Donor Peripheral Stem Cell Transplant and Donor Natural Killer Cell Transplant After Total-Body Irradiation, Thiotepa, Fludarabine, and Muromonab-CD3 in Treating Patients With Leukemia or Other Blood Diseases

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00450983
• Collaborator: National Cancer Institute (NCI) (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 1
• Locations: 2
• Duration (Months): 43
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell and donor natural killer cell transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain stem 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Removing the T cells from the donor cells before transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving a donor peripheral stem cell transplant and a donor natural killer cell transplant after total-body irradiation, thiotepa, fludarabine, and muromonab-CD3 works in treating patients with leukemia or other blood diseases.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease; Leukemia; Myelodysplastic Syndromes	Biological: muromonab-CD3; Biological: natural killer cell therapy; Drug: fludarabine phosphate; Drug: methotrexate; Drug: thiotepa; Genetic: gene expression analysis; Other: flow cytometry; Other: immunologic technique; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: in vitro-treated peripheral blood stem cell transplantation; Radiation: total-body irradiation	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the effect of haploidentical donor CD34+ purified peripheral blood stem cells and donor natural killer (NK) cells on the risk of developing grades III-IV acute graft-vs-host disease in patients with leukemia or other hematologic diseases.

Secondary

• Determine the risk for mortality from infection before day 180 in patients treated with this regimen.

• Determine the risk for graft rejection in patients treated with this regimen.

• Determine the risk for life-threatening infections in patients treated with this regimen.

• Determine the concentration of subsets of NK, NK-T, T cells, and dendritic cells in the CD34+ NK/NK-T-enriched graft.

• Determine cytomegalovirus-specific T-cells in product and donor graft.

• Determine the genotype and phenotype of donor killer cell immunoglobulin-like receptor expression according to time after hematopoietic stem cell transplantation (HSCT).

• Determine the reconstitution of NK function according to time after HSCT.

• Determine the expression of NKG2 ligands of leukemic blasts.

OUTLINE: Patients are stratified according to age (≤ 7 years vs > 7 years).

• Conditioning regimen: Patients 7 years of age or younger undergo total-body irradiation (TBI) twice daily on days -11 to -9. Patients over 7 years of age undergo TBI once on day -9. All patients receive thiotepa IV over 2 hours on days -8 and -7, fludarabine phosphate IV on days -6 to -3 and muromonab-CD3 on days -6 to 6. Patients with acute lymphoblastic leukemia or leukemia in the spinal fluid also receive methotrexate intrathecally prior to and after donor peripheral blood stem cell (PBSC) transplantation .

• Donor PBSC transplantation: Patients undergo donor PBSC transplantation comprising CD34+ purified PBSCs and natural killer (NK) cells on day 0.

Blood samples are collected in weeks 1-4, 6, 8, and 12. Analysis of samples includes quantitation of NK, NK-T, and T-cell subsets (CD3, CD4, and CD8) by flow cytometry; donor killer cell immunoglobulin-like receptor genotype and phenotype; interferon-gamma levels; and NK cytotoxicity. Samples are also analyzed by leukemic blast assay to determine if ligands that activate NK cells are expressed.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Transplantation of Haploidentical CD34+ Purified Peripheral Blood Stem Cells With NK-Cell Add-Back Following Conditioning With Total Body Irradiation, Thiotepa, Fludarabine and OKT3
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Outcome Measures

Primary Outcome Measures

1. Risk of Developing Grades III-IV Acute Graft-vs-host Disease (GVHD) [Up to day 100]

   Count of participants with acute GVHD grades III-IV.

Secondary Outcome Measures

1. Risk for Mortality From Infection Before Day 180 [Up to day 180]

   Count of participant deaths from infection up to day 180.

2. Risk for Graft Failure [Engraftment documented day +20]

   Count of participant that had graft failure.

3. Risk for Life-threatening Infections [Up to day 100]

   Count of participants with life-threatening infections

4. Concentration of NK, NK-T, T-cells, and Dendritic Cell Subsets in the CD34+ NK/NK-T-enriched Graft [Up to 5 years]

5. Cytomegalovirus-specific T Cells in Product and Donor Graft [Up to 5 years]

6. Genotype and Phenotype of Donor Killer Cell Immunoglobulin-like Receptor Expression According to Time After Hematopoietic Stem Cell Transplantation (HSCT) [Up to 5 years]

7. Reconstitution of NK Function According to Time After HSCT [Up to 5 years]

8. Expression of NKG2 Ligands of Leukemic Blasts [Up to 5 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following life-threatening hematological malignancies:

• Acute lymphoblastic leukemia meeting 1 of the following criteria:

• Advanced beyond first remission

• In first remission with high-risk prognostic features, including any of the following:

• Philadelphia chromosome-positive disease

• Chromosome 11q23 abnormality

• Hypodiploid

• Failed to achieve first remission within 1 month after induction

• Acute myeloid leukemia (AML) meeting 1 of the following criteria:

• Advanced beyond first remission

• First remission with high-risk prognostic features, including any of the following:

• Chromosome 11q23 abnormality

• Chromosome del 7q

• Secondary AML

• Failed to achieve first remission within 1 month after induction

• Myelodysplastic syndromes with International Prognostic Score > 1

• Chronic myelogenous leukemia in accelerated or blastic phase

• No active CNS disease

• No suitable HLA-matched related or unrelated donor available

• Haploidentical family member available as donor of partially HLA-matched peripheral blood stem cells

• Least degree of mismatch to HLA-A, B, C, DRB1, and DQB1

• No mismatch for a single HLA-A, B, C, DRB1, or DQB1 antigen

• Donor killer cell immunoglobulin-like receptor ligand group expression preferably different than patient

PATIENT CHARACTERISTICS:

• LVEF ≥ 45%

• DLCO ≥ 60% of predicted

• AST and ALT ≤ 2 times upper limit of normal (ULN) (unless due to malignancy)

• Bilirubin ≤ 2 times ULN (unless due to malignancy)

• No life expectancy < 6 months due to coexisting disease other than the malignancy

• No active infection (e.g., polymerase chain reaction [PCR] evidence for cytomegalovirus, human herpes virus 6, or invasive fungal infection)

• No prior infections without evidence of resolution by PCR or imaging studies within the past 2 months

• No hypersensitivity to murine antibodies

• No known HIV positivity

• Not pregnant or nursing

• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

• No prior marrow transplantation with total body irradiation > 400 cGy

• No concurrent therapies for seizure disorder

• No growth factors for 21 days after transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109-1023
2	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-1024

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Ann Woolfrey, MD, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ann Woolfrey, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00450983
• Other Study ID Numbers: 1965.00; R01AI053193; P30CA015704; FHCRC-1965.00; CDR0000533834
• First Posted: Mar 22, 2007
• Last Update Posted: May 24, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Ann Woolfrey, Principal Investigator, Fred Hutchinson Cancer Center: graft versus host disease; adult acute lymphoblastic leukemia in remission; recurrent adult acute lymphoblastic leukemia; childhood acute lymphoblastic leukemia in remission; recurrent childhood acute lymphoblastic leukemia; adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia in remission; recurrent adult acute myeloid leukemia; childhood acute myeloid leukemia in remission; recurrent childhood acute myeloid leukemia; secondary acute myeloid leukemia; de novo myelodysplastic syndromes; previously treated myelodysplastic syndromes; secondary myelodysplastic syndromes; accelerated phase chronic myelogenous leukemia; blastic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(15;17)(q22;q12); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22); childhood myelodysplastic syndromes
• Additional relevant MeSH terms: Leukemia; Preleukemia; Myelodysplastic Syndromes; Graft vs Host Disease; Syndrome; Methotrexate; Fludarabine phosphate; Fludarabine; Thiotepa; Muromonab-CD3

Study Results

Participant Flow

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Overall Participants	1
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	1.7
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Risk of Developing Grades III-IV Acute Graft-vs-host Disease (GVHD)
Description	Count of participants with acute GVHD grades III-IV.
Time Frame	Up to day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	1
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Risk for Mortality From Infection Before Day 180
Description	Count of participant deaths from infection up to day 180.
Time Frame	Up to day 180

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	1
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Risk for Graft Failure
Description	Count of participant that had graft failure.
Time Frame	Engraftment documented day +20

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	1
Count of Participants [Participants]	0 0%

4. Secondary Outcome

Title	Risk for Life-threatening Infections
Description	Count of participants with life-threatening infections
Time Frame	Up to day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	1
Count of Participants [Participants]	1 100%

5. Secondary Outcome

Title	Concentration of NK, NK-T, T-cells, and Dendritic Cell Subsets in the CD34+ NK/NK-T-enriched Graft
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Analysis for this endpoint not feasible due to funding constraint.

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	0

6. Secondary Outcome

Title	Cytomegalovirus-specific T Cells in Product and Donor Graft
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Analysis for this endpoint not feasible due to funding constraint.

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	0

7. Secondary Outcome

Title	Genotype and Phenotype of Donor Killer Cell Immunoglobulin-like Receptor Expression According to Time After Hematopoietic Stem Cell Transplantation (HSCT)
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Analysis for this endpoint not feasible due to funding constraint.

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	0

8. Secondary Outcome

Title	Reconstitution of NK Function According to Time After HSCT
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Analysis for this endpoint not feasible due to funding constraint.

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	0

9. Secondary Outcome

Title	Expression of NKG2 Ligands of Leukemic Blasts
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Analysis for this endpoint not feasible due to funding constraint.

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
Measure Participants	0

Adverse Events

Arm/Group Title	Treatment
Arm/Group Description	Following total-body irradiation, thiotepa, fludarabine, and muromonab-CD3, participants are given a donor peripheral stem cell transplant and a donor natural killer cell transplant.
All Cause Mortality
	Treatment
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Treatment
	Affected / at Risk (%)	# Events
Total	0/1 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.