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

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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:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Study Type Interventional
Study Design 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
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Patients Receiving NK Cell Infusion
Hide 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
Arm/Group Title Patients Receiving NK Cell Infusion
Hide 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
Hide 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
1.Primary Outcome
Title Number of Patients With an Objective Response
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide Description Cumulative incidence will be used to determine time to disease progression.
Time Frame Day 1 through Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
10 participants had disease progression
Arm/Group Title Patients Receiving NK Cell Infusion
Hide 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
Hide Description Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells.
Time Frame Day 14
Hide Outcome Measure Data
Hide 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
Hide 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%
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
Hide 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   --/-- 
Show Serious Adverse Events Hide 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%) 
Show Other (Not Including Serious) Adverse Events Hide 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%) 
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
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01181258     History of Changes
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