Laboratory-Treated T Cells in Treating Patients With High-Risk Relapsed Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelogenous Leukemia Previously Treated With Donor Stem Cell Transplant

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects of laboratory-treated T cells and to see how well they work in treating patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia (CML) that has returned after a period of improvement (relapsed), previously treated with donor stem cell transplant. Biological therapies, such as cellular adoptive immunotherapy, may stimulate the immune system in different ways and stop cancer cells from growing. Placing a gene that has been created in the laboratory into a person's T cells may make the body build an immune response to kill cancer cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the safety and potential toxicities associated with treating patients with high risk or relapsed AML, MDS, and CML after allogeneic hematopoietic cell transplantation (HCT) by adoptive transfer of virus-specific cluster of differentiation (CD)8 T cells genetically-modified to express a high affinity Wilms tumor 1 (WT1)-specific T cell receptor (TCR). II. Determine the anti-leukemic activity associated with treating patients with relapsed AML, MDS and CML after allogeneic HCT by adoptive transfer of virus-specific CD8 T cells genetically-modified to express a high affinity WT1-specific T cell receptor (TCR). SECONDARY OBJECTIVES: I. Determine the in vivo persistence of transferred T cells and ability to migrate to and accumulate in bone marrow. II. Determine the maintenance of TCR expression and function of transduced T cells. OUTLINE: Patients are assigned to 1 of 2 treatment arms. ARM I: Patients with no evidence of leukemia post-HCT receive WT1-sensitized T cells intravenously (IV) over 45 minutes (or longer for patients who are 15-30 kg) on days 0 and 14 and aldesleukin subcutaneously (SC) twice daily (BID) on days 14-28. ARM II: Patients with evidence of AML (minimal residual disease or overt relapse) post-HCT receive cyclophosphamide IV and fludarabine phosphate IV daily on days -4 to -2. Patients also receive WT1-sensitized T cells IV over 45 minutes (or longer for patients who are 15-30 kg) on days 0 and 21 and aldesleukin SC BID on days 14-28. After completion of study treatment, patients are followed up weekly for 4 weeks, at weeks 6 and 8, at 3, 6, 12 months, and then annually for up to 15 years.

Official Title
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Phase I/II Study of Adoptive Immunotherapy After Allogeneic HCT With Virus Specific CD8+ T Cells That Have Been Transduced to Express a WT1-Specific T Cell Receptor for Patients With Relapsed AML

Conditions
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Donor, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Acute Myeloid Leukemia, Hematopoietic Cell Transplant Recipient, HLA-A*0201 Positive Cells Present, Recurrent Acute Myeloid Leukemia

Intervention / Treatment
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* Biological: Aldesleukin
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Biological: WT1-Sensitized Allogeneic T-Lymphocytes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must express HLA-A*0201 Patients who are currently undergoing or who previously underwent matched allogeneic HCT for: AML: Prospective enrollment will now be limited to patients with relapsed disease (overt relapse or minimal residual disease) at any time post allogeneic HCT MDS will no longer be a criterion for eligibility CML will no longer be a criterion for eligibility Patients must have an HLA-matched donor of hematopoietic stem cells (related or unrelated) Patients must be able to provide blood and bone marrow samples and undergo the procedures required for this protocol Patients must be >= 15 kg, as patients with lower weight would be incapable of providing high volume and frequent blood samples for monitoring and analysis Patients must be able to give informed consent; parent or legal representative will be asked to consent for patients younger than 18 year old DONOR: Patient and donor (related or unrelated) must be HLA-matched and express HLA-A*0201 DONOR: Donor must be Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositive DONOR: Donor must be age 18 or older DONOR: In good general health DONOR: Able to give informed consent Exclusion Criteria: Central nervous system (CNS) tumor refractory to intrathecal chemotherapy and/or cranio-spinal radiation In patients whose leukemic cells are available for evaluation, the expression of WT1 in the patient's bone marrow will be determined; if WT1 expression in the patient's bone marrow is not highly expressed by polymerase chain reaction (PCR), the patient will be excluded from the study; patients with no evaluable leukemia will be eligible for enrollment based on the high frequency of positive leukemias (> 90%), and leukemia will be evaluated for WT1 expression if recurrence is detected Human immunodeficiency virus (HIV) seropositive; testing for HIV should be within 6 months of enrollment Medical or psychological conditions that would make the patient unsuitable candidate for cell therapy at the discretion of the principal investigator (PI) Pregnancy or breast-feeding; women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (B-hCG) pregnancy test result within 14 days before the first dose of WT1-specific T cell infusion; woman of non-childbearing potential will be defined as being postmenopausal greater than one year or who have had a bilateral tubal ligation or hysterectomy; all recipients of WT1-specific T cells will be counseled to use effective birth control during participation in this study and for 12 months after the last T cell infusion DONOR: Less than 18 years old DONOR: Active infectious hepatitis DONOR: HIV or human T-lymphotropic virus (HTLV) seropositive DONOR: Pregnancy or nursing DONOR: Significant medical conditions (e.g. immunosuppressive therapy) that would make the donor an unsuitable T cell donor DONOR: Unable to give informed consent
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (high-risk for relapse after HCT)<br>Patients with no evidence of leukemia or MDS post-HCT receive WT1-sensitized T cells IV over 45 minutes (or longer for patients who are 15-30 kg) on days 0 and 14 and aldesleukin SC BID on days 14-28. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: WT1-Sensitized Allogeneic T-Lymphocytes<br>* Given IV<br>|
| Experimental: Arm II (relapsed after HCT)<br>Patients with evidence of AML (minimal residual disease or overt relapse) post-HCT receive cyclophosphamide IV and fludarabine phosphate IV daily on days -4 to -2. Patients also receive WT1-sensitized T cells IV over 45 minutes (or longer for patients who are 15-30 kg) on days 0 and 21 and aldesleukin SC BID on days 14-28. | Biological: Aldesleukin<br>* Given SC<br>* Other names: Recombinant Human Interleukin-2;Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: WT1-Sensitized Allogeneic T-Lymphocytes<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-leukemic Potential Efficacy, in Terms of Duration of Response (Arm II) | Response is assessed throughout the 1 year post treatment timeframe. Morphologic criteria for response: Complete Response (CR) = Bone Marrow blasts <5%; no blasts with Auer rods; no extramedullary disease. Transfusion independent. Platelets ≥ 100,000/μl Absolute neutrophil count >1000/μl (CRi: incomplete hematologic recovery CRp: incomplete platelet recovery) Partial Response (PR) = Decrease of at least 50% in the percentage of blasts to 5-25% in the bone marrow and the normalization of blood counts as for CR. (PRi and PRp if incomplete hematologic or platelet recovery) Stable Disease (SD) = Failure to achieve at least PR, but no evidence of progression for >4 weeks. | Up to 1 year | 
| Efficacy, in Terms of Relapse Rate (Arm I) |  | At 1 year post-transplant | 
| Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm I) |  | Up to 1 year | 
| Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm II) |  | Up to 1 year | 
| Count of Participants Who Experienced Grade III-IV Acute Graft Versus Host Disease (GVHD) (Arm II) |  | Up to 1 year following infusion per patient | 
| Count of Participants Who Experienced Grade III-IV Acute Graft-versus-host Disease (GVHD) (Arm I) |  | Up to 1 year | 
| Treatment-related Toxicity Rate (Arm I) | Outcome will be reported as a count of participants that experienced adverse events. Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.0 | Up to 30 days after last study intervention per patient | 
| Treatment-related Toxicity Rate (Arm II) | Outcome will be reported as a count of participants that experienced adverse events. Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.0 | Up to 30 days after last study intervention per patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free Survival After T Cell Therapy |  | Up to 1 year | 
| Incidence of Relapse After T Cell Therapy (Arm II) |  | Up to 1 year | 
| Maintenance of T Cell Receptor (TCR) Expression of Transduced T Cells (Arm I) i.e. Persistence |  | Up to 28 days post intervention per patient | 
| Maintenance of Function of Transduced T Cells (Arm I) |  | Up to 28 days post intervention per patient | 
| Time to Progression After T Cell Therapy (Arm I) |  | Up to 1 year |