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

Phase 1

Terminated

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

Interventions: Biological: Aldesleukin
Other: Laboratory Biomarker Analysis
Drug: Cyclophosphamide
Biological: WT1-Sensitized Allogeneic T-Lymphocytes
Drug: Fludarabine Phosphate

Registration Number: NCT01640301

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 47

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (high-risk for relapse after HCT)	Aldesleukin	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.
Arm I (high-risk for relapse after HCT)	Laboratory Biomarker Analysis	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.
Arm I (high-risk for relapse after HCT)	WT1-Sensitized Allogeneic T-Lymphocytes	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.
Arm II (relapsed after HCT)	Aldesleukin	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.
Arm II (relapsed after HCT)	Laboratory Biomarker Analysis	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.
Arm II (relapsed after HCT)	WT1-Sensitized Allogeneic T-Lymphocytes	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.
Arm II (relapsed after HCT)	Cyclophosphamide	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.
Arm II (relapsed after HCT)	Fludarabine Phosphate	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.

Primary Outcome Measures

Name	Time	Method
Anti-leukemic Potential Efficacy, in Terms of Duration of Response (Arm II)	Up to 1 year	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.
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 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
Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm II)	Up to 1 year
Treatment-related Toxicity Rate (Arm I)	Up to 30 days after last study intervention per patient	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
Treatment-related Toxicity Rate (Arm II)	Up to 30 days after last study intervention per patient	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

Secondary Outcome Measures

Name	Time	Method
Incidence of Relapse After T Cell Therapy (Arm II)	Up to 1 year
Disease-free Survival After T Cell Therapy	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