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Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02573896
Recruitment Status : Active, not recruiting
First Posted : October 12, 2015
Last Update Posted : July 29, 2022
Sponsor:
Collaborators:
Nationwide Children's Hospital
United Therapeutics
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium

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

Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Dinutuximab Biological: NK Cells Drug: Lenalidomide Phase 1

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 dinutuximab and will assess the feasibility of adding lenalidomide at the recommended Phase II dose of the expanded NK cells with dinutuximab, for treatment of children with refractory or recurrent neuroblastoma.

Dinutuximab 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 dinutuximab. 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. Dinutuximab 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 dinutuximab 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 dinutuximab; 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Dose Escalation Study of Autologous Expanded Natural Killer (NK) Cells for Immunotherapy of Relapsed Refractory Neuroblastoma With Dinutuximab +/- Lenalidomide
Actual Study Start Date : January 14, 2019
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : August 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: NK cells with Dinutuximab & Lenalidomide
Patients in this arm will receive a designated dose of NK cells on Day 5 and 17.5 mg/m2/dose of dinutuximab on Day 1-4. Patients on Dose Level 4 will also receive 25mg/m2/dose of Lenalidomide during Day -6 through 14 of treatment.
Drug: Dinutuximab
17.5 mg/m2/day of dinutuximab will be given for 4 consecutive days (days 1-4 of each course) via intravenous infusion over ten hours.
Other Names:
  • Chimeric Monoclonal Antibody 14.18
  • MAB Ch 14.18
  • Unituxin

Biological: NK Cells
The designated dose of NK Cells will be infused on Day 5 by IV drip using a Y infusion set with a filter-less chamber. Cells should not be delivered at a rate faster than 10 ml/kg/hr (as determined by drip rate or syringe push rate), and should not take longer than one hour for total infusion time if possible.
Other Name: Natural Killer Cells

Drug: Lenalidomide
25 mg/m2/day of Lenalidomide will be given at Dose Level 4, once daily with or without food by mouth on days -6 through +14.




Primary Outcome Measures :
  1. NK cell production feasibility (lowest dose level) [ Time Frame: After cell expansion, day 4 of protocol therapy ]
    Proportion of patients whose NK cell product is at least 80% of 10^7 NK cells per kg (sufficient cells to give at least 1 dose at the lowest dose level).

  2. NK cell production feasibility [ Time Frame: After cell expansion, day 4 of protocol therapy ]
    Proportion of patients whose NK cell product is at least 80% of the planned dose for one dose

  3. MTD/RP2D determination [ Time Frame: all toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any Grade 3 or greater non-hematological toxicities on any course


Secondary Outcome Measures :
  1. Describe Non-Hematological Toxicities [ Time Frame: all toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any Grade 3 or greater non-hematological toxicities on any course

  2. Describe Hematological Toxicities [ Time Frame: all toxicities from enrollment through 30 days following end of protocol therapy ]
    Proportion of patients with any Grade 3 or greater hematological toxicities on any course

  3. Overall Response [ Time Frame: From Day 1 of protocol therapy through 30 days following end of protocol therapy ]
    Proportion of patients evaluable for response with a best overall response of CR/CR-MD/PR



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must be less than or equal to 30 years of age when registered on study
  2. 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.
  3. 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.
  4. All patients must have at least one of the following

    a) Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy b) No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma b1) Refractory disease- a best overall response of no response/stable disease since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.

    b2) Persistent disease- a best overall response of no partial response since diagnosis of high risk neuroblastoma and at least 4 cycles of induction therapy. No prior history of recurrent/progressive disease since the diagnosis of high risk neuroblastoma.

  5. 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 3 or more MIBG avid lesions, then no biopsy is required. If a patients has only 1 or 2 MIBG avid bone lesion sites then biopsy confirmation of neuroblastoma or ganglioneuroblastoma in at least one MIBG avid site present at the time of enrollment is required to be obtained at any time point prior to enrollment.
    3. For MIBG non-avid tumors, patients must have at least one FDG avid site and a biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma at any time prior to enrollment from at least one FDG-avid site.
  6. 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.
  7. 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. Lesions meeting size criteria will be considered measurable.
    2. In addition to size, a lesion needs to meet one of the following criteria except for patients with parenchymal CNS lesions which only need to meet size criteria:

    b1) MIBG avid. For patients with recurrent/progressive or refractory disease, no biopsy is required. For patients with persistent disease only: If a patient has only 1 or 2 MIBG avid lesions sites, then biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one MIBG avid site present at time of enrollment is required to be obtained. If a patient has 3 or more MIBG avid lesions, then no biopsy is required.

    b2) MIBG non avid tumors: Patients must have at least one FDG avid site and biopsy confirmation of neuroblastoma and/or ganglioneuroblastoma in at least one FDG-PET avid site present at the time of enrollment.

  8. At least one non-target soft tissue lesion that is not measurable, but had a biopsy positive for neuroblastoma and/or ganglioneuroblastoma or is MIBG avid at any time prior to enrollment.
  9. 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.
  10. 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

11) 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.

      12) 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.

      13) Patients with other ongoing serious medical issues must be approved by the study chairprior to registration.

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

      15) Ability to Swallow Pills

Exclusion Criteria:

  1. Pregnancy: Quantitative Serum B-HCG must be negative in girls who are post-menarchal.
  2. Breast feeding women are not eligible.
  3. Active or uncontrolled infection
  4. CNS metastasis.
  5. Hypersensitivity to thalidomide, including history of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs (dose level 4 only).
  6. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02573896


Locations
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United States, California
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027-0700
UCSF Helen Diller Family Comprehensive Cancer Center
San Francisco, California, United States, 94115
United States, Georgia
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
Atlanta, Georgia, United States, 30322
United States, Illinois
University of Chicago Comer Children's Hospital
Chicago, Illinois, United States, 60637
United States, Massachusetts
Childrens Hospital Boston, Dana-Farber Cancer Institute.
Boston, Massachusetts, United States, 02115
United States, Michigan
C.S Mott Children's Hospital
Ann Arbor, Michigan, United States, 48109
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104-4318
United States, Texas
Cook Children's Healthcare System
Fort Worth, Texas, United States, 76104
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
Nationwide Children's Hospital
United Therapeutics
Investigators
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Study Chair: Araz Marachelian, MD, MS Children's Hospital Los Angeles
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Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT02573896    
Other Study ID Numbers: NANT 2013-01
First Posted: October 12, 2015    Key Record Dates
Last Update Posted: July 29, 2022
Last Verified: July 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by New Approaches to Neuroblastoma Therapy Consortium:
relapsed refractory neuroblastoma
Additional relevant MeSH terms:
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Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Lenalidomide
Dinutuximab
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents