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Cellular Adoptive Immunotherapy in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndromes That Relapsed After Donor Stem Cell Transplant

Primary Purpose

Leukemia, Myelodysplastic Syndromes

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
aldesleukin
therapeutic allogeneic lymphocytes
therapeutic autologous lymphocytes
cytarabine
etoposide
mitoxantrone hydrochloride
allogeneic bone marrow transplantation
peripheral blood stem cell transplantation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, recurrent childhood acute lymphoblastic leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, 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), de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, T-cell adult acute lymphoblastic leukemia, T-cell childhood acute lymphoblastic leukemia, B-cell adult acute lymphoblastic leukemia, B-cell childhood acute lymphoblastic leukemia, childhood myelodysplastic syndromes

Eligibility Criteria

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

DISEASE CHARACTERISTICS: Undergoing allogeneic hematopoietic stem cell transplantation* from a major histocompatability complex (MHC)-identical related donor for 1 of the following: Primary refractory acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) AML or ALL beyond first remission Therapy-related AML at any stage Philadelphia chromosome (bcr-abl)-positive p190-positive ALL at any stage Acute leukemia at any stage arising from myelodysplastic syndromes or myeloproliferative disorders, including any of the following: Chronic myelomonocytic leukemia Chronic myelogenous leukemia Polycythemia vera Essential thrombocytosis Agnogenic myeloid metaplasia with myelofibrosis Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation NOTE: *Patients must be enrolled on study prior to undergoing transplantation Relapsed disease post-transplantation, as evidenced by 1 of the following criteria: Morphologic relapse, as defined by 1 or more of the following: Peripheral blasts in the absence of growth factor therapy Bone marrow blasts > 5% of nucleated cells Extramedullary chloroma or granulocytic sarcoma Flow cytometric relapse, as defined by the appearance of cells with abnormal immunophenotype consistent with leukemia relapse in the peripheral blood or bone marrow (detected before transplantation) Cytogenetic relapse, as defined by the appearance in 1 or more metaphases from bone marrow or peripheral blood cells of either a non-constitutional cytogenetic abnormality detected in at least 1 cytogenetic study performed before transplantation OR a new abnormality known to be associated with leukemia Molecular relapse, as defined by 1 of the following: 1 or more positive polymerase chain reaction (PCR) assays for clonotypic immunoglobulin heavy chain or T-cell receptor gene rearrangement in patients transplanted for B- or T-cell ALL respectively 1 or more positive post-transplantation reverse transcription PCR assays for p190 BCR-ABL mRNA fusion transcripts in patients transplanted for Philadelphia chromosome-positive p190-positive ALL No grade III or IV acute graft-versus-host disease (GVHD)** No extensive chronic GVHD** NOTE: **At time of post-transplant relapse PATIENT CHARACTERISTICS: Age 14 and over (patients < 14 years of age may be eligible if they are deemed to be of sufficient height and weight by the pediatric attending physician) Performance status Karnofsky 60-100% (at time of post-transplant relapse) Life expectancy Not specified Hematopoietic Not specified Hepatic Not specified Renal Not specified Other No preexisting major nonhematopoietic organ toxicity ≥ grade 3 (at time of post-transplant relapse) PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Concurrent immunosuppressive steroid therapy for GVHD allowed provided both of the following are true: Able to taper steroid dose to < 0.5 mg/kg/day No increase of > 1 grade in acute GVHD OR progression of chronic GVHD within 14 days after dose change Radiotherapy Not specified Surgery Not specified

Sites / Locations

  • Fred Hutchinson Cancer Research Center

Outcomes

Primary Outcome Measures

Toxicity

Secondary Outcome Measures

In vivo persistence of adoptively transferred T cells
Migration of adoptively transferred T cells to the bone marrow
Antileukemic activity

Full Information

First Posted
April 5, 2005
Last Updated
September 16, 2010
Sponsor
Fred Hutchinson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT00107354
Brief Title
Cellular Adoptive Immunotherapy in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndromes That Relapsed After Donor Stem Cell Transplant
Official Title
Phase I Study of Adoptive Immunotherapy With CD8 Minor Histocompatibility (H) Antigen-Specific CTL Clones for Patients With Relapsed of AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant
Study Type
Interventional

2. Study Status

Record Verification Date
September 2010
Overall Recruitment Status
Completed
Study Start Date
December 1998 (undefined)
Primary Completion Date
August 2009 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Fred Hutchinson Cancer Center

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Biological therapies, such as cellular adoptive immunotherapy, stimulate the immune system in different ways and stop cancer cells from growing. PURPOSE: This phase I trial is studying the side effects of cellular adoptive immunotherapy in treating patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes that relapsed after donor stem cell transplant.
Detailed Description
OBJECTIVES: Primary Determine the toxic effects of adoptive immunotherapy comprising CD8-positive minor histocompatability antigen-specific cytotoxic T-lymphocytes in patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes that relapsed after allogeneic hematopoietic stem cell transplantation. Secondary Determine the persistence of adoptively transfused T cells in vivo and assess their migration to the bone marrow in these patients. Determine the anti-leukemic activity of this therapy in these patients. OUTLINE: This is a pilot, open-label, nonrandomized study. Leukapheresis: Patients undergo leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) before transplantation. Donors undergo leukapheresis to obtain PBMCs to use as feeder cells for generating adoptive immunotherapy. Patient PBMCs are combined with donor PBMCs and expanded in vitro to generate CD8-positive minor histocompatability antigen-specific cytotoxic T-lymphocytes (CTLs) for adoptive immunotherapy. Transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell transplantation. Patients with a morphologic or flow cytometric relapse on or after day 100 post-transplantation proceed to cytoreductive chemotherapy. Patients with a molecular or cytogenetic relapse on or after day 100 post-transplantation proceed directly to adoptive immunotherapy. Patients with relapsed disease before day 100 post-transplantation are eligible to receive adoptive immunotherapy at a later date provided the patient continues to relapse and CTLs are available. Cytoreductive chemotherapy: The chemotherapy regimen for each patient is determined after consideration of prior chemotherapy, type of leukemia, and other clinical parameters. Two regimens to consider are: Mitoxantrone IV and etoposide IV on days -6 to -2 High-dose cytarabine IV over 2 hours twice daily on days -6, -4, and -2 Patients achieving a complete remission after completion of cytoreductive chemotherapy proceed to adoptive immunotherapy. Adoptive immunotherapy: Within 2-3 days after completion of cytoreductive chemotherapy, patients receive CTLs IV over 1-2 hours on days 0, 4, 11, 21, and 28 in the absence of unacceptable toxicity. Patients with evidence of persistent disease on or after day 35 OR relapsed disease after an initial response to CTLs receive a sixth infusion of CTLs followed, no more than 24 hours later, by interleukin-2 subcutaneously once daily for up 14 total doses in the absence of unacceptable toxicity. Patients with subsequent relapsed disease after day 48 may be eligible for retreatment. After completion of study treatment, patients are followed with bone marrow aspiration every 3 months for 1 year. PROJECTED ACCRUAL: A total of 25-30 patients (10-15 with acute myeloid leukemia or myelodysplastic syndromes AND 10-15 with acute lymphoblastic leukemia) will be accrued for this study within 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelodysplastic Syndromes
Keywords
recurrent adult acute lymphoblastic leukemia, recurrent adult acute myeloid leukemia, recurrent childhood acute lymphoblastic leukemia, recurrent childhood acute myeloid leukemia, secondary acute myeloid leukemia, refractory anemia with excess blasts in transformation, refractory anemia with excess blasts, 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), de novo myelodysplastic syndromes, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, T-cell adult acute lymphoblastic leukemia, T-cell childhood acute lymphoblastic leukemia, B-cell adult acute lymphoblastic leukemia, B-cell childhood acute lymphoblastic leukemia, childhood myelodysplastic syndromes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Masking
None (Open Label)

8. Arms, Groups, and Interventions

Intervention Type
Biological
Intervention Name(s)
aldesleukin
Intervention Type
Biological
Intervention Name(s)
therapeutic allogeneic lymphocytes
Intervention Type
Biological
Intervention Name(s)
therapeutic autologous lymphocytes
Intervention Type
Drug
Intervention Name(s)
cytarabine
Intervention Type
Drug
Intervention Name(s)
etoposide
Intervention Type
Drug
Intervention Name(s)
mitoxantrone hydrochloride
Intervention Type
Procedure
Intervention Name(s)
allogeneic bone marrow transplantation
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Primary Outcome Measure Information:
Title
Toxicity
Secondary Outcome Measure Information:
Title
In vivo persistence of adoptively transferred T cells
Title
Migration of adoptively transferred T cells to the bone marrow
Title
Antileukemic activity

10. Eligibility

Sex
All
Minimum Age & Unit of Time
14 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Undergoing allogeneic hematopoietic stem cell transplantation* from a major histocompatability complex (MHC)-identical related donor for 1 of the following: Primary refractory acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) AML or ALL beyond first remission Therapy-related AML at any stage Philadelphia chromosome (bcr-abl)-positive p190-positive ALL at any stage Acute leukemia at any stage arising from myelodysplastic syndromes or myeloproliferative disorders, including any of the following: Chronic myelomonocytic leukemia Chronic myelogenous leukemia Polycythemia vera Essential thrombocytosis Agnogenic myeloid metaplasia with myelofibrosis Refractory anemia with excess blasts Refractory anemia with excess blasts in transformation NOTE: *Patients must be enrolled on study prior to undergoing transplantation Relapsed disease post-transplantation, as evidenced by 1 of the following criteria: Morphologic relapse, as defined by 1 or more of the following: Peripheral blasts in the absence of growth factor therapy Bone marrow blasts > 5% of nucleated cells Extramedullary chloroma or granulocytic sarcoma Flow cytometric relapse, as defined by the appearance of cells with abnormal immunophenotype consistent with leukemia relapse in the peripheral blood or bone marrow (detected before transplantation) Cytogenetic relapse, as defined by the appearance in 1 or more metaphases from bone marrow or peripheral blood cells of either a non-constitutional cytogenetic abnormality detected in at least 1 cytogenetic study performed before transplantation OR a new abnormality known to be associated with leukemia Molecular relapse, as defined by 1 of the following: 1 or more positive polymerase chain reaction (PCR) assays for clonotypic immunoglobulin heavy chain or T-cell receptor gene rearrangement in patients transplanted for B- or T-cell ALL respectively 1 or more positive post-transplantation reverse transcription PCR assays for p190 BCR-ABL mRNA fusion transcripts in patients transplanted for Philadelphia chromosome-positive p190-positive ALL No grade III or IV acute graft-versus-host disease (GVHD)** No extensive chronic GVHD** NOTE: **At time of post-transplant relapse PATIENT CHARACTERISTICS: Age 14 and over (patients < 14 years of age may be eligible if they are deemed to be of sufficient height and weight by the pediatric attending physician) Performance status Karnofsky 60-100% (at time of post-transplant relapse) Life expectancy Not specified Hematopoietic Not specified Hepatic Not specified Renal Not specified Other No preexisting major nonhematopoietic organ toxicity ≥ grade 3 (at time of post-transplant relapse) PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Concurrent immunosuppressive steroid therapy for GVHD allowed provided both of the following are true: Able to taper steroid dose to < 0.5 mg/kg/day No increase of > 1 grade in acute GVHD OR progression of chronic GVHD within 14 days after dose change Radiotherapy Not specified Surgery Not specified
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Edus H. Warren, MD, PhD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109-1024
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
20071660
Citation
Warren EH, Fujii N, Akatsuka Y, Chaney CN, Mito JK, Loeb KR, Gooley TA, Brown ML, Koo KK, Rosinski KV, Ogawa S, Matsubara A, Appelbaum FR, Riddell SR. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens. Blood. 2010 May 13;115(19):3869-78. doi: 10.1182/blood-2009-10-248997. Epub 2010 Jan 13.
Results Reference
derived
PubMed Identifier
18299450
Citation
Rosinski KV, Fujii N, Mito JK, Koo KK, Xuereb SM, Sala-Torra O, Gibbs JS, Radich JP, Akatsuka Y, Van den Eynde BJ, Riddell SR, Warren EH. DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells. Blood. 2008 May 1;111(9):4817-26. doi: 10.1182/blood-2007-06-096313. Epub 2008 Feb 25.
Results Reference
derived

Learn more about this trial

Cellular Adoptive Immunotherapy in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndromes That Relapsed After Donor Stem Cell Transplant

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