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Leukemia, Acute Myelogenous (AML)Phase 1/2NCT00923910

Wilm's Tumor 1 Protein Vaccine to Treat Cancers of the Blood

A Phase 1/2 study testing WT1 Peptide-Pulsed Dendritic Cells, Donor Lymphocytes and IL-4 in people with Leukemia, Acute Myelogenous (AML) and Leukemia, Acute Lymphocytic (ALL), run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Background: Most patients with acute lymphoblastic leukemia (ALL) and many patients with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and non-Hodgkin's lymphoma (NHL) have a protein called Wilm's Tumor 1 (WT1) in their cancer cells. Read more about this study

Who is it for?
Ages 1 year to 74 years
What is being tested?
WT1 Peptide-Pulsed Dendritic Cells, Donor Lymphocytes and IL-4
Could I receive a placebo?
No, everyone receives an active treatment
How many people
10 participants
Where
1 siteUnited States
Study dates
22 Feb 2008to 15 Nov 2016
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 74 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Age greater than 1 year and less than 75 years.
  • One of the following Wilm's Tumor 1 (WT1)-expressing hematologic malignancies:
  • Acute lymphocytic leukemia (ALL), less than or equal to 25 percent marrow blasts.
  • Acute myelogenous leukemia (AML), less than or equal to 25 percent marrow blasts.
  • Chronic myelogenous leukemia (CML).
  • Chronic phase, recurrent after or resistant to donor lymphocyte infusion (DLI) or resistant to available abl kinase inhibitors
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  • Accelerated phase, less than 20 percent marrow blasts
  • Blastic phase, less than or equal to 25 percent marrow blasts
  • Myelodysplastic syndrome (MDS), less than 20 percent marrow blasts.
  • Non-Hodgkin's lymphoma (NHL), stage 4, less than or equal to 25 percent marrow blasts.
  • Hodgkin's lymphoma (HL)
  • There will be no restriction on the volume of extramedullary disease, with the exceptions of exclusions for central nervous system involvement or progression deemed unacceptably rapid.
  • WT1 expression will be confirmed by at least one of the following criteria:
  • Greater than 15 percent of malignant cells react with anti-WT1 by immunohistochemistry.
  • Positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control.
  • Human leukocyte antigen (HLA-A2) plus (heterozygous expression is acceptable).
  • Prior stem cell transplantation (SCT): Prior HLA-matched (5-6/6 antigen or 8-10/10 allele) related or unrelated allogeneic SCT required. Must be at least 42 days post-transplant, have had recovery of transplant-associated toxicity to less than grade 2, and have post-transplant donor engraftment as defined by donor chimerism greater than 50 percent (peripheral blood), neutrophil recovery to an absolute neutrophil count (ANC) greater than 500/microl independent of myeloid growth factors, and platelet recovery to greater than 20,000/microL independent of transfusion.
  • Disease status: Post-transplant residual or relapsed disease. Minimal residual disease (MRD) by polymerase chain reaction (PCR) or flow cytometry is acceptable in accordance with standard disease-specific diagnostic criteria.
  • Availability of previous allogeneic donor to donate cells again.
  • Prior therapy: Disease-specific therapy must be stopped at least 14 days prior to protocol Cycle 1 Day 1 (C1D1) and recovery of treatment-associated toxicity to greater than grade 2 is required prior to initiation of protocol therapy. Patients may have received prior DLI, but the last dose must be at least 28 days prior to C1D1 and there must be no active graft versus host disease (GVHD) greater than grade 1 acute or extensive chronic. Systemic immunosuppression must be stopped at least 28 days prior to protocol C1D1 and there must be no active GVHD greater than grade 1 acute or extensive chronic. There is no time restriction in regard to prior intrathecal chemotherapy provided there is complete recovery from any acute toxic effects of such. Patients receiving hydroxyurea are allowed.
  • Performance status of 0, 1, 2, or 3.
  • Renal function: Patients must have a serum creatinine less than or equal to 1.5 times the upper limit of normal based on age-specific normal range OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m^2.
  • Hepatic function: Patients must have a total bilirubin less than or equal to 2.0 mg/dl and alanine aminotransferase (ALT) less than or equal to 5 times the upper limit of normal based on age- specific normal ranges.
  • Ability to give informed consent. For patients less than 18 years of age, their legal guardian must give informed consent. Pediatric patients will be included in age appropriate discussion in order to obtain verbal assent.
  • Recipients of unrelated donor transplants must sign a release of information form to authorize National Marrow Donor Program (NMDP) transfer of information to the National Institutes of Health (NIH).
  • Subjects of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while they are being treated on this study.
  • Weight greater than or equal to 18 kg, and for unrelated donors only age greater than or equal to 18 years
  • Previous HLA-matched related or unrelated allogeneic donor. Donors must be 5-6/6 antigen or 8-10/10 allele matched.
  • HLA-A2 plus (heterozygous expression is acceptable).
  • Adequate venous access for peripheral apheresis, or consent to use a temporary central venous catheter for apheresis.
  • Donor selection will be in accordance with National Institutes of Health (NIH)/Clinical Center (CC) Department of Transfusion Medicine (DTM) criteria and, in the case of an unrelated donor, the National Marrow Donor Program (NMDP) standards. When a potentially eligible recipient of an unrelated donor product is identified, the recipient will complete an NMDP search transfer request to allow NIH NMDP staff to contact the NMDP Coordinating Center, who will, in turn, contact the donor's prior Donor Center. The NMDP Policy for Subsequent Donation Requests will be followed and the appropriate forms (Subsequent Donation Request form and Therapeutic T Cell Collection Prescription) will be submitted as required.
  • Ability to give informed consent. For donors less than 18 years of age, their legal guardian must give informed consent. Pediatric donors must give verbal assent and be cleared by social work and a mental health specialist to participate.

Who cannot join

  • Active graft versus host disease (GVHD) greater than grade 1 acute or extensive chronic.
  • Breast feeding or pregnant females (due to risk to fetus or newborn).
  • Central nervous system (CNS) malignancy by any of the following criteria:
  • Demonstration of malignant cells in the cerebrospinal fluid (CSF) in patients with leukemia or MDS as manifested by CSF white blood cell (WBC) greater than 5/microL and confirmation of CSF blasts.
  • Cranial neuropathies deemed secondary to the underlying malignancy.
  • CNS mass lesions deemed secondary to the underlying malignancy.
Show all 18Show fewer
  • Neuroblastoma (NB): History of CNS involvement without current evidence of CNS malignancy is NOT an exclusion.
  • Rapidly progressive malignancy and/or clinically significant systemic illness (e.g., severe unstable infections or organ dysfunction) that in the judgment of the PI would likely compromise the patient's ability to tolerate this therapy or interfere with the study procedures, including but not limited to a life expectancy of less than 3 months.
  • High risk of inability to comply with protocol requirements as determined by principal investigator, social work, and primary team.
  • Human immunodeficiency virus (HIV) infection or human T-lymphotrophic virus type 1 (HTLV-1) infection (due to associated immune suppression and decreased likelihood of developing an immune response to the vaccine and increased risk of severe infection).
  • Active hepatitis B or C infection as defined by seropositive for hepatitis B surface antigen (HbSAg) or hepatitis C and elevated liver transaminases.
  • Corticosteroids (dexamethasone equivalent up to 0.1 mg/kg/day) will be permitted. Topical agents and/or inhaled corticosteroids are permitted.
  • History of medical illness that in the estimation of the principal investigator (PI) or Department of Transfusion Medicine (DTM)/NMDP physician poses prohibitive risk to donation.
  • Anemia (Hb less than 10 gm/dl) or thrombocytopenia (less than 100,000/microliter).
  • Breast feeding or pregnant females (due to risk to fetus or newborn).
  • High risk of inability to comply with protocol requirements as determined by the principal investigator and donor center team.
  • Positive screening test for transfusion-transmissible infection in accordance with DTM or NMDP donation standards.
  • Kaposi's sarcoma

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

Official title: A Pilot Trial of WT1 Peptide-Loaded Allogeneic Dendritic Cell Vaccine and Donor Lymphocyte Infusion for WT1-Expressing Hematologic Malignancies

Background:

  • Most patients with acute lymphoblastic leukemia (ALL) and many patients with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and non-Hodgkin's lymphoma (NHL) have a protein called Wilm's Tumor 1 (WT1) in their cancer cells. This protein is thought to be able to influence the growth of these cancers.
  • A vaccine made with the WT1 protein may boost the immune system to help fight these cancers in patients whose cancer cells contain the protein.
Read more

Objectives:

  • To determine the safety, effectiveness and side effects of giving the WT1 vaccine and donor white blood cells to patients with AML, ALL, CML or NHL who have previously received standard treatment and undergone stem cell transplantation.
  • To determine the immune response to the WT1 vaccine and donor white blood cells in these patients and to determine if the response is related to the amount of WT1 protein in the patient's cancer cells.

Eligibility:

  • Patients between 1 and 75 years of age with the blood antigen human leukocyte antigen (HLA-A2) and the WT1 cancer protein who have persistent or recurrent blood cancers after stem cell transplantation.
  • The prior stem cell transplant donor must be willing to provide additional cells, which will be used to prepare the cellular vaccines and for donor lymphocyte (white blood cell) infusions.

Design:

  • Patients are given the WT1 vaccine every 2 weeks for 6 weeks (weeks 0, 2, 4, 6, 8, 10). Each vaccination consists of two injections in the upper arm or thigh.
  • On weeks 0, 4 and 8, patients also receive white blood cells from a donor to enhance the immune response. The cells are also given as a 15- to 30-minute infusion through a vein about 1 hour after the vaccine injection. Donor infusions are given only to patients with mild or no graft-vs-host disease resulting from their prior stem cell transplantation.
  • Periodic physical examinations, blood and urine tests, scans to evaluate disease and other tests as needed are done for 12 months after enrollment in the study.
Read the detailed description

Background:

  • Efforts to incorporate anti-tumor immunotherapy at stages of minimal residual disease (MRD) burden are limited by profound host immune depletion associated with standard anti-cancer therapies.
  • Allogeneic blood and marrow stem cell transplantation (SCT) can be curative for a number of hematologic malignancies. Part of the success of this approach is an allogeneic immunologic reaction that has been demonstrated to play a role in the eradication of residual malignant disease after transplant in certain cancers (the so called graft-versus-leukemia, GVL, or graft-versus-tumor, GVT, effect). Nonetheless, relapse remains the primary cause of treatment failure after allogeneic SCT.
  • The Wilm's tumor 1 (WT1) gene product is a tumor-associated antigen that represents a potential target for immunotherapy in a wide array of cancers. WT1 is expressed in most cases of acute leukemia and in many cases of chronic myelogenous leukemia and myelodysplastic syndromes. Importantly, WT1 has limited expression in normal tissues beyond embryogenesis. This trial represents an attempt to incorporate antigen-specific immunotherapy in the setting of allogeneic adoptive cell transfer.

Objectives:

  • To determine the safety, toxicity, and feasibility of donor-derived dendritic cell vaccination and donor lymphocyte infusion (DLI) after allogeneic SCT.
  • To determine the frequency and severity of graft-vs.-host disease (GVHD) in patients treated with peptide-loaded donor-derived dendritic cell vaccination and donor lymphocyte infusion (DLI).
  • To evaluate whether immunologic responses to WT1-specific peptides can be generated by peptide-loaded donor-derived dendritic cell vaccination and DLI after allogeneic SCT.
  • To evaluate whether clinical responses to WT1-specific peptides can be generated by peptide-loaded donor-derived dendritic cell vaccination and DLI after allogeneic SCT.
  • To evaluate whether immunologic and/or clinical responses may be associated with the degree of WT1 expression by malignant cells or pre-existing donor anti-WT1 immunity.

Eligibility:

  • HLA-A2 plus patients may be enrolled on this trial if they have relapsed or residual disease following allogeneic SCT for a WT1 expressing hematologic malignancy.
  • Donors from the previous SCT, related or unrelated, must be 5- or 6- antigen genotypic HLA-matched (single HLA-A or B locus mismatch allowed) and HLAA2 plus.

Design:

  • This is a pilot study, the primary aim of which is to assess safety and feasibility of this novel vaccine strategy aimed to enhance the GVL effect after allogeneic SCT.
  • Donor-derived dendritic cells prepared from peripheral blood monocytes will be loaded with a combination of three WT1-derived peptides. These peptides are each comprised of one WT1-derived oligomeric epitope known to bind to HLA-A2 and an 11-mer protein transduction epitope known to enhance peptide loading and antigen presentation.
  • Patients will receive donor-derived dendritic cell vaccines every 14 days for 6 doses. Donor leukocyte infusions (DLI) will also be administered with the vaccine.
  • Study endpoints will include toxicity, feasibility, antigen-specific immunity, and disease response.
  • This is an exploratory pilot trial. Up to 12 patients will be treated.
  • Stopping rules will take effect if excessive toxicity (e.g., GVHD) or inability to generate vaccines are observed.
Being tested
WT1 Peptide-Pulsed Dendritic Cells, Donor Lymphocytes, IL-4, KLH, WT1 Peptides
Keywords
WT1 Peptide Dendritic Cell Vaccine, Hematologic Malignancies, Relapse After Allogeneic Stem Cell Transplantation, Donor Lymphocyte Infusions, WT1-Positive, Dendritic Cell Vaccine, Tumor Immunotherapy, Allogeneic Adoptive Immunotherapy, Hodgkins Lymphoma, Leukemia, Acute Myelogenous Leukemia, AML, Acute Lymphocytic Leukemia, ALL, Chronic Myelogenous Leukemia, CML, Myelodysplasia Syndrome, Non-Hodgkin Lymphoma
Medical subject headings
Leukemia, Myeloid, Acute, Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Myelodysplastic Syndromes, Lymphoma, Non-Hodgkin, Hematologic Neoplasms, Hodgkin Disease, Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • WT1 Peptide-Pulsed Dendritic CellsDrug

    Also called Wilm's Tumor 1

  • Donor LymphocytesDrug

    Lymphocytes from donors (related or unrelated) collected via lymphapheresis.

  • IL-4Drug

    Also called Interleukin-4

    water-soluble protein; this study will use GMCSF (granulocyte macrophage colony stimulating factor)/IL-4 generated monocyte derived dendritic cells

  • KLHDrug

    Also called keyhole limpet hemocyanin

    Neoantigen known to induce helper responses; will be used concurrently as a vaccine adjuvant and control antigen.

  • WT1 PeptidesDrug

    dendritic cell vaccine

  • EndotoxinDrug

    Purified lipopolysaccharide prepared from E.Coli 0:113

  • DiphenhydramineDrug

    Also called Benadryl

    Pre-medication

  • AcetaminophenDrug

    Also called Tylenol

    Pre-medication

Study groups in NCT00923910
Study groupRoleWhat they receive
DonorsOtherRelated and unrelated donors undergo lymphapheresis to prepare cellular vaccines and to donate lymphocytes for infusion.
Receives: Drug: Donor Lymphocytes; Drug: Diphenhydramine; Drug: Acetaminophen
RecipientsExperimentalParticipants receive donor lymphocytes and vaccines prepared from donors.
Receives: Drug: WT1 Peptide-Pulsed Dendritic Cells; Drug: Donor Lymphocytes; Drug: IL-4; Drug: KLH; Drug: WT1 Peptides; Drug: Endotoxin; Drug: Diphenhydramine; Drug: Acetaminophen

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Toxicity

    Here is the number of participants with adverse events. For details of the adverse events, see the adverse event module.

    Measured: 21 months

  2. Number of Participants With Graft Versus Host Disease (GVHD) Greater Than or Equal to Grade 3

    Acute Graft versus Host Disease (GVHD) was graded by the modified Glucksberg scale. 0 = no GVHD normal, 4 = severe GVHD.

    Measured: 28 days following completion of last vaccine and/or DLI (donor lymphocyte infusion) administration

Secondary outcomes (5)

  1. Time to Immune Response

    Immune response was monitored by use of interferon gamma Enzyme-Linked Immunospot (ELISpot) and by delayed-type hypersensitivity (DTH) testing.

    Measured: 4 to 12 weeks

  2. Wilm's Tumor 1 (WT1) Enzyme-Linked Immunospot (ELISpot)

    WT1 expression of the hematologic malignancy was confirmed by either having greater than 15% of malignant cells react with anti-WT1 by immunohistochemistry or by having a positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control.

    Measured: 48 to 72 hours after placement

  3. Wilm's Tumor (WT1) Delayed-type Hypersensitivity (DTH)

    WT1 expression of the hematologic malignancy was confirmed by either having greater than 15% of malignant cells react with anti-WT1 by immunohistochemistry or by having a positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control. DTH skin testing was performed using KLH and with a cocktail of WT1 peptides as 2 separate injections. Enzyme-Linked Immunospot (ELISpot) was performed against each peptide and was considered positive if results were at least 10 spots above background on at least 2 measurements. DTH was considered positive if there was at least .5cm induration 48 to 72 hours after placement.

    Measured: 48 to 72 hours after placement

  4. Keyhole Limpet Hemocyanin (KLH) Delayed-type Hypersensitivity (DTH)

    KLH is a neoantigen known to induce helper response was used concurrently as a vaccine adjuvant and control antigen. DTH skin testing was performed using KLH and with a cocktail of WT1 peptides as 2 separate injections. Enzyme-Linked Immunospot (ELISpot) was performed against each peptide and was considered positive if results were at least 10 spots above background on at least 2 measurements. DTH was considered positive if there was at least .5cm induration 48 to 72 hours after placement.

    Measured: 48 to 72 hours after placement

  5. Number of Participants With Progressive Disease

    Progressive disease is at least a 20% increase in the sum of the longest diameter of all target lesions (i.e. tumor response). Response criteria for acute leukemia's is worse marrow classification (i.e., M status) with at least a 50% increase in the percentage of marrow blasts, or no change in marrow classification (i.e., M status), but a 50% or greater increase in absolute peripheral blast count or extent of medullary disease

    Measured: 4 to12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jun 2009 (estimated)
  2. Study start22 Feb 2008
  3. Primary completion18 Oct 2013
  4. Study completion15 Nov 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
10 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00923910
Sponsor's protocol ID
080051
Other IDs
08-C-0051
Status last verified
Mar 2017
First submitted
17 Jun 2009
Last updated
12 Apr 2017
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Appelbaum FR. Graft versus leukemia (GVL) in the therapy of acute lymphoblastic leukemia (ALL). Leukemia. 1997 May;11 Suppl 4:S15-7.

    PubMed 9179275

  • Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L, Buckner CD, Anasetti C, Appelbaum FR, Badger C, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood. 1989 May 1;73(6):1720-8.

    PubMed 2653460

  • Witz JP, Roeslin N, Avalos S, Morand G, Wihlm JM. [Benign tracheo-bronchial tumors. Other tumors]. Ann Chir. 1979 Oct;33(8):541-4. No abstract available. French.

    PubMed 229756

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing WT1 Peptide-Pulsed Dendritic Cells, Donor Lymphocytes and IL-4 in people with Leukemia, Acute Myelogenous (AML) and Leukemia, Acute Lymphocytic (ALL), run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Apr 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 May 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Toxicity (time frame: 21 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00923910, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Apr 2017.

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