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About
This phase I/II trial studies the side effects of laboratory-treated (central memory/naive) cluster of differentiation 8+ T cells (autologous Wilms tumor [WT]1-T cell receptor [TCRc]4 gene-transduced CD8-positive central memory T-cells [TCM]/naive T cells [TN] lymphocytes) and how well it works in treating patients with acute myeloid leukemia that is newly diagnosed or has come back. Genetically modified therapies, such as autologous WT1-TCRc4 gene-transduced CD8-positive TCM/TN lymphocytes, are taken from a patient's blood, modified in the laboratory so they specifically may kill cancer cells with a protein called WT1, and safely given back to the patient. The "genetically modified" T-cells have genes added in the laboratory to allow them to recognize leukemia cells that express WT1 and kill them.
Full description
PRIMARY OBJECTIVES:
I. Determine the safety/potential toxicities associated with treating high-risk acute myeloid leukemia (AML) patients with autologous CD8+ T cells (polyclonal Tn and Tcm cells; Epstein-Barr virus-specific T cells [Tebv cells]) that have been genetically-modified to express a high affinity WT1-specific TCR (TCRC4).
II. Determine the feasibility of reproducibly treating high-risk AML patients with autologous CD8+ T cells (polyclonal TN and TCM cells; Tebv cells) that have been genetically-modified to express a high affinity WT1-specific TCR (TCRC4).
III. Determine and compare the in vivo persistence in blood and at the primary tumor site (e.g. bone marrow, chloroma) of transferred autologous CD8+ T cells (polyclonal TN and TCM cells; TEBV cells) that have been genetically-modified to express a high affinity WT1-specific TCR (TCRC4).
EXPLORATORY OBJECTIVES:
I. Determine whether adoptively transferred autologous TCRC4-transduced CD8+ cells have anti-tumor activity in patients with acute myeloid leukemia.
Ia. In patients with measurable minimal residual disease (MRD) at the time of infusion of TCRC4-transduced CD8+ cells, changes in leukemic tumor burden will be measured by morphology, flow cytometry, cytogenetics/fluorescence in situ hybridization (FISH) and/or molecular testing at baseline and after infusion of T cells.
Ib. In all patients (those with or without measurable tumor burden prior to T cell transfer, including patients who convert to MRD-negative status during consolidation), the probability of relapse, disease-free survival and overall survival of patients receiving TCRC4-transduced CD8+ cells will be compared with patients in the observation arm.
II. Determine and compare the migration to the primary tumor site of subsets of the adoptively transferred autologous TCRC4-transduced CD8+ T cells (polyclonal TN and TCM cells; TEBV cells).
III. Determine and compare the in vivo functional capacity of transferred polyclonal autologous TCRC4-transduced CD8+ TCM, TN cells and TEBV CD8+ cells.
OUTLINE:
Beginning 4 weeks after completion of last course of consolidation chemotherapy, patients receive autologous WT1-TCRc4 gene-transduced CD8+ TCM/TN lymphocytes intravenously (IV) over 1-4 hours on day 0 and again after a minimum of 3 weeks. Beginning 6 hours after the second infusion of T cells, patients also receive aldesleukin subcutaneously (SC) twice daily (BID) for 14 days in the absence of disease progression or unacceptable toxicity. Patients who have clinically benefitted from T cell therapy may receive additional infusions of T cells and aldesleukin at the discretion of the principal investigator (PI) and the attending physician.
After completion of study treatment, patients are followed up weekly for 4 weeks, at 2, 3, 6, and 12 months, and then annually for 14 years thereafter.
Enrollment
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Inclusion criteria
Patients with (non-M3) acute myeloid leukemia (AML)
Patients must be >= 15 kg
Patients or parents/legal guardian must be able to give informed consent
Patients must be able to provide blood and marrow samples and to undergo the procedures required for this protocol
Elevated expression of WT1 in pre-treatment bone marrow or peripheral blood by either of two methods:
Demonstration of disease response to induction chemotherapy, in that patients must have achieve a morphologic remission (marrow that is at least 10% cellular with < 5% blasts on morphologic review) after 1-2 induction cycles, regardless of minimal residual disease or incomplete hematologic recovery (CRi)/incomplete platelet recovery (CRp) status
Determination of "high-risk" disease; subjects must meet one of the determinants of "high-risk disease", in terms of being at very high risk for relapse without allogeneic stem cell transplant, as per one of the follow criteria:
A designation of "adverse" risk disease at the time of diagnosis, as defined by cytogenetic and molecular abnormalities specifically outlined in the 2017 European LeukemiaNet (ELN) guidelines for diagnosis and management of AML; these patients will meet "high-risk" designation, regardless of minimal residual disease or CRi/CRp status
Relapsed leukemia; patients with cytogenetic or molecular classification other that adverse risk by ELN who go on to demonstrate disease relapse after a minimum duration of remission of 6 months, but who then attain a second complete remission with repeat induction chemotherapy; these patients will meet "high-risk" designation, regardless of minimal residual disease or CRi/CRp status
Minimal residual disease, as defined by having detectable disease by one of the following criteria, but otherwise being in morphologic remission
MRD by flow cytometry at any time after induction chemotherapy or during consolidation chemotherapy, when patients are otherwise classified as being in morphologic remission, and as defined by any abnormal myeloid blasts identified by flow cytometric analysis
Cytogenetic MRD, as defined by a disease-specific abnormal karyotype at any point in patients who are otherwise in morphologic remission
Molecular minimal residual disease (MRD) with one of the following markers, as specified below, in patients who are otherwise in morphologic remission:
CRi/CRp, as defined by neutrophil count < 1000/ul (CRi) and/or platelet count < 100,000/ul (CRp), but otherwise being in morphologic remission; in pediatric patients, a platelet threshold of < 80,000/ ul will be used, as per consensus pediatric response criteria
Human leukocyte antigen (HLA)-A*02:01 expression must be present for patient to be on treatment arm, HLA-A*02:01 expression absent in patients designated to observation arm
ELIGIBILITY FOR APHERESIS/BLOOD COLLECTION:
• HLA-A*02:01 expression
ELIGIBILITY FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS
Exclusion criteria
EXCLUSION FOR TREATMENT WITH TCRC4-TRANSDUCED CD8+ CELLS
Unable to generate antigen-specific WT1-specific CD8+ T cells for infusions; however, if a lower than planned number of cells is available, the patient will have the option to receive the generated WT1-specific T cells
Systemic steroids should be stopped 2 weeks before the start of treatment; topical and inhaled steroids are allowed
Symptomatic and refractory central nervous system (CNS) leukemia
Absolute neutrophil count (ANC) < 200/ul prior to treatment
Platelets < 20,000/ul prior to treatment
If a patient meets other treatment eligibility but otherwise demonstrates delayed or poor recovery of peripheral blood counts to the above neutrophil and/or platelet thresholds, then treatment with the T cell intervention will be allowed if:
Ongoing >= grade 3 cardiac, pulmonary, renal, gastrointestinal or hepatic toxicities according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4 toxicity criteria
Karnofsky performance status score (age >= 16 years) or Lansky play score (age < 16 years) =< 40%
Medical or psychological conditions that, according to the PI, would make the patient unsuitable candidate for cell therapy
Pregnancy or breast-feeding; women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test result within 14 days before the first dose of WT1-specific T cell infusions; 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
Treatment with alemtuzumab or other T cell-depleting antibodies within 6 months of T cell therapy
Documented new infection within 24 hours of T cell infusion, or concern for new infection as suggested by an oral temperature > 38.2 degrees Celsius (C) within 24 hours of T cell infusion
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9 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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