MT2014-25: Haplo NK With SQ IL-15 in Adult Relapsed or Refractory AML Patients

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT02395822
• Collaborator: (none)
• Enrollment: 17
• Location: 1
• Arm: 1
• Actual Duration (Months): 14
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

A phase II trial of CD3/CD19 depleted, IL-15 activated, donor natural killer (NK) cells in adults and subcutaneous IL-15 given after a preparative regimen for the treatment of relapsed or refractory acute myelogenous leukemia (AML). The primary objective is to study the potential efficacy of NK cells and IL-15 to achieve complete remission while maintaining safety.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia	Biological: IL-15	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 17 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: MT2014-25: Haploidentical Donor Natural Killer (NK) Cell Infusion With Subcutaneous Recombinant Human IL-15 (rhIL-15) in Adults With Refractory or Relapsed Acute Myelogenous Leukemia (AML)
• Actual Study Start Date: Oct 1, 2015
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Preparative Regimen and SubQ rHuIL-15 Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion

Biological: IL-15; Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total; Other Names: Interleukin-15

Outcome Measures

Primary Outcome Measures

1. < 5% Marrow Blast, no Circulating Peripheral Blasts and Neutrophil Count of > 1 x 10^9/L [Day 42 post NK cell infusion]

   Without platelet recovery

Secondary Outcome Measures

1. In Vivo Expansion (>100) of NK Cells (Defined at CD56+/CD3- Lymphocytes) [Day 14 post NK cell infusion]

2. Proportion of Patients Experiencing Grade, 3, 4, and 5 Toxicities (Assessed by CTCAE v. 4) [Days 1-5 and Days 8-12, 24 hours after the last IL-15 dose, Day +28, Day +42]

3. Treatment Related Mortality [6 months post-therapy]

4. Number of Subjects Achieving Complete Response, Defined as in Vivo Donor Derived NK Cell Expansion of > 100 Donor Derived NK Cells. [Day 42 post NK cell infusion]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria (Recipient):

• Meets ONE of the following disease criteria:

1. Primary AML induction failure: no CR after 2 or more induction attempts

2. Relapsed AML or Secondary AML (from MDS or treatment related): not in CR after 1 or more cycles of standard re-induction therapy

3. AML relapsed > 2 months after transplant: No re-induction required, and no more than 1 re-induction cycle is allowed.

4. Relapsed AML 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

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

• Available related HLA-haploidentical donor (aged 14 to 75 years) by at least Class I serologic typing at the A&B locus

• Karnofsky Performance Status ≥ 60%

• Patients must have adequate organ within 14 days (28 days for pulmonary and cardiac) of study registration

• Able to be off prednisone or other immunosuppressive medications for at least 3 days prior to NK cell infusion (excluding preparative regimen pre-medications).

• Agrees to use contraception prior to study entry and for the duration of study participation.

Exclusion Criteria (Recipient):

• Bi-phenotypic acute leukemia.

• Transplant < 60 days prior to study enrollment.

• Active autoimmune disease.

• History of severe asthma

• Uncontrolled intercurrent illness

• New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that has not been evaluated with bronchoscopy

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

• Pregnant women

• History of HIV, active or chronic hepatitis B, hepatitis C or HTLV-I infection

• Known hypersensitivity to any of the study agents used

• Received investigational drugs within the 14 days of study registration.

• Known active CNS involvement.

Criteria For Initial Donor Selection:

• Related donors (sibling, parent, offspring, parent or offspring of an HLA identical sibling).

• 14-75 years of age.

• At least 40 kilogram body weight.

• In general good health as determined by the evaluating medical provider.

• HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A&B locus.

• Not pregnant.

• Able and willing to undergo apheresis.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Jeffrey Miller, MD, 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: NCT02395822
• Other Study ID Numbers: 2014LS092
• First Posted: Mar 24, 2015
• Last Update Posted: Feb 20, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: AML; Relapsed; Refractory
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute

Study Results

Participant Flow

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Period Title: Overall Study
STARTED	17
COMPLETED	15
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Overall Participants	17
Age (Count of Participants)
<=18 years	1 5.9%
Between 18 and 65 years	10 58.8%
>=65 years	6 35.3%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57 (14)
Sex: Female, Male (Count of Participants)
Female	5 29.4%
Male	12 70.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	15 88.2%
Unknown or Not Reported	2 11.8%
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	14 82.4%
More than one race	0 0%
Unknown or Not Reported	3 17.6%
Region of Enrollment (Count of Participants)
United States	17 100%

Outcome Measures

1. Primary Outcome

Title	< 5% Marrow Blast, no Circulating Peripheral Blasts and Neutrophil Count of > 1 x 10^9/L
Description	Without platelet recovery
Time Frame	Day 42 post NK cell infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Measure Participants	15
Count of Participants [Participants]	5 29.4%

2. Secondary Outcome

Title	In Vivo Expansion (>100) of NK Cells (Defined at CD56+/CD3- Lymphocytes)
Time Frame	Day 14 post NK cell infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Measure Participants	15
Count of Participants [Participants]	4 23.5%

3. Secondary Outcome

Title	Proportion of Patients Experiencing Grade, 3, 4, and 5 Toxicities (Assessed by CTCAE v. 4)
Time Frame	Days 1-5 and Days 8-12, 24 hours after the last IL-15 dose, Day +28, Day +42

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Measure Participants	17
Count of Participants [Participants]	10 58.8%

4. Secondary Outcome

Title	Treatment Related Mortality
Time Frame	6 months post-therapy

Outcome Measure Data

Analysis Population Description

1 patient left the study

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Measure Participants	16
Count of Participants [Participants]	2 11.8%

5. Secondary Outcome

Title	Number of Subjects Achieving Complete Response, Defined as in Vivo Donor Derived NK Cell Expansion of > 100 Donor Derived NK Cells.
Time Frame	Day 42 post NK cell infusion

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
Measure Participants	15
Count of Participants [Participants]	1 5.9%

Adverse Events

Arm/Group Title	Preparative Regimen and SubQ rHuIL-15
Arm/Group Description	Preparative Regimen of Fludarabine and Cyclophosphamide IL-15 Activation of Donor NK Cells: IL-15 to Facilitate NK Cell Survival and Expansion IL-15: Preparative Regimen: Fludarabine 25 mg/m2 x 5 days start day -6 Cyclophosphamide 60 mg/kg x 2 days on day -5 and -4 (if < 4 months from prior transplant, omit day -4 dose) IL-15 Activated Donor NK Cells: The apheresis product (collected day -1) will be enriched for NK cells with the large-scale CliniMacs® device (Miltenyi) by depletion of CD3+ cells to remove T-lymphocytes and depletion of CD19+ cells to remove B-lymphocytes. The NK cell enriched product will be activated by overnight incubation with10 ng/ml IL-15 under GMP conditions and infused on day 0. IL-15 to Facilitate NK Cell Survival and Expansion: IL-15 at 2 mcg/kg subcutaneously (SC) beginning day +1, once a day for 5 days followed by a 2 day rest, and then once a day for 5 days for 10 doses total
All Cause Mortality
	Preparative Regimen and SubQ rHuIL-15
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Preparative Regimen and SubQ rHuIL-15
	Affected / at Risk (%)	# Events
Total	12/17 (70.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/17 (5.9%)
Immune system disorders
Cytokine Release Syndrome - Grade 3	3/17 (17.6%)
Cytokine Release Syndrome - Grade 4	2/17 (11.8%)
Infections and infestations
Abdominal Infection	1/17 (5.9%)
Endocarditis Infective	1/17 (5.9%)
Hepatitis Viral	1/17 (5.9%)
Infections and Infestations - Other, specify	1/17 (5.9%)
Lung Infection	1/17 (5.9%)
Sepsis	1/17 (5.9%)
Sinusitis	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Muscle Weakness Lower Limb	1/17 (5.9%)
Nervous system disorders
Intracranial Hemorrhage	1/17 (5.9%)
Seizure	1/17 (5.9%)
Renal and urinary disorders
Acute Kidney Injury	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Adult Respiratory Distress Syndrome	1/17 (5.9%)
Vascular disorders
Hypotension	1/17 (5.9%)
Other (Not Including Serious) Adverse Events
	Preparative Regimen and SubQ rHuIL-15
	Affected / at Risk (%)	# Events
Total	15/17 (88.2%)
Blood and lymphatic system disorders
Febrile neutropenia	2/17 (11.8%)
General disorders
Fatigue	2/17 (11.8%)
Flu like symptoms	1/17 (5.9%)
Gait disturbance	1/17 (5.9%)
Mouth/tongue sores	1/17 (5.9%)
Immune system disorders
Cytokine release syndrome	5/17 (29.4%)
Infections and infestations
Infections and infestations - Other, specify	1/17 (5.9%)
Sepsis	1/17 (5.9%)
Sinusitis	1/17 (5.9%)
Investigations
Alanine aminotransferase increased	1/17 (5.9%)
Aspartate aminotransferase increased	1/17 (5.9%)
Blood bilirubin increased	1/17 (5.9%)
Creatinine increased	1/17 (5.9%)
Weight gain	5/17 (29.4%)
Metabolism and nutrition disorders
Hypernatremia	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Back pain	1/17 (5.9%)
Chest wall pain	1/17 (5.9%)
Pain in extremity	1/17 (5.9%)
Nervous system disorders
Encephalopathy	2/17 (11.8%)
Headache	4/17 (23.5%)
Intracranial hemorrhage	1/17 (5.9%)
Nervous system disorders - Other, specify	1/17 (5.9%)
Seizure	1/17 (5.9%)
Non Convulsive Status Epilipticus	1/17 (5.9%)
Psychiatric disorders
Confusion	4/17 (23.5%)
Renal and urinary disorders
Acute kidney injury	2/17 (11.8%)
Respiratory, thoracic and mediastinal disorders
Hiccups	1/17 (5.9%)
Hypoxia	1/17 (5.9%)
Pneumonitis	1/17 (5.9%)
Pulmonary edema	3/17 (17.6%)
Respiratory failure	1/17 (5.9%)
Skin and subcutaneous tissue disorders
Periorbital edema	2/17 (11.8%)
Pruritus	1/17 (5.9%)
Rash maculo-papular	1/17 (5.9%)
Vascular disorders
Hypotension	2/17 (11.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.