Description:
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.
Title
- Brief Title: Penostatin, Rituximab and Ontak and Allogeneic Natural Killer (NK) Cells for Refractory Lymphoid Malignancies
- Official Title: Lymphodepleting Chemotherapy With Rituximab and Allogeneic Natural Killer Cells for Patients With Refractory Lymphoid Malignancies (MT2009-15)
Clinical Trial IDs
- ORG STUDY ID:
2009LS083
- SECONDARY ID:
MT2009-15
- SECONDARY ID:
1002M77545
- NCT ID:
NCT01181258
Conditions
- Non-Hodgkin Lymphoma
- Chronic Lymphocytic Leukemia
Interventions
Drug | Synonyms | Arms |
---|
Rituximab | Rituxan, MabThera | Patients Receiving NK Cell Infusion |
Interleukin-2 | IL-2 | Patients Receiving NK Cell Infusion |
Natural killer cells | NK cells | Patients Receiving NK Cell Infusion |
Cyclophosphamide | Cytoxan | Patients Receiving NK Cell Infusion |
Methylprednisolone | Medrol | Patients Receiving NK Cell Infusion |
Fludarabine | Fludara | Patients Receiving NK Cell Infusion |
Purpose
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
Trial Arms
Name | Type | Description | Interventions |
---|
Patients Receiving NK Cell Infusion | Experimental | 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
- Interleukin-2
- Natural killer cells
- Cyclophosphamide
- Methylprednisolone
- Fludarabine
|
Eligibility Criteria
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | N/A |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of Patients With an Objective Response |
Time Frame: | Month 2 Post Infusion |
Safety Issue: | |
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. |
Secondary Outcome Measures
Measure: | Serious Adverse Events |
Time Frame: | Day 1 through Month 12 |
Safety Issue: | |
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. |
Measure: | Time to Disease Progression |
Time Frame: | Day 1 through Month 12 |
Safety Issue: | |
Description: | Cumulative incidence will be used to determine time to disease progression. |
Measure: | Patients With Expansion of NK Cells |
Time Frame: | Day 14 |
Safety Issue: | |
Description: | Number of patients who experience in vivo expansion of allogeneic donor natural killer (NK) cells. |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Completed |
Lead Sponsor: | Masonic Cancer Center, University of Minnesota |
Trial Keywords
- related HLA-haploidentical donor
Last Updated
February 6, 2018