Trial record 2 of 21193 for:    United Therapeutics cell

Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified December 2015 by New Approaches to Neuroblastoma Therapy Consortium
Sponsor:
Collaborators:
M.D. Anderson Cancer Center
United Therapeutics
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier:
NCT02573896
First received: September 16, 2015
Last updated: December 11, 2015
Last verified: December 2015
  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.

Condition Intervention Phase
Neuroblastoma
Drug: Ch14.18
Biological: NK Cells
Drug: Lenalidomide
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Immunotherapy of Relapsed Refractory Neuroblastoma With Expanded NK Cells, ch14.18 and Lenalidomide

Resource links provided by NLM:


Further study details as provided by New Approaches to Neuroblastoma Therapy Consortium:

Primary Outcome Measures:
  • Feasibility of expanding NK cells from neuroblastoma patients and cryopreserving, shipping, and infusing multiple doses of NK cells. [ Time Frame: 2.5-3 years ] [ Designated as safety issue: Yes ]
    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 107 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 aliquots (treatments) available for each patient at the assigned dose.

  • Determination of the Maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of autologous expanded NK cells [ Time Frame: 2.5-3 years ] [ Designated as safety issue: Yes ]
    The toxicities and adverse events experienced during and following treatment on this protocol: These will be graded and classified according to the CTCAE v4.03.. The derived endpoints are (1) whether or not the patient experienced DLT, and (2) whether or not the patient discontinued treatment for reasons of toxicity or lack of tolerability. The criteria for whether or not a patient experiences a DLT are based on the toxicities and adverse events that occur during the 1st course.


Secondary Outcome Measures:
  • Toxicity (Per Patient) [ Time Frame: average 3 months ] [ Designated as safety issue: Yes ]
    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).

  • Evaluation of Clinical Response (Per Patient) [ Time Frame: average 120 days ] [ Designated as safety issue: No ]
    Response will be determined by the evaluation of CT/MRI scans and bone marrow biopsy


Estimated Enrollment: 24
Study Start Date: March 2016
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: NK cells with Ch14.18 & Lenalidomide
Patients 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.
Drug: Ch14.18
17.5 mg/m2/day of Ch.14.18 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.

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 are being given in combination in NANT 2011-04 where the safety and immunomodulatory effect has been established in that study at the dose level proposed in this study. 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.

  Eligibility

Ages Eligible for Study:   1 Month to 30 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02573896

Contacts
Contact: Araz Marachelian, MD, MS 323-361-5687 amarachelian@chla.usc.edu

Locations
United States, California
Children's Hospital Los Angeles Not yet recruiting
Los Angeles, California, United States, 90027-0700
Contact: Araz Marachelian, MD    323-361-5687    amarachelian@chla.usc.edu   
Lucille Salter Packer Children's Hospital, Stanford University Not yet recruiting
Palo Alto, California, United States, 94305
Contact: Claire - Twist, MD    650-723-5535    claire.twist@stanford.edu   
UCSF Helen Diller Family Comprehensive Cancer Center Not yet recruiting
San Francisco, California, United States, 94115
Contact: Katherine Matthay, MD    415-476-3831    matthayK@peds.ucsf.edu   
United States, Georgia
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Kelly Goldsmith, MD    404-785-0853    kgoldsm@emory.edu   
United States, Illinois
Children's Memorial Hospital - Chicago
Chicago, Illinois, United States, 60614
University of Chicago Comer Children's Hospital Not yet recruiting
Chicago, Illinois, United States, 60637
Contact: Susan L. Cohn, MD    773-702-2571    scohn@peds.bsd.uchicago.edu   
United States, Massachusetts
Childrens Hospital Boston, Dana-Farber Cancer Institute. Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Suzanne - Shusterman, MD    617-632-3725    suzanne_shusterman@dfci.harvard.edu   
United States, Michigan
C.S Mott Children's Hospital Not yet recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Gregory Yanik, MD    734-936-8785    gyanik@umich.edu   
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
Contact: Stephen Roberts, MD    212-639-4034    robertss@mskcc.org   
United States, Ohio
Cincinnati Children's Hospital Medical Center Not yet recruiting
Cincinnati, Ohio, United States, 45229-3039
Contact: Brian Weiss, MD    513-636-9863    brian.weiss@chmcc.org   
United States, Pennsylvania
Children's Hospital of Philadelphia Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104-4318
Contact: Yael Mosse, MD    215-590-0965    mosse@chop.edu   
United States, Texas
Cook Children's Healthcare System Not yet recruiting
Fort Worth, Texas, United States, 76104
Contact: Meaghan Granger, MD    682-885-4007    mgranger@cookchildrens.org   
MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Douglas J Harrison, MD    713-563-0893    DJHarrison@mdanderson.org   
United States, Washington
Seattle Children's Hospital Not yet recruiting
Seattle, Washington, United States, 98105
Contact: Julie Park, MD    206-987-1987      
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
M.D. Anderson Cancer Center
United Therapeutics
Investigators
Study Director: Araz Marachelian, MD, MS Children's Hospital Los Angeles
Study Chair: Dean Lee, MD, PhD M.D. Anderson Cancer Center
  More Information

Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT02573896     History of Changes
Other Study ID Numbers: NANT 2013-01 
Study First Received: September 16, 2015
Last Updated: December 11, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by New Approaches to Neuroblastoma Therapy Consortium:
relapsed refractory neuroblastoma

Additional relevant MeSH terms:
Neoplasms, Germ Cell and Embryonal
Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Lenalidomide
Thalidomide
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on August 25, 2016