Clinical Trials /

Ph I Trial of NAM NK Cells and IL-2 for Adult Pts With MM and NHL

NCT03019666

Description:

This is a phase I trial with pilot expansion of HLA-haploidentical or HLA-mismatched related donor nicotinamide expanded-natural killer (NAM-NK) cell based therapy for patients with relapsed or refractory multiple myeloma (MM) or relapsed/refractory CD20-positive non-Hodgkin lymphoma (NHL). The primary endpoint of the study is to determine the maximum tolerated dose (MTD) of NAM-NK cells while maintaining safety.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Ph I Trial of NAM NK Cells and IL-2 for Adult Pts With MM and NHL
  • Official Title: A Phase I Trial Testing NAM Expanded Haploidentical or Mismatched Related Donor Natural Killer (NK) Cells Followed by a Short Course of IL-2 for the Treatment of Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory CD20+ Non-Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2015LS057
  • SECONDARY ID: MT2015-46
  • NCT ID: NCT03019666

Conditions

  • Multiple Myeloma
  • Non-Hodgkin Lymphoma
  • Diffuse Large B Cell Lymphoma
  • Mantle-Cell Lymphoma
  • Follicular Lymphoma
  • Indolent B Cell Lymphoma
  • Primary Mediastinal Lymphoma
  • Lymphoplasmacytic Lymphoma

Interventions

DrugSynonymsArms
Nicotinamide Expanded Haploidentical or Mismatched Related Donor Natural Killer CellsNAM-NKMultiple Myeloma

Purpose

This is a phase I trial with pilot expansion of HLA-haploidentical or HLA-mismatched related donor nicotinamide expanded-natural killer (NAM-NK) cell based therapy for patients with relapsed or refractory multiple myeloma (MM) or relapsed/refractory CD20-positive non-Hodgkin lymphoma (NHL). The primary endpoint of the study is to determine the maximum tolerated dose (MTD) of NAM-NK cells while maintaining safety.

Trial Arms

NameTypeDescriptionInterventions
Multiple MyelomaExperimentalAfter a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, patients receive expanded NAM-NK cells followed by a short course of interleukin-2 (IL-2) to facilitate natural killer cell survival and expansion in vivo. Monoclonal antibodies and elotuzumab for Multiple Myeloma patients, will be administered prior to and after the natural killer cell infusion(s) to facilitate tumor targeting and antibody dependent cellular cytotoxicity (ADCC).
  • Nicotinamide Expanded Haploidentical or Mismatched Related Donor Natural Killer Cells
Non-Hodgkin LymphomaExperimentalAfter a lymphodepleting preparative regimen of cyclophosphamide and fludarabine, patients receive expanded NAM-NK cells followed by a short course of interleukin-2 (IL-2) to facilitate natural killer cell survival and expansion in vivo. Monoclonal antibodies and rituximab for Non-Hodgkin Lymphoma patients, will be administered prior to and after the natural killer cell infusion(s) to facilitate tumor targeting and antibody dependent cellular cytotoxicity (ADCC).
  • Nicotinamide Expanded Haploidentical or Mismatched Related Donor Natural Killer Cells

Eligibility Criteria

        Patient Inclusion Criteria:

          -  ≥18 to ≤70 years of age

          -  Meets one of the following disease criteria:

               -  Multiple Myeloma (MM) meeting one of the following:

                    -  relapsed/refractory disease after two lines of therapies, including a
                       proteasome inhibitor (bortezomib, carfilzomib or ixazomib) and an
                       immunomodulatory drug (thalidomide, lenalidomide or pomalidomide)

                    -  relapsed disease between 2-18 months of 1st autologous stem cell
                       transplantation,

                    -  relapsed disease at least 4 months after allogeneic stem cell
                       transplantation with no evidence of active graft versus host disease and no
                       availability of donor lymphocyte infusion

                    -  measurable disease defined as serum IgG, A, M M-protein ≥ 0.5g/dL or serum
                       IgD M-protein ≥ 0.5 g/dL, or urine M-protein ≥ 200 mg/24 hours

                    -  at least 4 weeks since plasmapheresis

                    -  at least 3 days between last corticosteroids and study treatment start

               -  CD20-positive B-cell Non-Hodgkin Lymphoma (NHL)

                    -  CD20 expression confirmed by flow cytometry or immunohistochemistry and
                       meeting one or more of the following:

                         -  evidence of relapsed/refractory disease that has failed conventional
                            therapy and failed/not eligible/refused studies of a higher priority,

                         -  relapsed disease at least 60 days after autologous stem cell
                            transplantation

                         -  relapsed disease at least 4 months after allogeneic stem cell
                            transplantation with no evidence of active graft versus host disease
                            and no availability of donor lymphocyte infusion

                         -  has measurable disease >1.5 cm in diameter

          -  HLA-haploidentical or mismatched related donor (aged 12 to 70 years) with
             donor/recipient match based on a minimum of intermediate resolution DNA based Class I
             typing of the A and B locus (at least 2/4 class I allele) and absence of recipient
             anti HLA antibodies against selected donor

          -  Karnofsky Performance Status ≥ 60% - appendix III

          -  Adequate organ function within 14 days of study registration (30 days for pulmonary
             and cardiac assessments) defined as:

               -  Bone Marrow: Total white blood cell (WBC) count ≥ 3000/μL, absolute neutrophil
                  count (ANC) ≥ 1000/μL, platelet count ≥ 75,000/μL and hemoglobin ≥ 8.0 g/dL - may
                  be waived if abnormalities are due to disease related bone marrow involvement

               -  Renal: creatinine ≤ 1.5 mg/dL or creatinine clearance ≥40mL/min using
                  Cockcroft-Gault formula

               -  Hepatic: ALT or AST ≤ 3 x upper limit of institutional normal (ULN), total
                  bilirubin ≤ 1.5 x ULN

               -  Pulmonary Function: oxygen saturation ≥ 90% on room air. If symptomatic or prior
                  known impairment, pulmonary function ≥ 50% corrected DLCO and FEV1 is required

               -  Cardiac Function: LVEF ≥ 40%, no uncontrolled angina, severe uncontrolled
                  ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or
                  active conduction system abnormalities

               -  Calcium (MM only): Corrected calcium < 11.5 mg/dL within 2 weeks prior to
                  enrollment

          -  Able to be off prednisone or other immunosuppressive medications for at least 3 days
             prior to NAM-NK cell infusion (excluding preparative regimen pre-medications)

          -  Sexually active females of child bearing potential and males with partners of child
             bearing potential must agree to use effective contraception during therapy and for 4
             months after completion of therapy

          -  Must have recovered from acute effects of prior therapy - at least 2 weeks should have
             elapsed since the last dose of chemotherapy

          -  Voluntary written consent

        Patient Exclusion Criteria:

          -  Active, untreated CNS involvement

          -  Chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL), or high-grade
             lymphomas (Burkittt's lymphoma/Lymphoblastic lymphoma)

          -  Pregnant or breastfeeding - The agents used in this study include those that fall
             under Pregnancy Category D - have known teratogenic potential. For elotuzumab arm:
             Women of child bearing potential must have a negative serum or urine pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 14 days of study
             treatment start (24 hours prior to the start of elotuzumab)

          -  Marked baseline prolongation of QT/QTc interval (e.g. demonstration of a QTc interval
             greater than 500 milliseconds)

          -  Class II or greater New York Heart Association Functional Classification criteria
             (appendix III) or serious cardiac arrhythmias likely to increase the risk of cardiac
             complications of cytokine therapy (e.g. ventricular tachycardia, frequent ventricular
             ectopy, or supraventricular tachyarrhythmia requiring chronic therapy)

          -  Active autoimmune disease requiring immunosuppressive therapy

          -  History of severe asthma, presently on chronic medications (a history of mild asthma
             requiring inhaled steroids only is eligible)

          -  New or progressive pulmonary infiltrates on screening chest x-ray or chest CT scan
             unless cleared for study by Pulmonary. Infiltrates attributed to infection must be
             stable/improving (with associated clinical improvement) after 1 week of appropriate
             therapy (4 weeks for presumed or documented fungal infections).

          -  Active uncontrolled bacterial, fungal, or viral infections - all prior infections must
             have resolved following optimal therapy

          -  Known hypersensitivity to any of the study agents used

          -  For MM patients only:

               -  Prior radiotherapy within 2 weeks prior to the administration of study drug"

               -  Surgery within 4 weeks

               -  Chemo within 3 weeks (6 weeks for melphalan, or monoclonal antibodies)

          -  Received investigational drugs within the 14 days before 1st dose of study drug

          -  High titer of donor specific anti-HLA antibodies (MFI >1000)

        DONOR INCLUSION CRITERIA:

          -  HLA-haploidentical or mismatched related donor/recipient match based on a minimum of
             intermediate resolution DNA based Class I typing of the A and B locus (at least 2/4
             class I allele) and absence of recipient anti HLA antibodies

          -  12 to 70 years of age - Priority should be given to age (<35 years), followed by HLA
             matching (haploidentical and if not available then fully mismatched donor).

          -  At least 40 kilogram body weight

          -  In general good health as determined by the evaluating medical provider

          -  Adequate organ function defined as:

               -  Hematologic: hemoglobin, WBC, platelet within 10% of upper and lower limit of
                  normal range of test (gender based for hemoglobin),

               -  Hepatic: ALT < 2 x upper limit of normal,

               -  Renal: serum creatinine < 1.8 mg/dl

          -  Performance of a donor infectious disease screen panel including CMV Antibody,
             Hepatitis B Surface Antigen, Hepatitis B Core Antibody, Hepatitis C Antibody, HIV PCR,
             HIV ½ Antibody, HTLVA ½ Antibody, Rapid Plasma (RPR) Treponema , Trypanosoma Cruzi (T.
             Cruzi), HCV by NAT, HIV by NAT and WNV (West Nile Virus) by NAT or per current panel -
             must be negative for HIV and active hepatitis B

          -  Not pregnant - females of childbearing potential must have a negative pregnancy test
             within 7 days of apheresis

          -  Able and willing to undergo apheresis

          -  Voluntary written consent (using assent form if donor < 18 years of age)
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:Accepts Healthy Volunteers

Primary Outcome Measures

Measure:Occurrence of any grade 4 or greater suspected adverse reaction
Time Frame:24 hours post infusion
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Occurrence of treatment related mortality (TRM)
Time Frame:2 months post infusion
Safety Issue:
Description:
Measure:Occurrence of disease response
Time Frame:28 days post infusion
Safety Issue:
Description:
Measure:Number of patients alive without progression
Time Frame:1 year post infusion
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Masonic Cancer Center, University of Minnesota

Trial Keywords

  • MM
  • NHL
  • NK Cell
  • NK Cells

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