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LMP-specific T-cells for Patients With Relapsed EBV-positive Lymphoma (ALCI)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00062868
Recruitment Status : Completed
First Posted : June 18, 2003
Results First Posted : February 7, 2020
Last Update Posted : June 9, 2020
Sponsor:
Collaborators:
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Helen Heslop, Baylor College of Medicine

Brief Summary:

This protocol is broken up into 2 portions to determine the maximum tolerated dose for treating patients with a type of lymph gland disease.

The 1st portion, called ALASCER are for people with a type of lymph gland cancer called Hodgkin or non-Hodgkin Lymphoma or Lymphoepithelioma which has returned or may return or has not gone away after treatment, including the best treatment we know for Lymphoma. While the 2nd portion (ALCI) also includes Lymphoepithelioma, severe chronic active EBV (SCAEBC), and leiomyosarcoma.

Some patients with Lymphoma show evidence of infection with the virus that causes infectious mononucleosis Epstein Barr virus (EBV) before or at the time of their diagnosis. EBV is found in the cancer cells of up to half the patients with Hodgkin's and non-Hodgkin Lymphoma, suggesting that it may play a role in causing Lymphoma. The cancer cells (in lymphoma) and some B cells (in SCAEBV) infected by EBV are able to hide from the body's immune system and escape destruction. Investigators want to see if special white blood cells, called T cells, that have been trained to kill EBV infected cells can survive in your blood and affect the tumor.

The investigators have used this sort of therapy to treat a different type of cancer that occurs after bone marrow or solid organ transplant called post transplant lymphoma. In this type of cancer the tumor cells have 9 proteins made by EBV on their surface. The investigators grew T cells in the laboratory that recognized all 9 proteins and were able to successfully prevent and treat post transplant lymphoma. However in Hodgkin disease and non-Hodgkin Lymphoma and SCAEBV, the tumor cells and B cells only express 2 EBV proteins. In a previous study we made T cells that recognized all 9 proteins and gave them to patients with Hodgkin disease. Some patients had a partial response to this therapy but no patients had a complete response. Investigators think one reason may be that many of the T cells reacted with proteins that were not on the tumor cells. In this present study we are trying to find out if we can improve this treatment by growing T cells that only recognize one of the proteins expressed on infected EBV Lymphoma cells called LMP-2a, and B cells called LMP1 and LMP2. These special T cells are called LMP specific cytotoxic T-lymphocytes (CTLs).

The purpose of the study is to find the largest safe dose of LMP specific cytotoxic T cells, to learn what the side effects are and to see whether this therapy might help patients with Hodgkin disease, non-Hodgkin Lymphoma, Lymphoepithelioma, SCAEBV or leiomyosarcoma.


Condition or disease Intervention/treatment Phase
Hodgkin Disease Non Hodgkin Lymphoma Lymphoepithelioma Leiomyosarcoma Biological: LMP1/2 CTLs (ALCI - Group A) Biological: LMP1/2 CTLs (ALCI - Group B) Biological: LMP1/2 CTLs (ALCI - Group C) Biological: LMP2 CTLs (ALSCER - Group A) Biological: LMP2 CTLs (ALSCER - Group B) Biological: LMP2 CTLs (ALSCER - Group C) Biological: LMP1/2 CTLs (ALCI - Expansion - Group A) Biological: LMP1/2 CTLs (ALCI - Expansion Group B) Biological: LMP1/2 CTLs (ALCI - Expansion Group C) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 74 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Administration of LMP-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma (ALCI) / Previously Known as: Administration of Neomycin Resistance Gene Marked LMP2A-Specific Cytotoxic T-Lymphocytes to Patents With Relapsed EBV-Positive Lymphoma (ALASCAR)
Actual Study Start Date : September 2003
Actual Primary Completion Date : April 2014
Actual Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: LMP1/2 CTLs (ALCI - Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
Biological: LMP1/2 CTLs (ALCI - Group A)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2 x 10^7 cells/m2; Day 14: 2 x 10^7 cells/m2

Dose Level Two

Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2

Dose Level Three

Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2


Experimental: LMP1/2 CTLs (ALCI - Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.
Biological: LMP1/2 CTLs (ALCI - Group B)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2

Dose Level Two

Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2

Dose Level Three

Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2


Experimental: LMP1/2 CTLs (ALCI - Group C)
Patients receiving CTLs following allogeneic stem cell transplant.
Biological: LMP1/2 CTLs (ALCI - Group C)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2

Dose Level Two

Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2

Dose Level Three

Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2


Experimental: LMP2A CTLs (ALASCER - Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
Biological: LMP2 CTLs (ALSCER - Group A)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2 x 10^7 cells/m2; Day 14: 2 x 10^7 cells/m2

Dose Level Two

Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2

Dose Level Three

Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2


Experimental: LMP2A CTLs (ALASCER - Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant
Biological: LMP2 CTLs (ALSCER - Group B)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2

Dose Level Two

Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2

Dose Level Three

Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2


Experimental: LMP2A CTLs (ALASCER - Group C)
Patients receiving CTLs following allogeneic stem cell transplant
Biological: LMP2 CTLs (ALSCER - Group C)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2

Dose Level Two

Day 0: 2x10^7 cells/m2; Day 14: 1x10^8 cells/m2

Dose Level Three

Day 0: 1x10^8 cells/m2; Day 14: 2x10^8 cells/m2


Experimental: LMP1/2 CTLs (ALCI - Expansion Group A)
Patients receiving CTLs as therapy for relapsed Lymphoma/Lymphoepithelioma/leiomyosarcoma or who are at risk for relapse
Biological: LMP1/2 CTLs (ALCI - Expansion - Group A)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2 x 10^7 cells/m2; Day 14: 2 x 10^7 cells/m2


Experimental: LMP1/2 CTLs (ALCI - Expansion Group B)
Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.
Biological: LMP1/2 CTLs (ALCI - Expansion Group B)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2


Experimental: LMP1/2 CTLs (ALCI - Expansion Group C)
Patients receiving CTLs following allogeneic stem cell transplant.
Biological: LMP1/2 CTLs (ALCI - Expansion Group C)

Each patient will receive 2 injections, 14 days apart, according to the following dosing schedules:

Dose Level One

Day 0: 2x10^7 cells/m2; Day 14: 2x10^7 cells/m2





Primary Outcome Measures :
  1. Dose Limiting Toxicity (DLT) Rate by the NCI Common Toxicity Criteria (CTCAE) v2.0 and the Method of Przepiorka et al (Protocol Appendix I) [ Time Frame: 6 weeks post second CLT infusion ]
    Dose limiting toxicity (DLT) rate is the proportion of participants with DLT. DLT will be defined as any toxicity that is irreversible, life threatening or Grade 3-4 considered to be primarily related to the LMP-specific cytotoxic T-lymphocytes (CTL) injection or development of Grade III-IV Graft versus host disease (GVHD). Toxicity will be evaluated according to the CTCAE Version 2.0. GVHD will be graded by the method of Przepiorka et al (protocol Appendix I).


Secondary Outcome Measures :
  1. Response Rate According to the Harmonization Project (Protocol 8.5.1) or RECIST Criteria. [ Time Frame: Up to 4 months after the last infusion ]

    Response rate is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) . All patients who receive the first infusion will be evaluable for response.

    In patients with detectable tumors and/or lymphadenopathy - response and progression will be evaluated using PET based imaging studies (whenever possible) based on the Harmonization Project (protocol 8.5.1). All available non-PET imaging studies will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.


  2. Grade III-IV Toxicity Rate in Participants Receiving an Extended Dosage Regimen According to the NCI Common Toxicity Criteria (CTCAE) Version 2.0 and the Method of Przepiorka et. al. (Protocol Appendix I). [ Time Frame: 6 weeks after the final injection ]
    Grade III-IV toxicity rate is defined as the proportion of participants who receive an extended dose regimen and developed Grade III-IV toxicity attributable to the CTL infusions at any time during the extended dosing regimen. Toxicity will be evaluated according to the CTCAE Version 2.0. GVHD will be graded by the method of Przepiorka et al (protocol Appendix I).



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.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

ALASCER (Part 1 of Study)

INCLUSION CRITERIA

  1. Any patient, regardless of age or sex, with EBV-positive Lymphoma, or lymphoepithelioma regardless of the histological subtype or EBV (associated)-T/NK-LPD.

    In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients in remission who have a high risk of relapse) OR any patient with primary disease or in first remission if immunosuppressive chemotherapy is contraindicated, e.g. patients who develop Hodgkin disease after solid organ transplantation or if the Lymphoma is a second malignancy e.g. a Richters transformation of CLL. (Group A) OR In remission or with minimal residual disease status after autologous or syngeneic SCT for Hodgkin's or non-Hodgkin's Lymphoma or lymphoepithelioma. (Group B) OR In remission or with detectable disease after allogeneic SCT. (Group C)

  2. Patients with life expectancy > 6 weeks.
  3. Patients with a Karnofsky/Lansky score of > 50
  4. No severe intercurrent infection.
  5. Donor HIV negative (if autologous product - patient must be HIV negative)
  6. No evidence of GVHD > Grade II at time of enrollment.
  7. If post allogeneic SCT must not have less than 50% donor chimerism in either peripheral blood or bone marrow
  8. Patient, parent/guardian able to give informed consent.
  9. Patients with bilirubin <3x normal, AST <5x normal, and Hgb >8.0 (see Section 7.2).
  10. Patients with a creatinine <2x normal for age
  11. Patients should have been off other investigational therapy for one month prior to entry in this study.

EXCLUSION CRITERIA

  1. Patients with a life expectancy of <6 weeks.
  2. Patients with a Karnofsky/Lansky score of < 50.
  3. Patients with a severe intercurrent infection.
  4. Patients with bilirubin >3x normal. AST >5x normal or abnormal prothrombin time.
  5. Patients with a creatinine >2x normal for age
  6. Donors who are HIV positive (Patients who are HIV positive - if autologous product)
  7. Patients with GVHD Grades III-IV
  8. Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this research. The male partner should use a condom.

Note: Patients who would be excluded from the protocol strictly for laboratory abnormalities can be included at the investigator's discretion after approval by the CCGT Protocol Review Committee and the FDA reviewer.

ALCI and ALCI Expansion (Part 2 of Study)

INCLUSION CRITERIA:

  1. Any patient, regardless of age or sex, with EBV-positive Hodgkin's or non-Hodgkin's Lymphoma, or lymphoepithelioma or leiomyosarcoma regardless of the histological subtype or EBV (associated)-T/NK-lymphoproliferative disease or Severe Chronic EBV#

    (#SCAEBV is defined as patients with high EBV viral load in plasma or PBMC (>4000 genomes per ug PBMC DNA) and/or biopsy tissue positive for EBV)

    a - In second or subsequent relapse (or first relapse or with active disease if immunosuppressive chemotherapy contraindicated or multiply relapsed patients currently in remission who have a high risk of relapse) OR with primary disease or in first or subsequent remission if immunosuppressive chemotherapy is contraindicated, e.g. patients who develop Hodgkin disease after solid organ transplantation or if the Lymphoma is a second malignancy e.g. a Richters transformation of CLL.(Group A)

    OR

    b - In remission or with minimal residual disease status after autologous or syngeneic SCT for Hodgkin's or non-Hodgkin's Lymphoma/Lymphoepithelioma/SCAEBV. (Group B)

    OR

    c - Patients in remission or with detectable disease after allogeneic SCT. (Group C)

  2. Patients with life expectancy 6 weeks or greater.
  3. Tumor tissue EBV positive
  4. Patients with a Karnofsky/Lansky score of 50 or greater
  5. Donor HIV negative (if autologous product - patient must be HIV negative)
  6. If post allogeneic SCT must not have less than 50% donor chimerism in either peripheral blood or bone marrow
  7. Patients with bilirubin 3x normal or less, AST 5x normal or less, and Hgb greater than 8.0
  8. Patients with a creatinine 2x normal or less for age
  9. Patients should have been off other investigational therapy for one month prior to entry in this study.
  10. Patient, parent/guardian able to give informed consent.

EXCLUSION CRITERIA:

  1. Patients with a severe intercurrent infection.
  2. Donors who are HIV positive or Patients who are HIV positive if autologous product to be used
  3. Patients with greater than Grade II GVHD
  4. Due to unknown effects of this therapy on a fetus, pregnant women are excluded from this research. The male partner should use a condom.

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): NCT00062868


Locations
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United States, Texas
Texas Children's Hospital
Houston, Texas, United States, 77030
The Methodist Hospital
Houston, Texas, United States, 77030
Sponsors and Collaborators
Baylor College of Medicine
The Methodist Hospital System
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
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Principal Investigator: Helen E Heslop, MD Center for Cell and Gene Therapy, Baylor College of Medicine
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Helen Heslop, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT00062868    
Obsolete Identifiers: NCT00070226, NCT00671164
Other Study ID Numbers: 9936-ALCI-ALASCAR
ALCI ( Other Identifier: Baylor College of Medicine )
ALASCAR ( Other Identifier: Baylor College of Medicine )
First Posted: June 18, 2003    Key Record Dates
Results First Posted: February 7, 2020
Last Update Posted: June 9, 2020
Last Verified: May 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Helen Heslop, Baylor College of Medicine:
Lymphoma
EBV-T/NK lymphoproliferative disease
Severe Chronic EBV
LMP1/2
CTL
EBV
Relapse
LMP2A
Additional relevant MeSH terms:
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Lymphoma
Hodgkin Disease
Leiomyosarcoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma