Brief Title
Therapeutic Allogeneic Lymphocytes and Aldesleukin in Treating Patients With High-Risk or Recurrent Myeloid Leukemia After Undergoing Donor Stem Cell Transplant
Official Title
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
Brief Summary
This phase I/II trial is studies the side effects of giving therapeutic allogeneic
lymphocytes together with aldesleukin and to see how well it works in treating patients with
high-risk or recurrent myeloid leukemia after undergoing donor stem cell transplant.
Biological therapies, such as therapeutic autologous lymphocytes, may stimulate the immune
system in different ways and stop cancer cells from growing. Aldesleukin may stimulate the
white blood cells to kill cancer cells. Giving therapeutic autologous lymphocytes together
with aldesleukin may kill more cancer cells
Detailed Description
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.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
Toxicity rate associated with infusing donor CD8+CTL clones specific for PR3
Secondary Outcome
In vivo persistence of transferred T-cells and assessment of migration to the bone marrow
Condition
Accelerated Phase Chronic Myelogenous Leukemia
Intervention
therapeutic allogeneic lymphocytes
Study Arms / Comparison Groups
Treatment (adoptive immunotherapy)
Description: Patients receive allogeneic CD8+ PR3-specific CTLs IV over 1-2 hours on days 0, 7, 14, 28, and 49 and aldesleukin SC twice daily on days 28-41 and 49-63 in the absence of unacceptable toxicity.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Biological
Estimated Enrollment
7
Start Date
September 2002
Completion Date
June 2011
Primary Completion Date
November 2009
Eligibility Criteria
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
Gender
All
Ages
N/A - N/A
Accepts Healthy Volunteers
No
Contacts
Gunnar Ragnarsson, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT00052598
Organization ID
1671.00
Secondary IDs
NCI-2010-00826
Responsible Party
Sponsor
Study Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
Study Sponsor
Gunnar Ragnarsson, Principal Investigator, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Verification Date
February 2017