Donor, Hematopoietic Cell Transplant Recipient, HLA-A*0201 Positive Cells Present, Recurrent Acute Myeloid Leukemia, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Therapy-Related Acute Myeloid Leukemia
Conditions
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.
Interventions
BIOLOGICALAldesleukin
Given SC
DRUGCyclophosphamide
Given IV
DRUGFludarabine Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
BIOLOGICALWT1-Sensitized Allogeneic T-Lymphocytes
Given IV
Sponsors
National Cancer Institute (NCI)
Fred Hutchinson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) | 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 |
| 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| 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 |
Countries
United States
Participant flow
Pre-assignment details
47 participants were enrolled on the study, meaning they signed the consent for treatment. However, 19 did not move on to treatment for various reasons.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (High-risk for Relapse After HCT) 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.
Aldesleukin: Given SC
Laboratory Biomarker Analysis: Correlative studies
WT1-Sensitized Allogeneic T-Lymphocytes: Given IV | 13 |
| Arm II (Relapsed After HCT) 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.
Aldesleukin: Given SC
Cyclophosphamide: Given IV
Fludarabine Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies
WT1-Sensitized Allogeneic T-Lymphocytes: Given IV | 15 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 8 |
Baseline characteristics
| Characteristic | Arm I (High-risk for Relapse After HCT) | Arm II (Relapsed After HCT) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical >=65 years | 4 Participants | 3 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 10 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 15 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 15 Participants | 28 Participants |
| Region of Enrollment United States | 13 participants | 15 participants | 28 participants |
| Sex: Female, Male Female | 5 Participants | 9 Participants | 14 Participants |
| Sex: Female, Male Male | 8 Participants | 6 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 8 / 15 |
| other Total, other adverse events | 12 / 13 | 15 / 15 |
| serious Total, serious adverse events | 5 / 13 | 5 / 15 |
Outcome results
Primary
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.
Time frame: Up to 1 year
Population: 4 patients in Arm II did not relapse and were not assessed. 1 pt progressed at their D365 visit timepoint which landed on D367. They were included in the count of participants that passed within their 1 year follow-up timeframe.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Anti-leukemic Potential Efficacy, in Terms of Duration of Response (Arm II) | 28 days |
Primary
Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm I)
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm I) | 6 Participants |
Primary
Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm II)
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Count of Participants Who Experienced Chronic Graft Versus Host Disease (GVHD) (Arm II) | 8 Participants |
Primary
Count of Participants Who Experienced Grade III-IV Acute Graft-versus-host Disease (GVHD) (Arm I)
Time frame: Up to 1 year
Population: All patients were evaluated for aGvHD greater than or equal to Grade 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Count of Participants Who Experienced Grade III-IV Acute Graft-versus-host Disease (GVHD) (Arm I) | 1 Participants |
Primary
Count of Participants Who Experienced Grade III-IV Acute Graft Versus Host Disease (GVHD) (Arm II)
Time frame: Up to 1 year following infusion per patient
Population: 2 patients were unevaluable for this outcome due to old documentation, unable to discern if the patient had acute GvHD greater than or equal to grade 3.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Count of Participants Who Experienced Grade III-IV Acute Graft Versus Host Disease (GVHD) (Arm II) | 0 Participants |
Primary
Efficacy, in Terms of Relapse Rate (Arm I)
Time frame: At 1 year post-transplant
Population: No patients in Arm I relapsed, so overall number of participants analyzed is 0
Primary
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
Time frame: Up to 30 days after last study intervention per patient
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Treatment-related Toxicity Rate (Arm I) | 12 Participants |
Primary
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
Time frame: Up to 30 days after last study intervention per patient
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Treatment-related Toxicity Rate (Arm II) | 15 Participants |
Secondary
Disease-free Survival After T Cell Therapy
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Disease-free Survival After T Cell Therapy | 13 Participants |
| Arm II (Relapsed After HCT) | Disease-free Survival After T Cell Therapy | 7 Participants |
Secondary
Incidence of Relapse After T Cell Therapy (Arm II)
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Incidence of Relapse After T Cell Therapy (Arm II) | 9 Participants |
Secondary
Maintenance of Function of Transduced T Cells (Arm I)
Time frame: Up to 28 days post intervention per patient
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Maintenance of Function of Transduced T Cells (Arm I) | 9 Participants |
Secondary
Maintenance of T Cell Receptor (TCR) Expression of Transduced T Cells (Arm I) i.e. Persistence
Time frame: Up to 28 days post intervention per patient
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 2 (Avelumab, MHC Class I Up-regulation, T Cells) | Maintenance of T Cell Receptor (TCR) Expression of Transduced T Cells (Arm I) i.e. Persistence | 12 Participants |
Secondary
Time to Progression After T Cell Therapy (Arm I)
Time frame: Up to 1 year
Population: No patients analyzed because no patients relapsed in Arm I