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Adoptive Immunotherapy With Activated Marrow Infiltrating Lymphocytes and Cyclophosphamide Graft-Versus-Host Disease Prophylaxis in Patients With Relapse of Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02342613
Recruitment Status : Recruiting
First Posted : January 21, 2015
Last Update Posted : May 10, 2021
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
This Phase 1 clinical study is designed to examine the safety and feasibility of using anti-CD3/CD28 activated marrow infiltrating lymphocytes (MILs) as treatment of relapse after allogeneic hematopoietic cell transplantation (alloHCT) for patients with hematologic malignancies with bone marrow involvement of their relapsed disease. These MILs will be derived from the bone marrow of the relapsed patient who had previously received post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis (PTCy-MILs). A bone marrow aspiration will be performed on the patient to collect ~200ml of marrow for ex vivo expansion. During this expansion process, T cells will be activated and expanded by co-stimulation with anti-CD3/anti-CD28 monoclonal antibodies covalently attached to super-paramagnetic microbeads. Patients will be treated with salvage therapy while this ex vivo expansion is ongoing. After the simultaneous salvage therapy and ex vivo expansion, the activated PTCy-MILs will be reinfused. Patients will be monitored with the primary objective being the feasibility of expanding to targeted dose levels activated PTCy-MILs that do not cause grade III-IV acute GVHD within the first 90 days after PTCy-MIL infusion.

Condition or disease Intervention/treatment Phase
Hematologic Malignancies Graft-Versus-Host Disease Biological: Activated PTCy-MILs Phase 1

Detailed Description:

Primary Objectives:

  1. Feasibility of generating activated PTCy-MILs in patients with relapsed disease involving the bone marrow.
  2. Toxicity of PTCy-MILs, specifically the rate of grade III-IV acute GVHD within the first 90 days after PTCy-MIL infusion.

Secondary Objectives

  1. Determination of an optimal safe dose for PTCy-MILs.
  2. Immunologic characterization of the PTCy-MIL product before and after expansion.
  3. Immune reconstitution after treatment with PTCy-MILs.
  4. Incidence and severity of chronic GVHD.
  5. Clinical responses (complete remissions, partial remissions, stable disease) as measured by criteria specific for the particular disease type.
  6. Progression-free and overall survival.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Adoptive Immunotherapy Utilizing Activated Marrow Infiltrating Lymphocytes Derived From Patients With Bone Marrow Relapse of Hematologic Malignancies After Allogeneic Hematopoietic Cell Transplantation Using Post-Transplantation Cyclophosphamide Graft-Versus-Host Disease Prophylaxis.
Actual Study Start Date : May 28, 2015
Estimated Primary Completion Date : January 31, 2023
Estimated Study Completion Date : January 31, 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: MILs treatment
Patients treated with the activated PTCy-MILs
Biological: Activated PTCy-MILs
The activated PTCy-MILs will be infused through standard blood tubing containing a 170-260 micron filter without an additional leukoreduction filter into a central IV site. Each of the bags will be infused at a rate of approximately 10 ml per minute. The IV line will be flushed with normal saline immediately after completion of PTCy-MILs infusion to ensure that all product has been infused into the patient.

Primary Outcome Measures :
  1. Feasibility of generating activated marrow infiltrating lymphocytes (MILs) from participants previously treated with post-transplantation cyclophosphamide (PTCy) (PTCy-MILs) who have relapsed disease involving the bone marrow [ Time Frame: 90 days ]
    Feasibility is measured as the number of participants who achieve: 1) The successful obtaining of PTCy-MILs; 2) The expansion of PTCy-MILs to at least 70% of the assigned dose level; 3) Successful infusion of PTCy-MILs; 4) The absence of grade III-IV acute graft-versus-host-disease (GVHD) for 90 days after PTCy-MILs infusion. Acute GVHD is defined by the Modified Keystone Criteria.

Secondary Outcome Measures :
  1. Optimal safe dose for PTCy-MILs [ Time Frame: 90 days ]
    Optimal safe dose is defined as the maximal MILs cell dose that can be expanded in at least 70% of patients at which upon administration does not exacerbate grade III/IV GVHD

  2. Immunologic characterization of the PTCy-MIL product before and after expansion [ Time Frame: up to 3 years ]
    Amount of MILs with expression of CD3, CD4, Cd8, CXCR4, CD45RO, CD62L, CD107a, FasL, markers of exhaustion and T-cell inactivation as identified by multi-color flow cytometry and functional studies of alloMILs and T-cell response.

  3. Number of participants who experience chronic GVHD [ Time Frame: up to 2 years post-transplant ]
    Chronic GVHD is defined by National Institutes of Health (NIH) criteria.

  4. Clinical Response [ Time Frame: up to 3 years ]
    Number of participants with complete remission (CR), partial remission (PR) and stable disease (SD) as assessed by bone marrow examination, CBC with differential, serum chemistries, cytogenetics and disease-specific molecular studies

  5. Progression-Free Survival [ Time Frame: up to 3 years ]
    Time from day of PTCy-MILs infustion to progression/relapse of disease or death from any cause, whichever occurs first

  6. Overall Survival [ Time Frame: up to 3 years ]
    Time alive from the day of PTCy-MILs infusion to death from any cause

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≥18 years old
  • Bone marrow relapse of a hematologic malignancy ≥6 months after alloHCT using PTCy
  • Donor CD3+ chimerism ≥ 30% measured in peripheral blood or bone marrow
  • ECOG performance status ≤ 2 or Karnofsky performance scale ≥ 70%.
  • Off all immunosuppressive drugs for 2 weeks prior to the PTCy-MILs collection.
  • Expectation of ability to safely undergo salvage treatment appropriate for the patient's malignant disease type as determined by the treating hematologist/ oncologist.

Exclusion Criteria:

  • Most recent alloHCT not utilizing PTCy.
  • Active GVHD requiring treatment.
  • Immunosuppression use within 28 days of PTCy-MIL infusion if prior grade II-IV acute GVHD.
  • Creatinine ≥ 2.5, total bilirubin > 3 times the upper limit of normal (ULN), or AST/ALT > 3 times the ULN.
  • HIV-1/2 or HTLV-1/2 positivity.
  • Life expectancy ≤ 90 days even with aggressive treatment, as determined by the treating hematologist/oncologist, which would preclude assessment of toxicity of PTCy-MILs

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 identifier (NCT number): NCT02342613

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Contact: Leo Luznik, MD 410-502-7732

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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21231
Contact: Leo Luznik, M.D.    410-502-3809      
Principal Investigator: Leo Luznik, M.D.         
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Institutes of Health (NIH)
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Principal Investigator: Leo Luznik, MD Sidney Kimmel Cancer Center at Johns Hopkins
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Identifier: NCT02342613    
Other Study ID Numbers: J1484
IRB00039074 ( Other Identifier: JHM IRB )
P01CA153962 ( Other Grant/Funding Number: NIH )
First Posted: January 21, 2015    Key Record Dates
Last Update Posted: May 10, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hematologic Neoplasms
Graft vs Host Disease
Immune System Diseases
Neoplasms by Site
Hematologic Diseases