Clinical Trials /

Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells

NCT02573896

Description:

This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

Related Conditions:
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells
  • Official Title: A Phase I Dose Escalation Study of Autologous Expanded Natural Killer (NK) Cells for Immunotherapy of Relapsed Refractory Neuroblastoma With Dinutuximab +/- Lenalidomide

Clinical Trial IDs

  • ORG STUDY ID: NANT 2013-01
  • NCT ID: NCT02573896

Conditions

  • Neuroblastoma

Interventions

DrugSynonymsArms
Ch14.18Chimeric Monoclonal Antibody 14.18, MAB Ch 14.18, UnituxinNK cells with Ch14.18 & Lenalidomide
NK CellsNatural Killer CellsNK cells with Ch14.18 & Lenalidomide
LenalidomideNK cells with Ch14.18 & Lenalidomide

Purpose

This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

Detailed Description

      This NANT trial will determine the maximum tolerated dose (MTD) of autologous expanded
      natural killer (NK) cells when combined with standard dosing of ch14.18 and will assess the
      feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells
      with ch14.18, for treatment of children with refractory or recurrent neuroblastoma.

      Ch14.18 is a chimeric antibody against GD2, which is expressed on a majority of neuroblastoma
      cells. It has been shown to increase EFS and OS in patients with high-risk neuroblastoma when
      given after autologous stem cell transplant in combination with subcutaneous GM-CSF and
      intravenous IL-2, followed by isotretinoin. Lenalidomide has been studied in children with
      solid tumors and can safely be given to patients based on 2 prior trials in children. It was
      also shown to have immunomodulatory effects and is synergistic with ch14.18. Lenalidomide is
      also an oral agent that can be given in the outpatient setting. Natural killer cells are
      lymphocytes of the innate immune system that have the ability to recognize and kill malignant
      cells, including neuroblastoma. Ch14.18 and lenalidomide both exert part of their anti-cancer
      effect through the activation of natural killer cells. Patients were given these in
      combination in the NANT 2011-04 study where the safety and immunomodulatory effect were
      established. The dose level proposed in this study is based off of these data. Natural killer
      cells are dysfunctional and low in number in many cancer patients, and number and function
      are further suppressed by chemotherapy and radiation. Investigators hypothesize that
      autologous NK cells can be expanded and activated ex vivo and readministered to restore
      number and function, and in combination with lenalidomide and ch14.18 will provide an
      anti-tumor effect in patients with relapsed or refractory neuroblastoma.

      Investigators will determine the feasibility of centralized expansion, cryopreservation, and
      distribution of autologous NK cells. Investigators will then determine the maximum tolerated
      dose by assessing the toxicities of autologous expanded NK cells given with ch14.18; by
      assessing the toxicities, cytokinetics and immunomodulatory effects, Investigators will
      select the recommended Phase II dose of the two-agent combination after dose escalation of
      the NK cells and then adding lenalidomide to the combination to establish the three-agent
      combination.

      Cytokinetics (persistence of infused NK cells) and immune function studies will be required
      for all patients entered on this study. In addition to routine assessment of response,
      quantification of rare tumor cell detection in blood and bone marrow using TLDA will also
      provide another measure of possible anti-tumor efficacy to support the rationale for the
      final schedule chosen.
    

Trial Arms

NameTypeDescriptionInterventions
NK cells with Ch14.18 & LenalidomideExperimentalPatients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of Ch14.18 on Day 1-4. Patients on Dose Level 4 will also receive 25mg/m2/dose of Lenalidomide during Day -6 through 14 of treatment.
  • Ch14.18
  • NK Cells
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a diagnosis of neuroblastoma either by histologic verification of
             neuroblastoma and/or demonstration of tumor cells in the bone marrow with increased
             urinary catecholamines.

          -  Patients must have a history of high-risk neuroblastoma according to COG risk
             classification at the time of study registration. Patients who were initially
             considered low or intermediate-risk, but then reclassified as high-risk are also
             eligible.

          -  Patients must have at least ONE of the following:

               1. Recurrent/progressive disease at any time prior to study enrollment

               2. Refractory disease

               3. Persistent disease

          -  Patients must have at least ONE of the following (lesions may have received prior
             radiation therapy as long as they meet the other criteria listed below):

               1. For recurrent/progressive or refractory disease, at least one MIBG avid bone
                  site.

               2. For persistent disease, If a patient has only 1 or 2 MIBG avid lesions AND a
                  Curie Score of 1-2, then biopsy confirmation of neuroblastoma and/or
                  ganglioneuroblastoma in at least one site present at the time of enrollment (bone
                  marrow, bone, or soft tissue) is required to be obtained at any time point prior
                  to enrollment.

               3. FDG-PET avid tumors: A biopsy confirmation of neuroblastoma and/or
                  ganglioneuroblastoma is required at any time prior to enrollment OR anatomical
                  imaging is required at the time of enrollment consistent with a bone metastasis
                  for at least one FDG-avid bone site.

          -  Any amount of neuroblastoma tumor cells in the bone marrow done at the time of study
             enrollment based on routine morphology with or without immunocytochemistry in at least
             one sample from bilateral aspirates and biopsies.

          -  At least one soft tissue lesion that meets criteria for a TARGET lesion as defined by:

               1. SIZE: Lesion can be accurately measured in at least one dimension with a longest
                  diameter ≥ 10 mm, or for lymph nodes ≥ 15 mm on short axis.

               2. In addition to measurable size, a lesion needs to meet the following criteria:

                    1. MIBG avid. For patients with persistent disease only: If a patient has only
                       1 or 2 MIBG avid lesions ANDa Curie Score of 1 - 2, then biopsy confirmation
                       of neuroblastoma and/or ganglioneuroblastoma in at least one site present at
                       time of enrollment is required to be obtained.

                    2. MIBG non avid tumors: These patients require a biopsy done at any time prior
                       to enrollment confirming neuroblastoma and/or ganglioneuroblastoma in at
                       least one soft tissue site (even if FDG-PET avid) present at the time of
                       enrollment.

          -  At least one non-target soft tissue lesion that is not measurable, but had a biopsy
             positive for neuroblastoma and/or ganglioneuroblastom or is MIBG avid at any time
             prior to enrollment.

          -  Patients must have a life expectancy of at least 12 weeks and a Lansky (≤16 years) or
             Karnofsky (>16 years) score of at least 50.

          -  Prior Therapy

               1. Patients must have fully recovered from the acute toxic effects of all prior
                  chemotherapy, immunotherapy, or radiotherapy prior to study registration.

               2. Patients must not have received the therapies indicated below after disease
                  evaluation or within the specified time period prior to registration on this
                  study as follows:

                    1. Myelosuppressive chemotherapy: must not have received within 2 weeks prior
                       to registration.

                    2. Biologic anti-neoplastics- agents not known to be associated with reduced
                       platelet or ANC counts (including retinoids): must not have received within
                       7 days prior to registration.

                    3. Monoclonal antibodies: must have received last dose at least 7 days or 3
                       half-lives whichever is longer, but no longer than 30 days (with recovery of
                       any associated toxicities), prior to protocol therapy.

                    4. Cellular Therapy (e.g. modified T cells, NK cells, dentritic cells etc.):
                       must not have received within 3 weeks and resolution of all toxicities.

                    5. Radiation: must not have received small port radiation within 7 days prior
                       to registration.

                    6. Hematopoietic Stem Cell Transplant:

                    7. IVIG

          -  All patients must have adequate organ function defined as:

          -  Hematological Function:

               1. Absolute Phagocyte count (APC= neutrophils and monocytes): ≥ 1000/µL

               2. Absolute Neutrophil count: ≥750/µL

               3. Absolute Lymphocyte count ≥ 500/µL

               4. Platelet count: ≥ 50,000/µL, transfusion independent (no platelet transfusions
                  within 1 week)

               5. Hemoglobin ≥ 10 g/dL (may transfuse)

               6. Patients with known bone marrow metastatic disease will be eligible for study as
                  long as they meet hematologic function criteria above.

          -  Renal Function: Age-adjusted serum creatinine ≤ to 1.5 x normal for age/gender OR
             creatinine clearance or GFR greater than or equal to 60 cc/min/1.73m2

          -  Liver Function: Total bilirubin ≤ 1.5 x normal for age, AND SGPT (ALT) 135 and SGOT
             (AST) ≤ 3 x upper limit of normal. Sinusoidal obstruction syndrome (SOS) if present,
             must be stable or improving clinically

          -  Cardiac Function: Normal ejection fraction documented by either echocardiogram or
             radionuclide MUGA evaluation OR Normal fractional shortening documented by
             echocardiogram

          -  Pulmonary Function: No dyspnea at rest, no oxygen requirement.

          -  Reproductive Status: All post-menarchal females must have a negative beta-HCG. Males
             and females of reproductive age and childbearing potential must use effective
             contraception for the duration of their participation.

          -  Patients with other ongoing serious medical issues must be approved by the study chair
             prior to registration.

          -  Patients may not receive any other anti-cancer agents or radiotherapy while on
             protocol therapy.

          -  Ability to Swallow Pills

        Exclusion Criteria:

          -  Pregnancy: Quantitative Serum B-HCG must be negative in girls who are post-menarchal.

          -  Breast feeding women are not eligible.

          -  Active or uncontrolled infection

          -  CNS metastasis.

          -  Hypersensitivity to thalidomide, including history of erythema nodosum if
             characterized by a desquamating rash while taking thalidomide or similar drugs (dose
             level 4 only).

          -  Patient declines participation in NANT 2004-05; unless the institution has been
             granted special exemption from mandatory registration on NANT 2004-05 by the NANT
             Operations Center.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:1 Month
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Feasibility of expanding NK cells from neuroblastoma patients and cryopreserving, shipping, and infusing multiple doses of NK cells.
Time Frame:2.5-3 years
Safety Issue:
Description:The number of viable NK cells finally available for infusion back into the patient: After NK expansion and verification that the resulting NK cells meet purity, gram stain, and endotoxin release criteria, NK cells will be divided into aliquots, each with sufficient cells for one infusion at the dose level the patient was assigned. So the primary measured endpoint is the number of viable NK cells. The derived endpoints, based on the number of viable NK cells in the final product are: (1) whether there are sufficient cells to give at least 1 dose at the lowest dose level (at least 80% of 10^7 NK cells per kg), (2) whether there are sufficient cells to give at least one dose at the assigned dose level (at least 80% of the planned dose for one dose), (3) the number of doses possible at the assigned dose level, and (4) the number of doses possible at the RP2D, as well as (5) the number of aliquots (treatments) available for each patient at the assigned dose.

Secondary Outcome Measures

Measure:Toxicity (Per Patient)
Time Frame:average 3 months
Safety Issue:
Description:Toxicity will be graded using the CTCAE criteria, version 4. The CTCAE provides descriptive terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be downloaded from the CTEP home page (http://ctep.cancer.gov).
Measure:Evaluation of Clinical Response (Per Patient)
Time Frame:average 120 days
Safety Issue:
Description:Response will be determined by the evaluation of CT/MRI scans and bone marrow biopsy

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:New Approaches to Neuroblastoma Therapy Consortium

Trial Keywords

  • relapsed refractory neuroblastoma

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