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A Phase II Study of The Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies


Phase 2
N/A
N/A
Open (Enrolling)
Both
Non-Hodgkin's Lymphoma, Epstein-Barr Virus

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Trial Information

A Phase II Study of The Therapeutic Effects Of Epstein-Barr Virus Immune T-Lymphocytes Derived From A Normal HLA- Compatible Or Partially- Matched Third-Party Donor in the Treatment of EBV Lymphoproliferative Disorders and EBV-Associated Malignancies


Inclusion Criteria:



- Pathologically documented EBV antigen positive lymphoproliferative disease, lymphoma
or other EBVassociated malignancy.

OR

- Evaluable disease as demonstrated by clinical and/or radiologic studies with elevated
blood levels of EBVDNA exceeding 500 copies/μl by quantitative real time pcr.

OR

- Persistent or recurrent elevations in levels of EBVDNA exceeding 500 copies/μl in
patients previously treated for EBVLPD with chemotherapy and/or Rituxan who do not
yet have clinically or radiologically evaluable disease but are at high risk of
disease recurrence.

- EBV-specific T-cells from donor of the patient's transplant are not available.

- EBV-specific T-cells are available for adoptive immune cell therapy from a consenting
third party donor. The third party EBV CTLs to be administered will be selected on
the basis of two criteria: 1) that they are matched for at least 2 HLA antigens and
2) that they are restricted by an allele shared with the EBV+ malignancy (if known),
or with the donor in HSCT recipients, or patient in organ transplant or
immunodeficient patients

- KPS or Lansky score ≥ 20.

- A life expectancy of at least 6 weeks.

- Adequate bone marrow, heart, lung, liver and kidney function at the time treatment
with EBV-specific

- T-cells is initiated, including:

1. Absolute neutrophil count (ANC) ≥ 1K/mcL, with or without GCSF support

2. Platelets ≥ 20,K/mcL

3. Creatinine ≤ 2.0mg/dl

4. ALT, AST < 3.0x and total bilirubin < 2.5x the institutional ULN

5. Stable blood pressure and circulation not requiring pressor support

6. Adequate cardiac function as demonstrated by EKG and/or echocardiographic
evidence

- However, abnormalities of specific organs will not be considered grounds for
exclusion if they are the result of the EBV+ malignancy or its treatment (e.g. a
renal allograft recipient with an EBVLPD may be on dialysis because the allograft was
rejected when the immune suppression was stopped as a first approach to treatment of
the EBVLPD).

- There is no age restriction to eligibility for this protocol.

- It is expected that five types of patients afflicted with EBV-associated lymphomas,
lymphoproliferative diseases or malignancies will be referred and will consent to
participate in this trial. These are:

- Patients developing EBV lymphomas or lymphoproliferative disorders following an
allogeneic hematopoietic progenitor stem cell transplant (HSCT) (ie: marrow, PBSC, or
umbilical cord blood). In these cases, the HSCT donor, if EBV-seropositive, will be
used as the donor of EBV-specific T-cells for adoptive immunotherapy wherever
possible, because the EBV-LPD are almost invariably derived from that marrow donor.
These patients will be enrolled onto protocol # IRB 95-024. However, if the HSCT
donor is EBV seronegative or not readily available (e.g. a cord blood transplant),
the patient will be a candidate to receive EBV- specific T-cells generated from a
third party seropositive donor that have been generated and stored in the MSKCC bank
of cryopreserved immune T-cells for adoptive cell therapy. For these patients, the
third party donor derived T cells to be used will be selected primarily on the basis
of matching for 2 HLA alleles shared by the transplant donor and recipient. However,
priority is given to T cells partially matched with, and restricted by, HLA alleles
of the transplant donor, since EBV + lymphomas in HSCT recipients are usually (but
not always) derived from the transplant donors' cells.

- Patients developing EBV lymphomas or lymphoproliferative disorders following an
allogeneic organ transplant. In these cases, the lymphoma is usually of recipient
origin. EBV-specific T-cells will be selected from the MSKCC Bank expanded from an
EBV-seropositive normal donor who is at least matched for 2 HLA alleles with the EBV
lymphoma. If the origin of the lymphoma is unknown, T-cells partially matched with
the transplant recipient will be used, since these lymphomas are usually of host
origin. Using this approach to donor selection, it is expected that the EBV-specific,
HLA restricted cytotoxic T-cells expanded from the HLA partially-matched donor would
be able to recognize and kill lymphoma cells presenting EBV antigens in the context
of an appropriate HLA restricting element. Priority will be given to the use of
partially matched EBV specific T cells known to be restricted by an HLA allele shared
by the lymphoma (or, if unknown, the patient).

- Patients with AIDS developing EBV lymphomas or lymphoproliferative diseases as a
consequence of the profound acquired immunodeficiency induced by HIV. For such
patients, EBV specific T-cells from third party seropositive donors who are HLA
compatible in at least 2 HLA alleles shared by the patient will be used.

Selection of T cells known to be restricted by an HLA allele shared by the patient will be
given priority.

- Patients who develop EBV lymphomas or lymphoproliferative diseases or other
EBV-associated malignancy as a consequence of profound immunodeficiencies associated
with a congenital immune deficit or acquired as a sequela of anti-neoplastic or
immunosuppressive therapy. For these patients, normal, EBV specific T-cells from
third party seropositive donors who are HLA compatible in at least 2 HLA alleles
shared by the patient will be used. Again, selection of T cells known to be
restricted by an HLA allele shared by the patient will be given priority.

- Patients who develop other EBV-associated malignancies without pre-existing immune
deficiency, including: EBV+ Hodgkin's and Non-Hodgkin's disease, EBV+ nasopharyngeal
carcinoma, EBV+ hemophagocytic lymphohistiocytosis, or EBV+ leiomyosarcoma. Normal,
EBV specific T-cells from third party seropositive donors who are HLA compatible in
at least 2 HLA alleles shared by the patient will be used. Again, selection of T
cells known to be restricted by an HLA allele shared by the patient will be given
priority.

Donor Eligibility

- Donors in Groups 1 and 2 (Section 5.1) would have already been determined to be
eligible and will have donated blood or leukocytes to establish EBV-specific T-cells
under IRB # 05-065, 07-055, or 95-024. There are no additional eligibility
requirements for these donors.

- Donors in Group 3 (section 5.1), however, will need to meet the following eligibility
requirements prior to donation:

- Donors must satisfy the criteria specified in FDA 21 CFR 1271 Donors must be typed
for HLA-A, B, C and DR

- Donors must have a hemoglobin value > 10g/dl

- Donors must be capable of undergoing, at least, a single standard 2 blood volume
leukapheresis or a donation of one unit of whole blood

Exclusion Criteria:

Patient Exclusion Criteria

The following patients will be excluded from this study:

- Patients with active (grade 2-4) acute graft vs. host disease (GVHD), chronic GVHD or
an overt autoimmune disease (e.g. hemolytic anemia) requiring high doses of
glucocorticosteroid (>0.5 mg/kg/day prednisone or its equivalent) as treatment

- Patients who are pregnant

- Patients with severe comorbidities, not related to their EBV-associated malignancy,
that would be expected to preclude their survival for the 6 weeks required to assess
response of T cell therapy Donor Exclusion Criteria

- HTLV/HIV(+) or Hepatitis B or C antigen(+) donors

- Donors who are known EBV seronegative

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

efficacy

Outcome Description:

The responses of the clinically and/or radiologically evident EBV LPD or malignancies will be identified three weeks post-infusion cycle as complete remission, partial remission, stable disease, or no response with disease progression based on the following criteria. Outcome responses will be captured post-first cycle and post final-cycle of infusions of EBV specific T cells. Best response observed in the full course of treatment will also be recorded as a distinct entity.

Outcome Time Frame:

3 weeks

Safety Issue:

No

Principal Investigator

Richard O'Reilly, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

11-130

NCT ID:

NCT01498484

Start Date:

December 2011

Completion Date:

December 2014

Related Keywords:

  • Non-Hodgkin's Lymphoma
  • Epstein-Barr Virus
  • EBV-specific T-cell lines
  • 11-130
  • Lymphoma
  • Lymphoma, Non-Hodgkin
  • Lymphoproliferative Disorders
  • Virus Diseases

Name

Location

Memorial Sloan Kettering Cancer CenterNew York, New York  10021