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Phase I/II Study of Adoptive Immunotherapy With CD8+ Proteinase 3 (Myeloblastin)-Specific CTL Clones for HLA-A2+ Patients With Relapse or Progression of Disease After Allogeneic Hematopoietic Stem Cell Transplant for High Risk Myeloid Leukemias


Phase 1/Phase 2
N/A
N/A
Not Enrolling
Both
Accelerated Phase Chronic Myelogenous Leukemia, Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Blastic Phase Chronic Myelogenous Leukemia, Childhood Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia

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Trial Information

Phase I/II Study of Adoptive Immunotherapy With CD8+ Proteinase 3 (Myeloblastin)-Specific CTL Clones for HLA-A2+ Patients With Relapse or Progression of Disease After Allogeneic Hematopoietic Stem Cell Transplant for High Risk Myeloid Leukemias


PRIMARY OBJECTIVES:

I. To determine the safety and potential toxicities associated with infusing donor CD8+
cytotoxic T lymphocytes (CTL) clones specific for Proteinase 3 (Myeloblastin) in patients
with relapse/progression of high risk myeloid leukemias after transplant.

SECONDARY OBJECTIVES:

I. To determine the in vivo persistence of transferred T cells and assess migration to the
bone marrow, a predominant site of leukemic relapse.

II. To determine if adoptively transferred proteinase 3 (PR3)-specific T cells mediate
antileukemic activity.

OUTLINE:

Patients receive allogeneic CD8+ PR3-specific CTLs intravenously (IV) over 1-2 hours on days
0, 7, 14, 28, and 49 and aldesleukin subcutaneously (SC) twice daily on days 28-41 and 49-63
in the absence of unacceptable toxicity.

After completion of study treatment, patients are followed up every 1-3 months.


Inclusion Criteria:



- Patients undergoing allogeneic hematopoietic stem cell transplantation for chronic
myelogenous leukemia (CML) in accelerated or blast phase, acute myeloid leukemia
(AML) beyond first remission, primary refractory AML, therapy-related AML at any
stage, or acute leukemia at any stage arising in a patient with an antecedent
diagnosis of a myelodysplastic or myeloproliferative syndrome (including chronic
myelomonocytic leukemia, CML, polycythemia vera, essential thrombocytosis, and
agnogenic myeloid metaplasia with myelofibrosis)

- Patients and donors must both be human leukocyte antigen (HLA)-A2 positive

- Patients must be able to provide blood and bone marrow samples required for this
protocol

- Eligibility for Prophylactic Treatment with CD8+ CTL After Transplant (Highest Risk
Subgroup):

- At time of planned treatment, CD8+ CTL specific for PR3 must have been generated and
have completed Quality Control (QC) testing

- Patients must have had > 5% morphologic blasts detectable in bone marrow or
peripheral blood just prior to or at the time of transplant

- Patients must have evidence of posttransplant recovery of normal hematopoiesis
(absolute neutrophil count [ANC] > 500/mm^3) for at least 7 days prior to the
initiation of CTL infusions

- Patients on immunosuppressive therapy for graft-versus-host disease (GVHD) are
eligible for treatment if not receiving corticosteroids or if the dose of
corticosteroids can be tapered to < the equivalent of 0.5 mg/kg/day of prednisone;
The patient's symptoms have to remain stable and unlikely to increase to stage III or
IV acute GVHD or chronic GVHD is unlikely to progress following the change in
immunosuppressive therapy, after an appropriate monitoring period, as deemed by the
patients treating physician and the principal investigator

- Eligibility for Treatment with CD8+ CTL at the Time of Relapse After Transplant (All
Others):

- At time of planned treatment, CD8+ CTL specific for PR3 must have been generated and
have completed Quality Control (QC) testing

- Patients must have evidence of recurrent/progressive disease posttransplant

- Morphologic relapse defined as one or more of the following: abnormal peripheral
blasts in absence of growth factor therapy, abnormal bone marrow blasts > 5% of
nucleated cells, extramedullary chloroma or granulocytic sarcoma

- Flow cytometric relapse defined as the appearance in the peripheral blood or bone
marrow of cells with an abnormal immunophenotype detected by flow cytometry that is
consistent with leukemia recurrence/progression

- Cytogenetic relapse/progression defined as the appearance in one or more metaphases
from bone marrow or peripheral blood cells of either a non-constitutional cytogenetic
abnormality identified in at least one cytogenetic study performed prior to
transplant or a new abnormality known to be associated with leukemia; (for CML), an
increase in the number of Ph+ metaphases from bone marrow or peripheral blood between
two consecutive samples after engraftment, or an increase in the percentage of
BCR/ABL+ cells by fluorescence in situ hybridization (FISH) between two consecutive
samples after engraftment

- Molecular relapse/progression defined as a polymerase chain reaction (PCR) assay of
bone marrow (BM) or peripheral blood mononuclear cells (PBMC) positive for the
presence of the BCR/ABL messenger ribonucleic acid (mRNA) fusion transcript that
quantitatively increases by greater than one order of magnitude on a subsequent
sample

- Patients on immunosuppressive therapy for GVHD at the time of relapse are eligible
for treatment if not receiving corticosteroids or if the dose of corticosteroids can
be tapered to < the equivalent of 0.5 mg/kg/day of prednisone; the patient's symptoms
have to remain stable and unlikely to increase to stage III or IV acute GVHD or
chronic GVHD is unlikely to progress following the change in immunosuppressive
therapy, after an appropriate monitoring period, as deemed by the patient's treating
physician and the principal investigator

Exclusion Criteria:

- Exclusions for Treatment at the Time of Relapse/Progression After Transplant:

- Patients for whom CD8+ CTL clones specific for PR3 have not been generated by the
time of disease relapse/progression post-transplant; these patients can potentially
be treated later if CTL become available; patients whose malignant cells do not
overexpress PR3, based on direct analysis of a bone marrow sample with > 50% blasts
or of leukemia cells isolated for expression analysis; in either case, patients will
be informed about the availability of other treatment protocols for which they might
be eligible

- Patients with Karnofsky performance status or Lansky play score =< 30%

- Patients with current stage III or IV GVHD unresponsive to therapy or requiring
therapy with anti-CD3 mAb, prednisone > 0.5 mg/kg/day (or corticosteroid equivalent),
or other treatments resulting in the ablation or inactivation of T cells (such as
other anti-T cell monoclonal antibodies); although the concurrent use of
cyclosporine, FK506, or mycophenolate mofetil (MMF) is not strictly an exclusion
criterion, attempts should be made to discontinue it if possible

- Patients requiring concurrent therapy with hydroxyurea or other agents that may
interfere with the function or survival of infused CTL clones

- Patients with a preexisting nonhematopoietic organ toxicity that is deemed by the
principal investigator to place the patient at unacceptable risk for treatment on the
protocol

- Patients with graft rejection or failure

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Toxicity rate associated with infusing donor CD8+CTL clones specific for PR3

Outcome Time Frame:

From the first CTL infusion to 4 weeks after the final dose of CTL or IL-2

Safety Issue:

Yes

Principal Investigator

Gunnar Ragnarsson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Food and Drug Administration

Study ID:

1671.00

NCT ID:

NCT00052598

Start Date:

September 2002

Completion Date:

June 2011

Related Keywords:

  • Accelerated Phase Chronic Myelogenous Leukemia
  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • Adult Acute Myeloid Leukemia With Del(5q)
  • Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
  • Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)
  • Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
  • Blastic Phase Chronic Myelogenous Leukemia
  • Childhood Chronic Myelogenous Leukemia
  • Childhood Myelodysplastic Syndromes
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Blast Crisis
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myeloid, Accelerated Phase
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109