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

NCT01181258 | Completed Phase 2 Results DMC

• 3 other identifiers: 2009LS083MT2009-151002M77545
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia

Keywords

related HLA-haploidentical donor

Outcome Measures

Primary Outcomes (1)

• 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.

  Month 2 Post Infusion

Secondary Outcomes (3)

• Serious Adverse Events

  Day 1 through Month 12

• Time to Disease Progression

  Day 1 through Month 12

• Patients With Expansion of NK Cells

  Day 14

Study Arms (1)

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

Drug: Rituximab; Biological: Interleukin-2; Biological: Natural killer cells; Drug: Cyclophosphamide; Drug: Methylprednisolone; Drug: Fludarabine

Interventions

Rituximab DRUG

375 mg/m\^2 administered intravenously (IV) weekly \* 4, (day -7, -1, +6, +13) pre-infusion with natural killer cells (NK)

Also known as: Rituxan, MabThera

Patients Receiving NK Cell Infusion

Interleukin-2 BIOLOGICAL

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.

Also known as: IL-2

Patients Receiving NK Cell Infusion

Natural killer cells BIOLOGICAL

administered intravenously 1.5 to 8 \* 10\^7 cells/kg on Day 0 (day of NK cell infusion)

Also known as: NK cells

Patients Receiving NK Cell Infusion

Cyclophosphamide DRUG

60 mg/kg administered intravenously (IV) for 2 hours on day -5 after Fludarabine.

Also known as: Cytoxan

Patients Receiving NK Cell Infusion

Methylprednisolone DRUG

1 mg/kg on Days -2 through +9 as an intravenous (IV) infusion.

Also known as: Medrol

Patients Receiving NK Cell Infusion

Fludarabine DRUG

25 mg/m\^2/day administered as a 1 hour IV infusion once a day for 5 doses (day -6 through day -2).

Also known as: Fludara

Patients Receiving NK Cell Infusion

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (1)

• 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.

  PMID: 29218366 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

Rituximab; Interleukin-2; IL32 protein, human; Cyclophosphamide; Methylprednisolone; fludarabine; fludarabine phosphate

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Hematologic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Lymphokines; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. Veronika Bachanova
• Organization: Masonic Cancer Center, University of Minnesota

bach0173@umn.edu

612-625-5469

Study Officials

• Veronika Bachanova, MD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2010
• First Posted: August 13, 2010
• Study Start: August 1, 2010
• Primary Completion: September 1, 2015
• Study Completion: July 1, 2016
• Last Updated: February 6, 2018
• Results First Posted: May 18, 2017

Record last verified: 2016-01

Locations

US (1)