Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia
Conditions
Keywords
related HLA-haploidentical donor
Brief summary
In this study the investigators investigate a cell therapy strategy that could harness allogeneic effectors that can potentially mediate anti-lymphoma effect. The investigators have designed a novel lymphodepleting conditioning regimen followed by infusion of donor-derived natural killer (NK) cells and interleukin-2 (IL-2) for patients with refractory lymphoid malignancies.
Detailed description
This is a single center phase II trial designated to expand donor NK cells and induce remissions in patients with refractory non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) using chemotherapy followed by haploidentical NK cells and IL2. Primary Objective is to evaluate the objective response rate (PR+CR) at 2 months post haploidentical NK cell infusion in patients with refractory Non Hodgkin's Lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Secondary Objective is to 1) evaluate the safety and tolerability of lymphodepleting chemotherapy, rituximab, and methylprednisone as determined by incidence of serious adverse events; 2) evaluate in vivo expansion of allogeneic donor NK cells at day 14; 3) determine time to progression Exploratory Objective is to 1) correlate clinical response with frequencies of peripheral blood T reg cells after chemotherapy; 2) correlate clinical response with donor KIR-B-content score determined by genotype; 3) monitor phenotypic and functional characteristics of natural killer cells and regulatory T cells in vivo; 4) correlate clinical response with donor FcR polymorphism. * Pre-NK cell infusion chemotherapeutic regimen consist of 1) Rituximab 375mg/m2 IV weekly x 4, start day -7; 2) Fludarabine 25 mg/m2 IV day -6 through day -2; 3) Cyclophosphamide 60mg/kg IV day -5; 4) Methylprednisolone 1 mg/kg day -2 through day +9. * NK cell infusion using IL2 activated donor NK cells 1.5 to 8 x 107 cells/kg IV day 0 * IL2 SC 9 million IU every other day x 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 Accrual Goal: Up to 17 patients will be enrolled
Interventions
DRUGRituximab
375 mg/m\^2 administered intravenously (IV) weekly \* 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK)
BIOLOGICALInterleukin-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.
BIOLOGICALNatural killer cells
administered intravenously 1.5 to 8 \* 10\^7 cells/kg on Day 0 (day of NK cell infusion)
DRUGCyclophosphamide
60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine.
DRUGMethylprednisolone
1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion.
DRUGFludarabine
25 mg/m\^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through day -2).
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients of any age with diagnosis of: * Relapsed/refractory lymphoma (B cell non-Hodgkin) who have lack of objective response to at least two prior chemotherapy regimens * Relapsed chronic lymphocytic leukemia with high risk features: lack of objective response or relapse within 6 months following nucleoside-analogue based chemotherapy regimen or patients with 17p deletion CLL who lacked objective response to at least 1 preceding chemotherapy regimen * Available related HLA haploidentical NK cell donor by at least Class I serologic typing at the A&B locus (age 12-75 years) * Karnofsky \> 70% for patients 16 years and older and Lansky play score \> 50 for patients under 16 years of age * Measurable disease based on modified Response Evaluation Criteria in Solid Tumors (RECIST) * Have acceptable organ function as defined within 28 days of enrollment: * Hematologic: platelets ≥ 80,000 x 10\^9/L; hemoglobin ≥ 9 g/dL, unsupported by transfusions within 7 days; absolute neutrophile count (ANC) ≥ 1000 x 10\^9/L, unsupported by Granulocyte colony-stimulating factor (G-CSF) or Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) for 10 days or Neulasta for 21 days - the hematologic requirements are waived for patients with inadequate counts due to known bone marrow involvement by disease who are otherwise eligible * Renal: calculated glomerular filtration rate (GFR) \> 50 ml/min * Hepatic: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 5 x upper limit of normal and total bilirubin ≤3 mg/dl - hepatic requirements are waived for patients with known disease involvement in the liver if otherwise eligible * Pulmonary function: \>40% corrected Carbon Monoxide Diffusing Capacity (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) * Cardiac: no symptoms of uncontrolled cardiac disease, left ventricular ejection fraction ≥ 40% * Able to be off prednisone or other immunosuppressive medications for at least 3 day prior to Day 0 (excluding denileukin diftitox pre-medications) * Sexually active women of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device \[IUD\], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment. * Voluntary written consent
Exclusion criteria
* Pregnant or lactating. The agents used in this study may be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. All females of childbearing potential must have a blood test or urine study within 14 days prior to enrollment to rule out pregnancy. Women of childbearing age must use appropriate contraceptive method. * Active central nervous system (CNS) lymphoma/leukemia - Patients with prior CNS involvement are eligible provided that it has been treated and is in remission. * Active serious infection (pulmonary infiltrates or lesions are allowed only after the appropriate diagnostic testing is negative for infection or appropriate therapy was initiated for probable infection) * Pleural effusion large enough to be detectable on chest x-ray (CXR) * Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology * Active concurrent malignancy (except skin cancer) * Epstein-Barr virus (EBV) post-transplant lymphoproliferative disorder * Positive HBsAg. If HBcAb is positive, Hepatitis B DNA by PCR will be evaluated. Positive anti HBcAb with an undetectable viral load does not exclude the patient. * Any investigational therapy in the past 30 days * Patients following allogeneic stem cell transplantation are eligible in the absence of graft versus host disease and are off immunosuppression for at least 30 days * Known allergy to any of the study agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With an Objective Response | Month 2 Post Infusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serious Adverse Events | Day 1 through Month 12 | 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 to Disease Progression | Day 1 through Month 12 | Cumulative incidence will be used to determine time to disease progression. |
| Patients With Expansion of NK Cells | Day 14 | Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 | 16 |
| Total | 16 |
Baseline characteristics
| Characteristic | Patients Receiving NK Cell Infusion |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 6 / 15 |
Outcome results
Primary
Number of Patients With an Objective Response
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
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients Receiving NK Cell Infusion | Number of Patients With an Objective Response | 4 Participants |
Secondary
Patients With Expansion of NK Cells
Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients Receiving NK Cell Infusion | Patients With Expansion of NK Cells | 0 Participants |
Secondary
Serious Adverse Events
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
Population: One participant developed sepsis prior to receiving the NK cell infusion and was withdrawn from the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Patients Receiving NK Cell Infusion | Serious Adverse Events | 15 Participants |
Secondary
Time to Disease Progression
Cumulative incidence will be used to determine time to disease progression.
Time frame: Day 1 through Month 12
Population: 10 participants had disease progression
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Patients Receiving NK Cell Infusion | Time to Disease Progression | 38 days |