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Acute Myelogenous LeukemiaPhase 1/2NCT00303667

Donor Natural Killer Cells and Aldesleukin in Treating Patients w/High Risk AML Undergoing Donor Stem Cell Transplant

A Phase 1/2 study testing aldesleukin, natural killer cells and cyclophosphamide in people with Acute Myelogenous Leukemia, run by Masonic Cancer Center, University of Minnesota 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
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Trial summary

RATIONALE: Giving chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total body irradiation, before peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
Acute Myelogenous Leukemia
What is being tested?
aldesleukin, natural killer cells and cyclophosphamide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
50 participants
Where
1 siteUnited States
Study dates
Jan 2005to Mar 2011
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 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 4.2 High risk acute myeloid leukemia (AML) fitting within one of the following disease groups:
  • Primary induction failure defined as no complete remission (CR) after two or more induction cycles. For primary induction failure (PIF) or refractory AML, the patient must have <5% circulating blasts (and <1000 absolute circulating blasts) beyond Day 28 after last chemo. During work-up period if circulating blasts rise above these levels, the patient is ineligible. The use of hydrea or other non-induction cytotoxic agents is not allowed to reduce blasts and achieve this eligibility. If the blasts are higher than these limits, the patient should be treated on an alternative therapeutic protocol or receive another reinduction attempt. (See section 7 regarding final check of blast status within 7 days of preparative regimen start).
  • Relapsed AML with low disease burden must have less than 5% marrow blasts at time of enrollment for patients who did not receive re-induction or measured at least 28 days from the start of reinduction therapy for patients who did receive re-induction (maximum of 2 re-induction attempts). Patients who have relapsed more than 12 months following a prior HCT and did not reach CR following one re-induction cycle but have less than 10% marrow blasts are eligible.
  • CR3 or greater. This will include CRp defined as CR without platelet recovery to 100,000/mcL.
  • CR1 or CR2 with high risk features (therapy induced, prior myelodysplastic syndrome [MDS] or myeloproliferative disease [MPD], high risk cytogenetic or molecular phenotype) with no available alternate (sibling, unrelated donor [URD] or umbilical cord blood [UCB]) donors.
  • Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and CFS must be clear for at least 2 weeks prior to enrollment.
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  • Available related HLA-haploidentical donor (3-5 of 6 HLA, A, B and DRB1 matched)
  • Karnofsky performance status > 50
  • Pulmonary Function: oxygen saturation ≥ on room air and diffusion lung capacity for carbon monoxide (DLCOcor) ≥ 40%
  • Cardiac Function: Ejection fraction (EF) ≥ 30%, no uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
  • Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to Day 0
  • Women of child bearing potential must have a negative pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment
  • Human anti-mouse antibody (HAMA) monitoring: All subjects will be questioned about prior exposure to antibody therapy (including OKT3, rituximab, trastuzumab, etc).
  • For subjects with no prior antibody therapy exposure, no further action will be taken
  • For subjects who have received previous antibody therapies 10 ml of serum will be drawn before starting therapy. The presence of HAMA will not preclude proceeding with treatment.
  • Voluntary written consent signed before performance of any study related procedure not part of the normal medical care.

Who cannot join

  • Biphenotypic leukemia
  • New or progressive pulmonary infiltrates on screening chest x-ray or chest computed tomography (CT) scan that has not been evaluated with bronchoscopy, if feasible. Infiltrates attributed to infection must be stable/improving (with associated clinical improvement) after 1 week of appropriate therapy (2 weeks for presumed or documented fungal infections). Surgical resection waives any waiting requirements.
  • Uncontrolled bacterial or viral infections. Chronic asymptomatic viral hepatitis is allowed.
  • Known hypersensitivity to any of the study agents used
  • Received other investigational drugs within the 14 days before enrollment
  • Donor Selection:
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  • 12-75 years of age
  • > 40 kilogram body weight
  • In general good health as determined by the evaluating physician
  • Donors must be HLA-A, B, DRB1 haploidentical (3-5/6 antigens HLA, A, B, DRB1) match to recipient. Patients and donors will be typed for HLA-A, B and C using at least intermediate resolution DNA techniques for DRB1 at high (allele) resolution. KIR B genotyping will be done on all haploidentical donors, and when feasible, the donor with the most favorable KIR gene profile will be used.
  • Able and willing to have up to 4 separate apheresis collections per formed
  • Not pregnant
  • Human immunodeficiency virus (HIV): HIV-1, HIV-2 negative; HTLV-1, HTLV-2 negative, Hepatitis B and C negative
  • Voluntary written consent

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Masonic Cancer Center, University of Minnesota

    Minneapolis, Minnesota, 55455

Other trials in United States

About this study

Official title: Reduced Intensity Haploidentical Hematopoietic Stem Cell Transplantation (HSCT) Supplemented With Donor Natural Killer (NK) Cell Infusions in Patients With High Risk Myeloid Malignancies Who Are Unsuitable for Fully Myeloablative Transplantation

RATIONALE: Giving chemotherapy, such as fludarabine phosphate and cyclophosphamide, and total body irradiation, before peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells and natural killer (NK) cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Giving IL-2 (aldesleukin) after NK cell infusion may stimulate them to kill any remaining cancer cells.

PURPOSE: This phase I/II (currently enrolling in phase II) trial is studying how well a donor natural killer cell infusion works in treating patients who are undergoing donor stem cell transplant for acute myeloid leukemia.

Read the detailed description

OBJECTIVES:

Primary

  • To determine the disease-free survival at 6 months and 1 year in patients with high-risk myeloid malignancies who undergo a reduced-intensity haploidentical hematopoietic stem cell transplantation (HSCT) supplemented with donor natural killer (NK) cells.

Secondary

  • To evaluate the in vivo expansion of a donor CD3- CD19- selected NK cell product administered after a preparative regimen of cyclophosphamide, fludarabine, and total body irradiation (TBI) and HSCT in these patients.
  • To determine the rate of graft failure defined by absolute neutrophil count (ANC) < 500/mm³ by day 28.
  • To determine the incidence of grade III-IV acute graft-versus-host disease (GVHD) at 6 months.
  • To determine the rate of treatment-related mortality at day 100.
  • To determine the incidence of chronic GVHD at 12 months.
  • To determine the incidence of disease relapse at 12 months.
  • To determine the incidence of post-transplant lymphoproliferative disorder at 12 months.

Correlative

  • To correlate immune reconstitution of the in vivo expanded haploidentical NK cells with clinical outcomes.

OUTLINE: This is an open-label study.

Patients receive fludarabine intravenous (IV) over 1 hour on days -18 to -14 and cyclophosphamide IV over 2 hours on days -16 and -15. Patients receive cyclosporin A on Day -15 through Day -8. Patients undergo total body irradiation on day -13. Patients then receive an infusion of donor natural killer cells on day -12 and interleukin-2 subcutaneously on alternating days between days -12 to -2. Patients receive thymoglobulin (ATG) and undergo allogeneic peripheral blood stem cell transplantation on day 0.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study.

Keywords
NK cells, natural killer cells, immunotherapy, hematopoietic cell transplant, acute myelogenous leukemia
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

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

  • aldesleukinBiological

    Also called Interleukin-2, IL-2

    Administered subcutaneously (SQ) 9 million units every other day beginning Day -12 through -2 (evening of natural killer cell infusion) for a total of 6 doses.

  • natural killer cellsBiological

    Also called therapeutic allogeneic lymphocytes

    Infusion given on Day -12; The targeted infused cell dose of CD3- CD19- selected NK product is within the range of 2-3 x 10^7 cells/kg.

  • cyclophosphamideDrug

    Also called Cytoxan

    Administered intravenously (IV) 50 mg/kg on Day -15

  • fludarabine phosphateDrug

    Also called Fludara

    Administered intravenously (IV) 40 mg/m^2 on Days -18 through -14

  • allogeneic hematopoietic stem cell transplantationProcedure or surgery

    Also called PBSC

    On day 0, patients will receive an allogeneic transplant using pool cells from the day -1 and day 0 PBSC which will be CD34+ selected as the donor graft. The graft will be infused over 15-60 minutes.

  • total body irradiationRadiation

    Administered on Day -13, 200 cGy two times.

  • ThymoglobulinBiological

    Also called rabbit ATG

    intravenous (IV) 3 mg/kg on Day 0 (day of donor CD34 cell infusion)

  • Cyclosporin ADrug

    Also called CSA

    1.5 mg/kg by mouth or intravenously for target dose range of 150-250; day -15 through day -8.

  • cyclophosphamideDrug

    Also called Cytoxan

    Administered intravenously (IV) 50 mg/kg on Days -16 and -15

  • fludarabine phosphateDrug

    Also called Fludara

    Administered intravenously (IV) 35 mg/m^2 on Days -18 through -14

Study groups in NCT00303667
Study groupRoleWhat they receive
SCT w/Donor Natural Killer Cells - short schemaExperimentalPatients with high risk myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation, receiving fludarabine phosphate (daily dose of 40mg/m^2), cyclophosphamide (administered on Day -15 only), cyclosporin A, total body irradiation, natural killer cells, aldesleukin, and thymoglobulin.
Receives: Biological: aldesleukin; Biological: natural killer cells; Drug: cyclophosphamide; Drug: fludarabine phosphate; Procedure: allogeneic hematopoietic stem cell transplantation; Radiation: total body irradiation; Biological: Thymoglobulin; Drug: Cyclosporin A
SCT w/Donor Natural Killer Cells - extended schemaExperimentalPatients with high risk myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation, receiving fludarabine phosphate (daily dose of 35mg/m^2), cyclophosphamide (administered on Days -15 and -16), cyclosporin A, total body irradiation, natural killer cells, aldesleukin, and thymoglobulin.
Receives: Biological: aldesleukin; Biological: natural killer cells; Procedure: allogeneic hematopoietic stem cell transplantation; Radiation: total body irradiation; Biological: Thymoglobulin; Drug: Cyclosporin A; Drug: cyclophosphamide; Drug: fludarabine phosphate

What is being measured

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

  1. Disease-free Survival at 6 Months

    Number of patients alive without evidence of disease at 6 months after transplant

    Measured: Month 6

  2. Disease-free Survival at 1 Year

    Number of patients alive without evidence of disease at 1 year after transplant

    Measured: 1 Year

Secondary outcomes (7)

  1. In Vivo Expansion of a Donor NK Cells NK Cell Product

    Number of patients with in vivo expansion of donor NK cells. In vivo expansion of NK cell is defined as detection of >100 donor-derived NK cells per microliter of blood.

    Measured: 12 - 14 days after NK cell infusion

  2. Number of Patients With Graft Failure

    Number of patients with graft failure defined as <500 donor neutrophils count by day 28 in the absence of residual or relapsed leukemia

    Measured: Day 28

  3. Incidence of Grade III-IV Acute Graft Versus Host Disease

    Grade III-IV acute graft versus host disease is a severe short term complication created by infusion of donor cells into a foreign host

    Measured: Month 6

  4. Number of Patients With Treatment-Related Mortality

    Death within the first 100 days related to treatment in patients without relapse or persistent disease.

    Measured: Day 100

  5. Incidence of Chronic Graft Versus Host Disease

    Chronic graft versus host disease is a severe long term complication created by infusion of donor cells into a foreign host

    Measured: 1 Year

  6. Number of Patients With Disease Relapse

    Disease relapse is the recurrence of leukemia in patients who had cleared their leukemia after treatment. Patients with persistent leukemia are not evaluable for relapse.

    Measured: 1 Year

  7. Incidence of Post-transplant Lymphoproliferative Disorder (PTLD)

    Post-transplant lymphoproliferative disorder (PTLD) is a virally-driven cancer of the lymphoid cells caused by immunosuppressive drugs taken after allogeneic stem cell transplantation to prevent or control graft versus host disease.

    Measured: 1 Year

Timeline

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

  1. First posted17 Mar 2006 (estimated)
  2. Study startJan 2005
  3. Primary completionMar 2011
  4. Study completionMar 2011

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
50 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00303667
Sponsor's protocol ID
2004LS042
Other IDs
UMN-MT2003-23, UMN-IRB-0405M60481
Status last verified
Dec 2017
First submitted
15 Mar 2006
Last updated
28 Dec 2017
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing aldesleukin, natural killer cells and cyclophosphamide in people with Acute Myelogenous Leukemia, run by Masonic Cancer Center, University of Minnesota 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 16 inclusion and 14 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 28 Dec 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 3 Jul 2015). 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?

Disease-free Survival at 6 Months (time frame: Month 6). 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 NCT00303667.

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 28 Dec 2017.

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