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 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

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Donor; Hematopoietic Cell Transplant Recipient; HLA-A*0201 Positive Cells Present
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Cyclophosphamide; Biological: Aldesleukin; Drug: Fludarabine Phosphate; Biological: WT1-Sensitized Allogeneic T-Lymphocytes

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Aldesleukin; Given SC; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2; Biological: WT1-Sensitized Allogeneic T-Lymphocytes; Given IV
EXPERIMENTAL: 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Cyclophosphamide; Given IV; Other Names: Cytoxan; CTX; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; Biological: Aldesleukin; Given SC; Other Names: Proleukin; 125-L-Serine-2-133-interleukin 2; r-serHuIL-2; Recombinant Human IL-2; Recombinant Human Interleukin-2; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; Fludara; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; SH T 586; Biological: WT1-Sensitized Allogeneic T-Lymphocytes; Given IV

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Chapuis AG, Egan DN, Bar M, Schmitt TM, McAfee MS, Paulson KG, Voillet V, Gottardo R, Ragnarsson GB, Bleakley M, Yeung CC, Muhlhauser P, Nguyen HN, Kropp LA, Castelli L, Wagener F, Hunter D, Lindberg M, Cohen K, Seese A, McElrath MJ, Duerkopp N, Gooley TA, Greenberg PD. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat Med. 2019 Jul;25(7):1064-1072. doi: 10.1038/s41591-019-0472-9. Epub 2019 Jun 24.
• Oda SK, Daman AW, Garcia NM, Wagener F, Schmitt TM, Tan X, Chapuis AG, Greenberg PD. A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia. Blood. 2017 Nov 30;130(22):2410-2419. doi: 10.1182/blood-2017-04-777052. Epub 2017 Oct 17.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 6, 2012
• Primary Completion (ACTUAL): March 20, 2020
• Study Completion (ACTUAL): March 20, 2020

Study Registration Dates

• First Submitted: November 29, 2011
• First Submitted That Met QC Criteria: July 12, 2012
• First Posted (ESTIMATE): July 13, 2012

Study Record Updates

• Last Update Posted (ACTUAL): July 14, 2022
• Last Update Submitted That Met QC Criteria: June 28, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Recurrence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Aldesleukin; Cyclophosphamide; Fludarabine; Fludarabine phosphate; Interleukin-2
• Other Study ID Numbers: 2498.00 (OTHER: Fred Hutch/University of Washington Cancer Consortium); P01CA018029 (U.S. NIH Grant/Contract); 2498; NCI-2011-03362 (REGISTRY: CTRP (Clinical Trial Reporting Program)); RG9212029 (OTHER: Fred Hutch/University of Washington Cancer Consortium)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No