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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

Primary Purpose

CD19 Positive, Mantle Cell Lymphoma, Recurrent Diffuse Large B-Cell Lymphoma

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Autologous Hematopoietic Stem Cell Transplantation

Carmustine

Cytarabine

Etoposide

Filgrastim

Melphalan

Rituximab

Umbilical Cord Blood-derived Natural Killer Cells

About this trial

This is an interventional treatment trial for CD19 Positive

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Sites / Locations

M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (CAR transduced CB-NK cells, chemotherapy, ASCT)

Arm Description

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.

Outcomes

Primary Outcome Measures

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

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)

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.

Secondary Outcome Measures

Progression-free survival (PFS) time

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

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

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

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.

Full Information

NCT ID

NCT03579927

First Posted

June 25, 2018

Last Updated

January 27, 2020

Sponsor

M.D. Anderson Cancer Center

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT03579927

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

January 2020

Overall Recruitment Status

Withdrawn

Why Stopped

Lack of Funding

Study Start Date

October 3, 2019 (Actual)

Primary Completion Date

October 3, 2019 (Actual)

Study Completion Date

October 3, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

M.D. Anderson Cancer Center

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (CAR transduced CB-NK cells, chemotherapy, ASCT)

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Autologous Hematopoietic Stem Cell Transplantation

Other Intervention Name(s)

Autologous Hematopoietic Cell Transplantation, autologous stem cell transplantation

Intervention Description

Undergo ASCT

Intervention Type

Drug

Intervention Name(s)

Carmustine

Other Intervention Name(s)

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

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Cytarabine

Other Intervention Name(s)

.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

Intervention Description

Given IV

Intervention Type

Drug

Intervention Name(s)

Etoposide

Other Intervention Name(s)

Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16-213, VP-16, VP-16-213

Intervention Description

Given IV

Intervention Type

Biological

Intervention Name(s)

Filgrastim

Other Intervention Name(s)

FILGRASTIM, LICENSE HOLDER UNSPECIFIED, G-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, Tevagrastim

Intervention Description

Given SC

Intervention Type

Drug

Intervention Name(s)

Melphalan

Other Intervention Name(s)

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

Intervention Description

Given IV

Intervention Type

Biological

Intervention Name(s)

Rituximab

Other Intervention Name(s)

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

Intervention Description

Given IV

Intervention Type

Biological

Intervention Name(s)

Umbilical Cord Blood-derived Natural Killer Cells

Other Intervention Name(s)

Cord Blood NK Cells, Umbilical Cord Blood-derived NK Cells

Intervention Description

Given CAR.CD19-CD28-zeta-2A-iCasp9-IL15-transduced CB-NK cells IV

Primary Outcome Measure Information:

Title

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

Description

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.

Time Frame

Up to 30 days within natural killer (NK) cell infusion

Title

Complete response (CR) or partial response (PR)

Description

Time Frame

At day 30 post NK cell infusion

Secondary Outcome Measure Information:

Title

Progression-free survival (PFS) time

Description

Time Frame

At day 100

Title

Overall survival (OS) time

Description

Time Frame

At day 100

Title

Response status

Description

Participants have a bone marrow aspiration and/or biopsy to check the status of the disease.

Time Frame

16 weeks

Title

Number of chimeric antigen receptor (CAR) NK cells in blood by flow cytometry

Description

Time Frame

Up to 16 weeks post CAR NK cell infusion

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Katy Rezvani

Organizational Affiliation

M.D. Anderson Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

M D Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

34515338

Citation

Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Results Reference

derived

Links:

URL

http://www.mdanderson.org

Description

MD Anderson Cancer Center Website

Learn more about this trial

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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