Trial Outcomes & Findings for Penostatin, Rituximab and Ontak and Allogeneic Natural Killer (NK) Cells for Refractory Lymphoid Malignancies (NCT NCT01181258)

Last Updated: 2018-02-06

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

16 participants

Primary outcome timeframe

Month 2 Post Infusion

Results posted on

2018-02-06

Participant Flow

Participant milestones

Participant milestones
Measure	Patients Receiving NK Cell Infusion 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 Study STARTED	16
Overall Study COMPLETED	16
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Patients Receiving NK Cell Infusion n=16 Participants 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
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	14 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants
Sex: Female, Male Male	13 Participants n=5 Participants
Region of Enrollment United States	16 participants n=5 Participants

PRIMARY outcome

Timeframe: Month 2 Post Infusion

Population: 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.

Outcome measures

Outcome measures
Measure	Patients Receiving NK Cell Infusion n=14 Participants 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
Number of Patients With an Objective Response	4 Participants

SECONDARY outcome

Timeframe: Day 1 through Month 12

Population: One participant developed sepsis prior to receiving the NK cell infusion and was withdrawn from the study.

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.

Outcome measures

Outcome measures
Measure	Patients Receiving NK Cell Infusion n=15 Participants 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
Serious Adverse Events	15 Participants

SECONDARY outcome

Timeframe: Day 1 through Month 12

Population: 10 participants had disease progression

Cumulative incidence will be used to determine time to disease progression.

Outcome measures

Outcome measures
Measure	Patients Receiving NK Cell Infusion n=10 Participants 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
Time to Disease Progression	38 days Interval 22.0 to 43.0

SECONDARY outcome

Timeframe: Day 14

Population: 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.

Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells.

Outcome measures

Outcome measures
Measure	Patients Receiving NK Cell Infusion n=14 Participants 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
Patients With Expansion of NK Cells	0 Participants

Adverse Events

Patients Receiving NK Cell Infusion

Serious events: 6 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Patients Receiving NK Cell Infusion n=15 participants at risk 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
Infections and infestations Sepsis	13.3% 2/15 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.
Respiratory, thoracic and mediastinal disorders Dyspnea	6.7% 1/15 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.
Respiratory, thoracic and mediastinal disorders Bronchospasm	6.7% 1/15 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.
Cardiac disorders Hypertension	6.7% 1/15 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.
Blood and lymphatic system disorders Thrombotic Thrombocytopenic Purpura	6.7% 1/15 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.
Blood and lymphatic system disorders Febrile Neutropenia	13.3% 2/15 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.

Other adverse events

Other adverse events
Measure	Patients Receiving NK Cell Infusion n=15 participants at risk 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
Renal and urinary disorders Acute Kidney Injury	13.3% 2/15 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.
Musculoskeletal and connective tissue disorders Back/Chest Spasms	6.7% 1/15 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.
Vascular disorders Capillary Leak Syndrome	6.7% 1/15 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.
Eye disorders Chemosis, Eye	6.7% 1/15 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.
General disorders Chest Pain	6.7% 1/15 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.
General disorders Chills	93.3% 14/15 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.
Psychiatric disorders Confusion	6.7% 1/15 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.
Investigations Creatinine Increased	20.0% 3/15 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.
Eye disorders Dry Eyes	6.7% 1/15 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.
Respiratory, thoracic and mediastinal disorders Dyspnea	33.3% 5/15 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.
General disorders Edema	53.3% 8/15 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.
General disorders Fever	60.0% 9/15 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.
General disorders Flu-like Symptoms	6.7% 1/15 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.
Nervous system disorders Headache	40.0% 6/15 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.
Vascular disorders Hypertension	93.3% 14/15 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.
Vascular disorders Hypotension	53.3% 8/15 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.
Respiratory, thoracic and mediastinal disorders Hypoxia	20.0% 3/15 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.
General disorders Infusion Related Reaction	40.0% 6/15 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.
General disorders Injection Site Reaction	53.3% 8/15 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.
Musculoskeletal and connective tissue disorders Left Jaw Pain	6.7% 1/15 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.
Musculoskeletal and connective tissue disorders Leg Pain	6.7% 1/15 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.
Respiratory, thoracic and mediastinal disorders Nasal Congestion	6.7% 1/15 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.
Gastrointestinal disorders Nausea	6.7% 1/15 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.
Musculoskeletal and connective tissue disorders Neck Pain	6.7% 1/15 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.
Blood and lymphatic system disorders Neutropenic Fever	53.3% 8/15 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.
Nervous system disorders Peripheral Neuropathy	6.7% 1/15 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.
Respiratory, thoracic and mediastinal disorders Pneumonitis/Pulmonary Infiltrates	20.0% 3/15 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.
Cardiac disorders Prolonged QTC Interval	6.7% 1/15 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.
Skin and subcutaneous tissue disorders Rash/Desquamation	46.7% 7/15 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.
Cardiac disorders Tachycardia	13.3% 2/15 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.
Metabolism and nutrition disorders Tumor Lysis Syndrome	6.7% 1/15 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.
General disorders Tumor Pain	6.7% 1/15 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.
General disorders Upper Extremity Swelling/Edema	13.3% 2/15 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.
Investigations Weight Gain	13.3% 2/15 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.

Additional Information

Dr. Veronika Bachanova

Masonic Cancer Center, University of Minnesota

Phone: 612-625-5469

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place