Hematopoietic Stem Cell Transplantation
Biological: Umbilical Cord Blood-derived Natural Killer Cells
Given CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells IV
- 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.
- 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.
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 70 Years (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Age 18-70.
- 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.
- 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.
- 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.
- Availability of autologous peripheral blood stem cell graft, containing at least 6.0 x 10^6 CD34+ cells/kg.
- Performance status < 2 (ECOG).
- Negative Beta HCG in woman with child-bearing potential.
- 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.
- Primary CNS lymphoma.
- Grade >/= 3 non-hematologic toxicity from prior therapy that has not resolved to </= G1.
- Prior whole brain irradiation.
- Active hepatitis B, either active carrier (HBsAg +) or viremic (HBV DNA >/= 10,000 copies/mL, or >/= 2,000 IU/mL).
- Evidence of either cirrhosis or stage 3-4 liver fibrosis in patients with chronic hepatitis C or positive hepatitis C serology.
- Active infection requiring parenteral antibiotics.
- HIV infection.
- Radiation therapy in the month prior to enroll.
- 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.
- 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): NCT03579927
|United States, Texas|
|M D Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Katy Rezvani||M.D. Anderson Cancer Center|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||M.D. Anderson Cancer Center|
|Other Study ID Numbers:||
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 )
|First Posted:||July 9, 2018 Key Record Dates|
|Last Update Posted:||January 29, 2020|
|Last Verified:||January 2020|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Immune System Diseases
Antineoplastic Agents, Immunological
Nitrogen Mustard Compounds