Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Biological Therapy in Treating Patients With Advanced Acute or Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia Who Are Undergoing Stem Cell Transplantation

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	75 and under	NCI	FHCRC-1655.00 5430, NCT00052520

Objectives

Primary

1. Determine the safety and potential toxicities associated with infusing donor CD8+ CTL clones for WT1 in patients at high risk for post-transplant relapse of myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL).

Secondary

1. Determine the in vivo persistence of transferred T-cells and assess migration to the bone marrow, predominant site of leukemic relapse.
2. Determine if adoptively transferred WT1-specific T-cells mediate antileukemic activity.

Entry Criteria

Disease Characteristics:

• Planned allogeneic stem cell transplantation for one of the following diagnoses:
  • Refractory anemia with excess blasts (RAEB)
  • Refectory anemia with excess blast in transformation (RAEB-t)
  • Chronic myelogenous leukemia (CML) beyond chronic phase
  • Primary refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL)
  • AML or ALL beyond first remission
  • Therapy-related AML at any stage
  • Philadelphia chromosome-positive ALL at any stage
  • Acute leukemia at any stage arising from myelodysplastic or myeloproliferative syndromes, including:
    • Chronic myelomonocytic leukemia
    • CML
    • Polycythemia vera
    • Essential thrombocytosis
    • Angiogenic myeloid metaplasia with myelofibrosis



• Patient and donor must both express an HLA-allele for which it is possible to generate WT1-specific clones



• No grade III or IV graft-versus-host disease unresponsive to therapy or requiring therapy with any of the following:
  • Prednisone or corticosteroid equivalent > 0.5 mg/kg/day
  • Anti-CD3 monoclonal antibody
  • Other treatments resulting in T-cell inactivation or ablation



• No graft rejection or failure



• Able and willing to provide blood and bone marrow samples



• Highest-risk disease group: More than 5% blasts detected in bone marrow or peripheral blood just prior to or at time of transplantation



• Relapsed-disease group: One of the following types of relapsed disease after transplantation:
  • Morphologic relapse defined by one or more of the following:
    • Peripheral blasts in absence of growth factor therapy
    • Bone marrow blasts more than 5% of nucleated cells
    • Extramedullary chloroma or granulocytic sarcoma
  • Cells with abnormal immunophenotype and consistent with leukemia relapse in the peripheral blood or bone marrow detected by flow cytometry
  • Cytogenetic relapse defined as the appearance in 1 or more metaphases from peripheral blood or bone marrow of either a non-constitutional cytogenetic abnormality identified in at least 1 cytogenetic study performed before transplantation or a new abnormality known to be associated with leukemia
  • An increase in the number of Philadelphia chromosome metaphases from bone marrow or peripheral blood between 2 consecutive samples in patients with CML
  • An increase in the percentage of bcr-abl positive cells by fluorescence in situ hybridization between 2 consecutive samples
  • Molecular relapse defined as one of the following:
    • 1 or more positive PCR assays for clonotypic immunoglobulin heavy chain (IgH) gene rearrangement for patients with B-cell ALL
    • 1 or more positive PCR assays for T-cell receptor (TCR) gene rearrangement for patients with T-cell ALL
    • 1 or more positive post-transplantation reverse transcription PCR assays for bcr-abl mRNA fusion transcripts in patients with bcr-abl-positive ALL
    • A positive PCR assay for bcr-abl mRNA fusion transcript that quantitatively increases by > 1 order of magnitude on a subsequent sample in patients with CML

Prior/Concurrent Therapy:

Biologic therapy

• See Disease Characteristics

Chemotherapy

• No concurrent hydroxyurea

Endocrine therapy

• See Disease Characteristics
• Concurrent immunosuppressive therapy for graft-versus-host disease (GVHD) allowed if meets 1 of the following criteria:
  • Corticosteroid dose can be tapered to no more than 0.5 mg/kg/day without an increase to grade III or IV acute GVHD or progression of chronic GVHD

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No other concurrent agents that may interfere with the function or survival of infused CTL clones

Patient Characteristics:

Age

• 75 and under

Performance status

• Karnofsky 40-100%

  OR

• Lansky 40-100%

Life expectancy

• Not specified

Other

• No pre-existing nonhematopoietic organ toxicity greater than grade 2

Expected Enrollment

A total of 10-15 patients will be accrued for this study within 3-5 years.

Outcomes

Safety and toxicity by Common Toxicity Criteria at 2 years
Aplasia

In vivo persistence of transferred T cells and migration to the bone marrow by Multimer staining and T-cell receptor analysis periodically up to 2 years or until no detectable clones
Antileukemic activity by clinical response (bone marrow and peripheral blood analysis) periodically up to 2 years
Hematopoietic suppression (i.e., neutropenia, lymphopenia, thrombocytopenia, and anemia)
Grade 3 or 4 renal dysfunction
Grade 3 or 4 toxicity in any organ system
Efficacy as measured by response rate and remission

Outline

This is a pilot study.

Donors undergo leukapheresis for stem cell harvest to generate CD8-positive Wilms' tumor (WT1) gene-specific cytotoxic T-lymphocyte (CTL) clones at the time of allogeneic stem cell transplantation.

After post-transplantation hematopoietic recovery, patients receive treatment for either highest-risk disease (prophylactically) or relapsed disease.

• Highest-risk disease group: Patients receive CD8-positive Wilms' tumor (WT1) gene-specific CTL clones IV over 1-2 hours on days 0, 14, and 28. Patients receive interleukin-2 subcutaneously twice daily on days 28-42 in the absence of unacceptable toxicity.



• Relapsed-disease group: Some patients with evidence of leukemic relapse may receive standard salvage chemotherapy prior to donor CTL infusions and then receive CD8-positive Wilms' tumor (WT1) gene-specific CTL clones and interleukin-2 as in the highest-risk group.

Patients in both groups who have progressive disease after complete or partial response to therapy may be eligible for retreatment with CD8-positive Wilms' tumor (WT1) gene-specific CTL clones.

Blood samples may be collected monthly and patients may undergo a bone marrow biopsy every 3 months. Samples are analyzed for WT1 specific T cells via multimer staining and flow cytometric analysis; functional anti-WT1 activity; other immunological parameters; WT 1 expression; and potential genetic markers. In addition samples may be assessed by morphology, flow cytometry, PCR or cytogenetic analysis.

After completion of study treatment, patients are followed for up to 2 years.

Trial Contact Information

Trial Lead Organizations

Fred Hutchinson Cancer Research Center

Gunnar Ragnarsson, MD, MSC, Protocol chair		Ph: 206-667-5918 Email: gunnib@u.washington.edu

U.S.A.
Washington
	Seattle
	Fred Hutchinson Cancer Research Center
		Gunnar Ragnarsson, MD, MSC	Ph:  206-667-5918
			Email: gunnib@u.washington.edu
	Seattle Cancer Care Alliance
		Clinical Trials Office - Seattle Cancer Care Alliance	Ph:  800-804-8824

Registry Information
Official Title		Phase I/II Study Of Adoptive Immunotherapy With CD8+ WT1-Specific CTL Clones for Patients with Advanced MDS, CML, AML or ALL After Allogeneic Hematopoietic Stem Cell Transplant
Trial Start Date		2002-09-09
Trial Completion Date		2010-08-15 (estimated)
Registered in ClinicalTrials.gov		NCT00052520
Date Submitted to PDQ		2002-10-09
Information Last Verified		2009-07-05
NCI Grant/Contract Number		CA18029, CA96669, CA15704

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