Haploidentical Natural Killer Cells to Treat Refractory or Relapsed Acute Myelogenous Leukemia (AML)

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01106950
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 29
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a phase II therapeutic study of related donor HLA-haploidentical NK-cell based therapy after a high dose of fludarabine/cyclophosphamide with denileukin diftitox preparative regimen for the treatment of poor prognosis acute myelogenous leukemia (AML).

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myelogenous, Acute	Biological: Natural Killer Cells; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Denileukin diftitox; Procedure: Donor lymphapheresis; Drug: IL-2	Phase 2

Detailed Description

Patients achieving a complete remission and neutrophil recovery (ANC > 500) for at least 4 weeks will be considered for allogeneic transplant to prolong remission (independent of this study).

All patients, including those who go on to transplant, will be followed to determine disease free survival, treatment related mortality, and time to relapse.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Adoptive Transfer of Haploidentical Natural Killer Cells to Treat Refractory or Relapsed AML MT2010-02
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treated Patients Patients are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.

Biological: Natural Killer Cells; Given by infusion on Day 0. The product is T cell-depleted (CD3-) and B cell-depleted (CD19). Target dose for infusion is < or = 8 x 10^7 nucleated cells/kilogram.; Drug: Fludarabine; Administered as a 1 hour intravenous infusion once a day for 5 doses beginning on day -6.; Other Names: Fludara ; Drug: Cyclophosphamide; Administered as a 2 hour intravenous infusion with high volume fluid flush and mesna per institutional guidelines on day -5 and -4 one hour after fludarabine infusion. (Day -4 administration may be omitted if patient has had a transplant in the previous 4 months.); Other Names: Cytoxan ; Drug: Denileukin diftitox; 12 ug/kg/day will be administered on day -1 and day -2 intravenously.; Other Names: Ontak ; Procedure: Donor lymphapheresis; Day -1 before planned NK cell infusion, the donor will undergo lymphapheresis (Removal of lymphocytes from donated blood, with the remainder of the blood retransfused into the donor).; Drug: IL-2; Administered after NK cell infusion, 10 million units every other day for a total of 6 doses. (Patients weighing less than 45 kilograms will receive a dose of 5 million units/m^2 every other day for 6 doses).; Other Names: Interleukin-2

Outcome Measures

Primary Outcome Measures

1. Percent of Patients With Successful Expansion of Natural Killer Cells After Infusion [Day 14]

   The primary objective of this study was to estimate the incidence of in vivo expansion of natural killer (NK) cells 14 days after infusion of an allogeneic donor product enriched for NK progenitors. Successful in vivo donor NK cell expansion was defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/ul in the patient's peripheral blood 14 days after infusion.

Secondary Outcome Measures

1. Percent of Patients With Complete Remission of Disease [At least 4 weeks after last dose (28 days)]

   Disease response was defined as complete remission (disease response) by morphologic criteria including <5% blasts in a moderately cellular or cellular marrow. Complete remission was also correlated with NK cell expansion in vivo, IL-15 levels and donor/recipient KIR B genotyping, and Treg depletion.

2. Percent of Patients With Disease Free Survival [Month 6]

   Number of patients alive and disease free at 6 months. The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.

3. Percent of Patients With Incidence of Relapse [Month 6]

   Number of patients who have had a relapse(the return of disease after its apparent recovery/cessation) after obtaining a complete remission of their disease.

4. Number of Patients With Treatment-Related Death [Day 100]

   Number of patients who died within the first 100 days of treatment due to toxicity.

5. Percent of Patients With Natural Killer Cell Expansion Versus KIR Genotype Versus Treg Depletion [Day 14]

   Association between in vivo natural killer (NK) cell expansion and complete response without platelet recovery (CRp) with donor killer immunoglobulin-like (KIR) genotype and Treg depletion. In vivo donor NK cell expansion was correlated with regulatory T-cell (Treg) depletion as detected on flow cytometry.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• ≥ 2 years of age

• Meets one of the following disease criteria:

• Primary acute myelogenous leukemia (AML) induction failure: no complete remission (CR) after 2 or more induction attempts

• Relapsed acute myelogenous leukemia (AML): not in CR after 1 or more cycles of standard re-induction therapy. For patients > 60 years of age the 1 cycle of standard chemotherapy is not required if either of the following criteria is met:

• relapse within 6 months of last chemotherapy

• blast count < 30% within 10 days of starting protocol therapy

• Secondary AML from myelodysplastic syndrome (MDS)

• AML relapsed > 2 months after transplant who do not have the option of donor lymphocyte infusions (e.g. recipients of autologous or umbilical cord blood [UCB] transplants) Patients with prior central nervous system (CNS) involvement are eligible provided that it has been treated and CSF is clear for at least 2 weeks or magnetic resonance imaging (MRI) stable prior to enrollment. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.

• Available related HLA-haploidentical donor (3-5 of 6 HLA-A, B and C)

• Karnofsky Performance Status > 50% or Lansky Play score > 50

• Adequate organ function defined as:

• Creatinine: ≤ 2.0 mg/dL (for pediatric patients - ClCr > 50 ml/min or age adjusted Cr)

• Hepatic: Liver function tests (LFT's) < 5 x upper limit of institutional normal (ULN)

• Pulmonary Function: oxygen saturation ≥ 90% on room air and pulmonary function

50% corrected Diffusion lung capacity for carbon monoxide (DLCO) and Forced expiratory volume in one second (FEV1) Oxygen saturation [>92%] can be used in child where pulmonary function tests (PFT's) cannot be obtained. (Testing required only if symptomatic or prior known impairment.)

• Cardiac Function: Ejection fraction (EF) ≥ 40%, 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 natural killer (NK) cell infusion (excluding denileukin diftitox pre-meds)

• 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.

• Voluntary written consent

Exclusion Criteria:

• Bi-phenotypic acute leukemia

• Transplant < 60 days prior to study enrollment

• New or progressive pulmonary infiltrates on screening chest x-ray or chest computated 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 (4 weeks for presumed or documented fungal infections). Surgical resection waives any waiting requirements.

• Uncontrolled bacterial or viral infections - chronic asymptomatic viral hepatitis is allowed

• Pleural effusion large enough to be detectable on chest x-ray

• Known hypersensitivity to any of the study agents used

• Received investigational drugs within the 14 days before enrollment

• Known active CNS involvement

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Jeffrey S. Miller, M.D., Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT01106950
• Other Study ID Numbers: 2010LS010; MT2010-02; 1003M79954
• First Posted: Apr 20, 2010
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: acute myelogenous leukemia; primary acute myelogenous leukemia; secondary acute myelogenous leukemia; relapsed acute myelogenous leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cyclophosphamide; Fludarabine; Interleukin-2; Denileukin diftitox

Study Results

Participant Flow

Recruitment Details	Study entry was open to patients 2 years and older regardless of gender, race, or ethnic background.
Pre-assignment Detail	Seventeen patients were enrolled, however, 2 patients did not receive Ontak (study drug) and were not included in the analysis.

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Period Title: Overall Study
STARTED	15
COMPLETED	15
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Overall Participants	15
Age (Count of Participants)
<=18 years	4 26.7%
Between 18 and 65 years	8 53.3%
>=65 years	3 20%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44 (23.4)
Sex: Female, Male (Count of Participants)
Female	6 40%
Male	9 60%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Percent of Patients With Successful Expansion of Natural Killer Cells After Infusion
Description	The primary objective of this study was to estimate the incidence of in vivo expansion of natural killer (NK) cells 14 days after infusion of an allogeneic donor product enriched for NK progenitors. Successful in vivo donor NK cell expansion was defined by measuring an absolute circulating donor-derived NK cell count of >100 cells/ul in the patient's peripheral blood 14 days after infusion.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Measure Participants	15
Number [Percentage of patients]	27

2. Secondary Outcome

Title	Percent of Patients With Complete Remission of Disease
Description	Disease response was defined as complete remission (disease response) by morphologic criteria including <5% blasts in a moderately cellular or cellular marrow. Complete remission was also correlated with NK cell expansion in vivo, IL-15 levels and donor/recipient KIR B genotyping, and Treg depletion.
Time Frame	At least 4 weeks after last dose (28 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Measure Participants	15
Number [Percentage of patients]	53

3. Secondary Outcome

Title	Percent of Patients With Disease Free Survival
Description	Number of patients alive and disease free at 6 months. The length of time after treatment ends that a patient survives without any signs or symptoms of that cancer or any other type of cancer. In a clinical trial, measuring the disease-free survival is one way to see how well a new treatment works.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Measure Participants	15
Number [Percentage of patients]	33

4. Secondary Outcome

Title	Percent of Patients With Incidence of Relapse
Description	Number of patients who have had a relapse(the return of disease after its apparent recovery/cessation) after obtaining a complete remission of their disease.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Measure Participants	15
Number [Percentage of patients]	53

5. Secondary Outcome

Title	Number of Patients With Treatment-Related Death
Description	Number of patients who died within the first 100 days of treatment due to toxicity.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable (Treated) Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Measure Participants	15
Number [Percentage of patients]	13

6. Secondary Outcome

Title	Percent of Patients With Natural Killer Cell Expansion Versus KIR Genotype Versus Treg Depletion
Description	Association between in vivo natural killer (NK) cell expansion and complete response without platelet recovery (CRp) with donor killer immunoglobulin-like (KIR) genotype and Treg depletion. In vivo donor NK cell expansion was correlated with regulatory T-cell (Treg) depletion as detected on flow cytometry.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable (Treated) Patients (Expansion=No)	Evaluable (Treated) Patients (Expansion=Yes)
Arm/Group Description	KIR matched: Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.	KIR mismatched: Patients with acute myeloid leukemia (AML) were treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
Measure Participants	7	8
Number [Percentage of patients]	43	13

Adverse Events

Adverse Event Reporting Description	Due to chemotherapy as prep for the NK cell infusion, it is expected that all patients will experience severe depression of their blood counts and other related toxicities. Adverse event (AE) collection will focus on targeted AEs and unexpected AEs at specific time points in relation to the NK cell infusion and IL-2 injections.
Arm/Group Title	Treated Patients
Arm/Group Description	Patients with acute myeloid leukemia (AML) are treated with donor natural killer cells, fludarabine, cyclophosphamide, Denileukin diftitox, Donor lymphapheresis and IL-2.
All Cause Mortality
	Treated Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treated Patients
	Affected / at Risk (%)	# Events
Total	12/15 (80%)
Blood and lymphatic system disorders
Blood disorder	5/15 (33.3%)	5
Bone marrow hypocellular	1/15 (6.7%)	1
Hematologic toxicity - ANC<500	1/15 (6.7%)	1
febrile neutropenia	3/15 (20%)	3
Cardiac disorders
Atrial fibrillation	1/15 (6.7%)	1
Left ventricular systolic dysfunction	1/15 (6.7%)	1
Gastrointestinal disorders
Typhilitis	1/15 (6.7%)	1
Infections and infestations
Lung Infection	1/15 (6.7%)	1
Encephalitis infection	1/15 (6.7%)	1
Infections and infestations- other	1/15 (6.7%)	1
Sepsis	2/15 (13.3%)	2
Nervous system disorders
Intracranial hemorrhage	1/15 (6.7%)	1
Renal and urinary disorders
Acute kidney injury	3/15 (20%)	3
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/15 (6.7%)	1
Pleural hemorrhage	1/15 (6.7%)	1
Pneumonitis	1/15 (6.7%)	1
dyspnea	1/15 (6.7%)	1
Respiratory failure	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Infusion related reaction	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Treated Patients
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Edema - grade 1	15/15 (100%)	113
Edema - grade 2	9/15 (60%)	36
Edema - grade 3	7/15 (46.7%)	28
Edema - grade 4	3/15 (20%)	8
Bruising - grade 2	1/15 (6.7%)	1
Blood disorder - grade 3	1/15 (6.7%)	1
Febrile neutropenia - grade 3	1/15 (6.7%)	1
Cardiac disorders
Hypertension - grade 1	14/15 (93.3%)	58
Hypertension - grade 2	9/15 (60%)	42
Hypertension - grade 3	13/15 (86.7%)	63
Hypertension - grade 4	8/15 (53.3%)	20
Hypotension - grade 1	15/15 (100%)	142
Hypotension - grade 2	7/15 (46.7%)	20
Hypotension - grade 3	6/15 (40%)	7
Hypotension - grade 4	4/15 (26.7%)	12
Heart failure - grade 4	1/15 (6.7%)	1
Left ventricular systolic dysfunction - grade 3	1/15 (6.7%)	1
Endocrine disorders
Increased creatinine - grade 2	1/15 (6.7%)	1
Increased creatinine - grade 3	1/15 (6.7%)	1
Gastrointestinal disorders
Abdominal distension - grade 2	1/15 (6.7%)	1
Emesis - grade 3	1/15 (6.7%)	1
General disorders
Gum/jaw pain - grade 2	4/15 (26.7%)	5
Headache - grade 1	2/15 (13.3%)	2
Fever - grade 1	15/15 (100%)	107
Fever - grade 2	4/15 (26.7%)	4
Fever - grade 3	3/15 (20%)	5
Fever - grade 4	15/15 (100%)	62
Chest pain - grade 3	1/15 (6.7%)	1
Headache - grade 2	1/15 (6.7%)	1
Headache - grade 4	1/15 (6.7%)	1
Immune system disorders
Autoimmune disorder - grade 1	15/15 (100%)	146
Autoimmune disorder - grade 2	2/15 (13.3%)	2
Autoimmune disorder - grade 3	9/15 (60%)	12
Autoimmune disorder - grade 4	1/15 (6.7%)	1
Investigations
Infusion related reaction - grade 1	15/15 (100%)	156
Infusion related reaction - grade 2	3/15 (20%)	4
Infusion related reaction - grade 3	4/15 (26.7%)	4
Nervous system disorders
Confusion - grade 4	1/15 (6.7%)	2
Chills - grade 1	15/15 (100%)	130
Chills - grade 2	14/15 (93.3%)	23
Chills - grade 3	13/15 (86.7%)	28
Confusion - grade 3	1/15 (6.7%)	1
Renal and urinary disorders
Acute kidney injury - grade 1	2/15 (13.3%)	2
Acute kidney injury - grade 2	2/15 (13.3%)	2
Acute kidney injury - grade 3	2/15 (13.3%)	2
Respiratory, thoracic and mediastinal disorders
Diffuse alveolar hemorrhage - grade 5	5/15 (33.3%)	5
Dyspnea - grade 1	15/15 (100%)	133
Dyspnea - grade 2	7/15 (46.7%)	10
Dyspnea - grade 3	7/15 (46.7%)	15
Dyspnea - grade 4	5/15 (33.3%)	10
Dyspnea - grade 5	4/15 (26.7%)	15
Hypoxia - grade 1	15/15 (100%)	147
Hypoxia - grade 3	5/15 (33.3%)	10
Hypoxia - grade 4	10/15 (66.7%)	20
Hypoxia - grade 5	4/15 (26.7%)	4
Pneumonitis/pulmonary infiltrates - grade 1	15/15 (100%)	164
Pneumonitis/pulmonary infiltrates - grade 3	6/15 (40%)	12
Pneumonitis/pulmonary infiltrates - grade 4	1/15 (6.7%)	2
Pneumonitis/pulmonary infiltrates - grade 5	2/15 (13.3%)	4
Adult respiratory distress syndrome - grade 4	1/15 (6.7%)	1
Pneumonitis/pulmonary infiltrates - grade 2	1/15 (6.7%)	1
Pneumonitis - grade 4	1/15 (6.7%)	1
Lung infection - grade 4	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Rash/desquamation - grade 1	15/15 (100%)	152
Rash/desquamation - grade 2	4/15 (26.7%)	9
Rash/desquamation - grade 3	4/15 (26.7%)	7
Rash/desquamation - grade 4	1/15 (6.7%)	13
Vascular disorders
Intracranial hemorrhage - grade 2	1/15 (6.7%)	1

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.