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Phase I/II Study of Adoptive Immunotherapy With CD8+ WT1-Specific CTL Clones for Patients With Advanced MDS, CML, AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant


Phase 1/Phase 2
N/A
N/A
Open (Enrolling)
Both
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, 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), B-cell Adult Acute Lymphoblastic Leukemia, B-cell Childhood Acute Lymphoblastic Leukemia, Childhood Chronic Myelogenous Leukemia, Childhood Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Essential Thrombocythemia, Polycythemia Vera, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Excess Blasts in Transformation, Relapsing Chronic Myelogenous Leukemia, Secondary Acute Myeloid Leukemia, T-cell Adult Acute Lymphoblastic Leukemia, T-cell Childhood Acute Lymphoblastic Leukemia

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Trial Information

Phase I/II Study of Adoptive Immunotherapy With CD8+ WT1-Specific CTL Clones for Patients With Advanced MDS, CML, AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant


PRIMARY OBJECTIVES:

I. To determine the safety and potential toxicities associated with infusing donor CD8+
cytotoxic T lymphocyte (CTL) clones specific for Wilms' tumor (WT1) in patients who have
relapsed or at a high risk of relapse post transplant for myelodysplastic syndromes (MDS),
chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic
leukemia (ALL).

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 WT1-specific T cells mediate antileukemic
activity.

OUTLINE: Donors undergo leukapheresis for stem cell harvest to generate CD8-positive WT1
gene-specific CTL clones at the time of allogeneic stem cell transplantation.

After post-transplantation hematopoietic recovery, patients receive treatment for either
highest-risk disease (prophylactically) or relapsed disease.

Highest-risk disease group: Patients receive CD8-positive WT1 gene-specific CTL clones
intravenously (IV) over 1-2 hours on days 0, 14, and 28. Beginning 2-4 hours after CTL
infusion, patients receive interleukin-2 subcutaneously (SC) twice daily on days 28-42 in
the absence of unacceptable toxicity.

Relapsed-disease group: Some patients with evidence of leukemic relapse may receive standard
salvage chemotherapy prior to donor CTL infusions and then receive CD8-positive WT1
gene-specific CTL clones and interleukin-2 as in the highest-risk group.

Patients in both groups who have progressive disease after complete or partial response to
therapy may be eligible for retreatment with CD8-positive WT1 gene-specific CTL clones.

After completion of study treatment, patients are followed every 3 months for 2 years.


Inclusion Criteria:



- Eligibility for Enrollment:

- a.

- i) Pre-transplant: Patients undergoing allogeneic hematopoietic stem cell
transplantation for refractory anemia with excess blasts (RAEB), refractory
anemia with excess blasts in transformation (RAEB-t), CML beyond chronic
phase, AML beyond first remission, Philadelphia chromosome
(BCR-ABL)-positive ALL at any stage, any ALL beyond first remission,
primary refractory AML or ALL, 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);

- ii) Post-transplant: Patients who have relapsed after transplant
(morphologic, flow cytometric, cytogenetic and molecular relapse) can be
offered enrollment on the protocol and may undergo therapy if it is
considered possible to control their disease while waiting for the
generation of study therapy

- b. Patients and donors must both express an human leukocyte antigen (HLA)-allele
for which it is possible to generate WT1-specific clones for

- c. 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 WT1 must have been
generated and have completed Quality Control (QC) testing

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

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

- c. 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 WT1 must have been
generated and have completed Quality Control (QC) testing

- a. Patients must have evidence of recurrent disease post transplant; this
includes patients with the following:

- i) 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

- ii) 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

- iii) Cytogenetic relapse 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

- iv) Molecular relapse defined as: one or more positive polymerase chain
reaction (PCR) assays for the presence of clonotypic immunoglobulin heavy
chain (IgH) or T cell receptor (TCR) gene rearrangement in patients
transplanted for B-or T-cell acute lymphoblastic leukemia, respectively;
one or more positive post transplant reverse transcription (RT)-PCR assays
for the presence of BCR-ABL messenger ribonucleic acid (mRNA) fusion
transcripts in patients transplanted for Philadelphia chromosome
(BCRABL)-positive acute lymphoblastic leukemia; (for CML) a PCR assay of
bone marrow (BM) or peripheral blood mononuclear cell (PBMC) positive for
the presence of the BCR/ABL mRNA fusion transcript that quantitatively
increases by greater than one order of magnitude on a subsequent sample

- b. 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 patients treating physician and the
principal investigator

- DONOR: Both the patient and donor must have an HLA-allele which it is possible to
generate WT1-specific clones for

- DONOR: If a separate leukapheresis via peripheral intravenous access can be arranged,
the stem cell donor will undergo leukapheresis to provide the required PBMC no sooner
than 2 weeks before or after the stem cell mobilization and harvest

- DONOR: If a separate leukapheresis is not possible, a portion of the PBMC from the
donor's peripheral blood stem cell harvest may potentially be used to generate
WT1-specific CTL clones; the feasibility of this option will depend upon the minimal
cell dose required for transplantation and the presence of an excess harvest yield
and the possibility of generating CTL from this product

- DONOR: Some donors will be asked to provide both a separate leukapheresis and a
portion of the peripheral blood mononuclear cells (PBMC) from the donor's peripheral
blood stem cell harvest

- DONOR: Leukapheresis donors must be age 18 or older

Exclusion Criteria:

- Patients for whom CD8+ CTL clones specific for WT1 have not been generated in time
for planned infusion (these patients can potentially be treated later if CTL become
available); Also we will exclude patients whose malignant cells do not over express
WT-1, 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 MMF is not strictly an exclusion criteria, 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

- DONOR: Medical conditions precluding either leukapheresis or blood donation may
include but are not limited to:

- Inadequate age or weight (leukapheresis donors must be age 18 or older, other
criteria per physician discretion)

- Active infection, with or without antibiotic treatment

- Recent hepatitis exposure, hepatitis A or B antigenemia, or hepatitis C antibody
positivity

- Pregnancy or nursing; HIV or human T-lymphotropic virus (HTLV) infection

- Severe cardiovascular disease (e.g., uncontrolled hypertension, recent
myocardial infarction [MI], or unstable angina)

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety 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 WT1 in patients at high risk for post transplant relapse of CML, AML, or ALL

Outcome Description:

Assessed by Common Terminology Criteria (CTC) version 3.0.

Outcome Time Frame:

Up to 4 weeks after the final dose of CTL

Safety Issue:

Yes

Principal Investigator

Merav Bar

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:

1655.00

NCT ID:

NCT00052520

Start Date:

September 2002

Completion Date:

Related Keywords:

  • Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
  • 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)
  • B-cell Adult Acute Lymphoblastic Leukemia
  • B-cell Childhood Acute Lymphoblastic Leukemia
  • Childhood Chronic Myelogenous Leukemia
  • Childhood Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
  • Essential Thrombocythemia
  • Polycythemia Vera
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Acute Myeloid Leukemia
  • Refractory Anemia With Excess Blasts
  • Refractory Anemia With Excess Blasts in Transformation
  • Relapsing Chronic Myelogenous Leukemia
  • Secondary Acute Myeloid Leukemia
  • T-cell Adult Acute Lymphoblastic Leukemia
  • T-cell Childhood Acute Lymphoblastic Leukemia
  • Congenital Abnormalities
  • Anemia
  • Anemia, Refractory
  • Anemia, Refractory, with Excess of Blasts
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Polycythemia
  • Polycythemia Vera
  • Thrombocythemia, Essential
  • Anemia, Aplastic
  • Thrombocytosis

Name

Location

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