Penostatin, Rituximab and Ontak and Allogeneic Natural Killer (NK) Cells for Refractory Lymphoid Malignancies

• ClinicalTrials.gov Identifier: NCT01181258
• Recruitment Status: Completed
• First Posted: August 13, 2010
• Results First Posted: May 18, 2017
• Last Update Posted: February 6, 2018
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia
• Interventions: Drug: Rituximab; Biological: Interleukin-2; Biological: Natural killer cells; Drug: Cyclophosphamide; Drug: Methylprednisolone; Drug: Fludarabine
• Enrollment: 16

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Patients Receiving NK Cell Infusion
Arm/Group Description	Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
Period Title: Overall Study
Started	16
Completed	16
Not Completed	0

Baseline Characteristics

Arm/Group Title		Patients Receiving NK Cell Infusion
Arm/Group Description		Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
Overall Number of Baseline Participants		16
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	16 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	14 87.5%
	>=65 years	2 12.5%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	16 participants
	Female	3 18.8%
	Male	13 81.3%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	16 participants
		16

Outcome Measures

1. Primary Outcome

Title	Number of Patients With an Objective Response
Description	The number of patients with a partial response (PR) or complete response (CR). For patients with non-hodgkin's lymphoma: CR - complete disappearance of all detectable clinical evidence of disease and disease-related symptoms. PR - at least a 50% decrease in sum of the product of the diameters of up to six of the largest dominant nodes or nodal masses. For patients with chronic lymphocytic leukemia: CR - disappearance of all palpable disease, normalization of the blood counts without transfusions, bone marrow aspirate lymphocyte percentage < 30%, and no evidence of disease on bone marrow biopsy. PR - 50% or more reduction in palpable disease as well as one or more of the remaining features: neutrophils >= 1.5 × 109/L or 50% improvement over baseline, platelets more than 100 × 109/L or 50% improvement over baseline, and hemoglobin more than 11.0 g/dL or 50% improvement over baseline without transfusions.
Time Frame	Month 2 Post Infusion

Outcome Measure Data

Analysis Population Description

Two participants were not evaluable. One patient died prior to receiving NK cell infusion and one did not survive by day 14; therefore 14 patients were analyzed for this outcome measure.

Arm/Group Title	Patients Receiving NK Cell Infusion
Arm/Group Description:	Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	4 28.6%

2. Secondary Outcome

Title	Serious Adverse Events
Description	Number of participants experiencing serious adverse events that occur during study. Adverse event collection for the purposes of this study will focus on targeted adverse events and unexpected adverse events at specific time points in relation to the NK cell infusion and post infusion IL2 injections.
Time Frame	Day 1 through Month 12

Outcome Measure Data

Analysis Population Description

One participant developed sepsis prior to receiving the NK cell infusion and was withdrawn from the study.

Arm/Group Title	Patients Receiving NK Cell Infusion
Arm/Group Description:	Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
Overall Number of Participants Analyzed	15
Measure Type: Count of Participants; Unit of Measure: Participants
	15 100.0%

3. Secondary Outcome

Title	Time to Disease Progression
Description	Cumulative incidence will be used to determine time to disease progression.
Time Frame	Day 1 through Month 12

Outcome Measure Data

Analysis Population Description

10 participants had disease progression

Arm/Group Title	Patients Receiving NK Cell Infusion
Arm/Group Description:	Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
Overall Number of Participants Analyzed	10
Median (Full Range); Unit of Measure: days
	38; (22 to 43)

4. Secondary Outcome

Title	Patients With Expansion of NK Cells
Description	Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Two participants were not evaluable. One patient died prior to receiving NK cell infusion and one did not survive by day 14; therefore 14 patients were analyzed for this outcome measure.

Arm/Group Title	Patients Receiving NK Cell Infusion
Arm/Group Description:	Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
Overall Number of Participants Analyzed	14
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	Fifteen patients were dosed with the NK cell infusion and therefore were assessed for adverse events. One patient died prior to the NK cell infusion.
Arm/Group Title	Patients Receiving NK Cell Infusion
Arm/Group Description	Non-Myeloablative Conditioning Using Rituximab, Fludarabine, Cyclophosphamide and Methylprednisolone followed by Interleukin 2-activated Allogeneic Natural Killer Cells infusion for Patients with Refractory NHL and CLL Rituximab: 375 mg/m^2 administered intravenously (IV) weekly * 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK) Interleukin-2: subcutaneously administered 9 million international units (IU) every other day * 6 doses over 2 weeks begin 1 to 24 hours after NK cell infusion. If weight < 45 kilograms, give IL-2 at 5 million units/m2 on same schedule. Natural killer cells: administered intravenously 1.5 to 8 * 10^7 cells/kg on Day 0 (day of NK cell infusion) Cyclophosphamide: 60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine Methylprednisolone: 1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion Fludarabine: 25 mg/m^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through
All-Cause Mortality
	Patients Receiving NK Cell Infusion
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Patients Receiving NK Cell Infusion
	Affected / at Risk (%)
Total	6/15 (40.00%)
Blood and lymphatic system disorders
Thrombotic Thrombocytopenic Purpura	1/15 (6.67%)
Febrile Neutropenia	2/15 (13.33%)
Cardiac disorders
Hypertension	1/15 (6.67%)
Infections and infestations
Sepsis	2/15 (13.33%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/15 (6.67%)
Bronchospasm	1/15 (6.67%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Patients Receiving NK Cell Infusion
	Affected / at Risk (%)
Total	15/15 (100.00%)
Blood and lymphatic system disorders
Neutropenic Fever	8/15 (53.33%)
Cardiac disorders
Prolonged QTC Interval	1/15 (6.67%)
Tachycardia	2/15 (13.33%)
Eye disorders
Chemosis, Eye	1/15 (6.67%)
Dry Eyes	1/15 (6.67%)
Gastrointestinal disorders
Nausea	1/15 (6.67%)
General disorders
Chest Pain	1/15 (6.67%)
Chills	14/15 (93.33%)
Edema	8/15 (53.33%)
Fever	9/15 (60.00%)
Flu-like Symptoms	1/15 (6.67%)
Infusion Related Reaction	6/15 (40.00%)
Injection Site Reaction	8/15 (53.33%)
Tumor Pain	1/15 (6.67%)
Upper Extremity Swelling/Edema	2/15 (13.33%)
Investigations
Creatinine Increased	3/15 (20.00%)
Weight Gain	2/15 (13.33%)
Metabolism and nutrition disorders
Tumor Lysis Syndrome	1/15 (6.67%)
Musculoskeletal and connective tissue disorders
Back/Chest Spasms	1/15 (6.67%)
Left Jaw Pain	1/15 (6.67%)
Leg Pain	1/15 (6.67%)
Neck Pain	1/15 (6.67%)
Nervous system disorders
Headache	6/15 (40.00%)
Peripheral Neuropathy	1/15 (6.67%)
Psychiatric disorders
Confusion	1/15 (6.67%)
Renal and urinary disorders
Acute Kidney Injury	2/15 (13.33%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/15 (33.33%)
Hypoxia	3/15 (20.00%)
Nasal Congestion	1/15 (6.67%)
Pneumonitis/Pulmonary Infiltrates	3/15 (20.00%)
Skin and subcutaneous tissue disorders
Rash/Desquamation	7/15 (46.67%)
Vascular disorders
Capillary Leak Syndrome	1/15 (6.67%)
Hypertension	14/15 (93.33%)
Hypotension	8/15 (53.33%)

Limitations and 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.

Results Point of Contact

• Name/Title: Dr. Veronika Bachanova
• Organization: Masonic Cancer Center, University of Minnesota
• Phone: 612-625-5469
• EMail: bach0173@umn.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bachanova V, Sarhan D, DeFor TE, Cooley S, Panoskaltsis-Mortari A, Blazar BR, Curtsinger JM, Burns L, Weisdorf DJ, Miller JS. Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol Immunother. 2018 Mar;67(3):483-494. doi: 10.1007/s00262-017-2100-1. Epub 2017 Dec 7.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT01181258
• Other Study ID Numbers: 2009LS083; MT2009-15 ( Other Identifier: Blood and Marrow Transplantation Program ); 1002M77545 ( Other Identifier: IRB, University of Minnesota )
• First Submitted: August 12, 2010
• First Posted: August 13, 2010
• Results First Submitted: April 10, 2017
• Results First Posted: May 18, 2017
• Last Update Posted: February 6, 2018