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Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

Primary Purpose

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)

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
therapeutic allogeneic lymphocytes
aldesleukin
peripheral blood stem cell transplantation
allogeneic bone marrow transplantation
laboratory biomarker analysis
gene expression analysis
immunologic technique
flow cytometry
polymerase chain reaction
cytogenetic analysis
staining method
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment

Arm Description

See Detailed Description

Outcomes

Primary Outcome Measures

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
Assessed by Common Terminology Criteria (CTC) version 3.0.

Secondary Outcome Measures

Relapse of disease
Patients achieving complete remission with chemotherapy and T cell infusions will be followed to determine the duration of response. The proportion of responders will be estimated with associated confidence intervals. Duration of remission will be summarized using time-to-event methods, which will allow estimates to be made while some patients remain in remission.

Full Information

First Posted
January 24, 2003
Last Updated
March 27, 2017
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00052520
Brief Title
Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
September 2002 (undefined)
Primary Completion Date
April 2011 (Actual)
Study Completion Date
June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase I/II trial is studying the side effects of biological therapy and to see how well it works in treating patients with advanced myelodysplastic syndrome, chronic myeloid leukemia, acute myeloid leukemia, or acute lymphoblastic leukemia. Biological therapies, including immunotherapy, can potentially be used to stimulate the immune system and stop cancer cells from growing. Immunotherapy given to patients who have undergone donor stem cell transplantation may be a way to eradicate remaining cancer cells
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
37 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment
Arm Type
Experimental
Arm Description
See Detailed Description
Intervention Type
Biological
Intervention Name(s)
therapeutic allogeneic lymphocytes
Other Intervention Name(s)
ALLOLYMPH
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
aldesleukin
Other Intervention Name(s)
IL-2, Proleukin, recombinant human interleukin-2, recombinant interleukin-2
Intervention Description
Given SC
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo transplantation
Intervention Type
Procedure
Intervention Name(s)
allogeneic bone marrow transplantation
Other Intervention Name(s)
bone marrow therapy, allogeneic, bone marrow therapy, allogenic, transplantation, allogeneic bone marrow, transplantation, allogenic bone marrow
Intervention Description
Undergo transplantation
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
gene expression analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
immunologic technique
Other Intervention Name(s)
immunological laboratory methods, laboratory methods, immunological
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
polymerase chain reaction
Other Intervention Name(s)
PCR
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
cytogenetic analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
staining method
Other Intervention Name(s)
Staining
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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
Description
Assessed by Common Terminology Criteria (CTC) version 3.0.
Time Frame
Up to 4 weeks after the final dose of CTL
Secondary Outcome Measure Information:
Title
Relapse of disease
Description
Patients achieving complete remission with chemotherapy and T cell infusions will be followed to determine the duration of response. The proportion of responders will be estimated with associated confidence intervals. Duration of remission will be summarized using time-to-event methods, which will allow estimates to be made while some patients remain in remission.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Merav Bar
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Biological Therapy in Treating Patients With Advanced Myelodysplastic Syndrome, Acute or Chronic Myeloid Leukemia, or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

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