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MIBG With Dinutuximab +/- Vorinostat

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03332667
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : May 11, 2022
Sponsor:
Collaborator:
United Therapeutics
Information provided by (Responsible Party):
New Approaches to Neuroblastoma Therapy Consortium

Brief Summary:
131I-Metaiodobenzylguanidine (131I-MIBG) is one of the most effective therapies utilized for neuroblastoma patients with refractory or relapsed disease. In this pediatric phase 1 trial, 131I-MIBG will be given in combination with dinutuximab, a chimeric 14.18 monoclonal antibody. This study will utilize a traditional Phase I rolling 6 dose escalation design to determine a recommended phase 2 pediatric dose. An expansion cohort of an additional 6 patients will then be enrolled. If tolerable, vorinostat will then be added to the third dose level. A 6 patient expansion cohort may then be enrolled.

Condition or disease Intervention/treatment Phase
Neuroblastoma Radiation: 131I-MIBG Drug: Dinutuximab Drug: Vorinostat Drug: Sargramostim Drug: Potassium Iodide Phase 1

Detailed Description:
131I-Metaiodobenzylguanidine (131I-MIBG) is one of the most effective therapies utilized for neuroblastoma patients with refractory or relapsed disease. Data from pre-clinical and adult studies suggest that radiation can enhance the efficacy of immunotherapy and targeted therapies such as dinutuximab. This first pediatric phase 1 trial of 131I-MIBG in combination with dinutuximab and vorinostat aims to determine the recommended phase 2 pediatric dose of these three therapies in combination.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of 131I-MIBG With Dinutuximab +/- Vorinostat for Relapsed/Refractory Neuroblastoma
Actual Study Start Date : September 12, 2018
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : March 2023


Arm Intervention/treatment
Experimental: 131I-MIBG with Dinutuximab
Patients will receive 131I-MIBG on day 1. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy. Dinutuximab and 131I-MIBG dose will be based on the dose level assigned at the time of patient registration. Patient will receive GM-CSF on days 8-17 and 29-38 at 250 mcg/m2. All patients will receive autologous hematopoietic stem cell infusion on day 15 (+/- 2) of therapy
Radiation: 131I-MIBG
Patients will receive 131I-MIBG on day 1. 131I-MIBG dose will be based on the dose level assigned at the time of patient registration
Other Names:
  • 131I-Metaiodobenzylguanidine
  • Iobenguane sulfate
  • m-Iodobenzylguanidine sulfate
  • MIBG

Drug: Dinutuximab
Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy. Dinutuximab dose will be based on the dose level assigned at the time of patient registration.
Other Names:
  • Chimeric Monoclonal Antibody 14.18
  • MAB Ch 14.18
  • Unituxin
  • Ch14.18

Drug: Sargramostim
Sargramostim (GM-CSF) will be given on day 8-17 at 250 mcg/m^2

Drug: Potassium Iodide
Potassium iodide will be given by mouth at a dose of 6mg/kg 8-12 hours prior to infusion of 131I-MIBG on Day 1 and then 1mg/kg/dose by mouth starting 4-6 hours after completion of MIBG infusion and continuing every 4 hours on protocol days 1-7 and then 1mg/kg/dose by mouth once daily on protocol days 8-45

Experimental: 131I-MIBG with Dinutuximab and Vorinostat
Patients will receive vorinostat on days 0-13. 131I-MIBG will be received on day 1. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy. Dinutuximab and 131I-MIBG dose will be based on the dose level assigned at the time of patient registration. Patient will receive GM-CSF on days 8-17 and 29-38 at 250 mcg/m2. All patients will receive autologous hematopoietic stem cell infusion on day 15 (+/- 2) of therapy
Radiation: 131I-MIBG
Patients will receive 131I-MIBG on day 1. 131I-MIBG dose will be based on the dose level assigned at the time of patient registration
Other Names:
  • 131I-Metaiodobenzylguanidine
  • Iobenguane sulfate
  • m-Iodobenzylguanidine sulfate
  • MIBG

Drug: Dinutuximab
Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy. Dinutuximab dose will be based on the dose level assigned at the time of patient registration.
Other Names:
  • Chimeric Monoclonal Antibody 14.18
  • MAB Ch 14.18
  • Unituxin
  • Ch14.18

Drug: Vorinostat
Vorinostat will be given on day 0-13. Vorinostat dose will be based on the dose level assigned at the time of patient registration.
Other Name: Zolina

Drug: Sargramostim
Sargramostim (GM-CSF) will be given on day 8-17 at 250 mcg/m^2

Drug: Potassium Iodide
Potassium iodide will be given by mouth at a dose of 6mg/kg 8-12 hours prior to infusion of 131I-MIBG on Day 1 and then 1mg/kg/dose by mouth starting 4-6 hours after completion of MIBG infusion and continuing every 4 hours on protocol days 1-7 and then 1mg/kg/dose by mouth once daily on protocol days 8-45




Primary Outcome Measures :
  1. MTD/RP2D determination Cohort A [ Time Frame: All toxicities from enrollment until completion of course 1 (Day 56) ]
    Proportion of patients with Course 1 DLT in Cohort A

  2. MTD/RP2D determination Cohort B [ Time Frame: All toxicities from enrollment until completion of course 1 (Day 56) ]
    Proportion of patients with Course 1 DLT in Cohort B

  3. Describe Non-Hematological Toxicities Cohort A [ 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 in Cohort A

  4. Describe Non Hematological Toxicities Cohort B [ 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 in Cohort B


Secondary Outcome Measures :
  1. Overall Response Cohort A [ 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 for patients in Cohort A

  2. Overall Response Cohort B [ 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 for patients in Cohort B



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 30 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have evidence of MIBG uptake into tumor at ≥ 1 site (bone or soft tissue) within 28 days prior to study entry and subsequent to any intervening therapy.
  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

    1. Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy
    2. 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):

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

    b) 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.

    c) 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:

    a) 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.

    b) 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 8. Therapeutic MIBG 9. Investigational medicines covered under another IND 10. Medications interfering with MIBG uptake 11. Medications that prolong QTc (Part B only) 12. Valproic acid (Part B only) 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 chair prior to registration.

      14) Autologous peripheral blood stem cells (PBSC)•The minimum dose for peripheral blood stem cells is 2.0 x 106viable CD34+ cells/kg. Patients who do not meet this minimum requirement for available PBSCs are not eligible. •Only un-purged stem cells are allowed unless a center has separate FDA approval for infusion of purged stem cells. •For patients whose body weight exceeds ideal body weight (IBW) by more than 20%, adjusted body weight may be used for the calculation of PBSC dose 15) Physician deems that there is reasonable ability to obtain vorinostat via commercial supply (Part B Only)

Exclusion Criteria:

  • Pregnancy, breast feeding, or unwillingness to use effective contraception during the study.
  • Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
  • Patients with disease of any major organ system that would compromise their ability to withstand therapy.
  • Patients who have received prior allogeneic stem cell transplant
  • Patients who have received prior solid organ transplantation
  • Patients must not have received prior total body irradiation
  • Prior HDAC inhibitor given in combination with therapeutic 131I-MIBG(Part B only)
  • The maximum total allowable dose of 131I-MIBG that can be given per institutional guidelines must be at least 90% of the calculated 131I-MIBG dose or the patient is not eligible.
  • Patients who are on hemodialysis.
  • Patients with an active or uncontrolled infection.
  • Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C.
  • Patient declines participation in NANT 2004-05, the NANT Biology Study
  • Patients and/or families who are physically and psychologically unable to cooperate with the radiation safety isolation.
  • Patients with a history of having to discontinue anti-GD2 antibody therapy due to toxicity are not eligible.
  • Prior anti-GD2 therapy is not otherwise an exclusionary criteria unless it was given in combination with therapeutic 131I-MIBG.

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): NCT03332667


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

Locations
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United States, California
Children's Hospital Los Angeles Recruiting
Los Angeles, California, United States, 90027-0700
Contact: Araz Marachelian, MD    323-361-5687    amarachelian@chla.usc.edu   
UCSF Helen Diller Family Comprehensive Cancer Center Recruiting
San Francisco, California, United States, 94143
Contact: Kieuhoa Vo, MD         
United States, Colorado
Children Hospital of Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Margaret Macy, MD    720-777-8856    Margaret.macy@childrenscolorado.org   
United States, Georgia
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus Recruiting
Atlanta, Georgia, United States, 30322
Contact: Kelly Goldsmith, MD    404-785-0853    kgoldsm@emory.edu   
United States, Illinois
University of Chicago, Comer Children's Hospital Recruiting
Chicago, Illinois, United States, 60637
Contact: Ami L. Desai, MD    773-843-3943    adesai12@peds.bsd.uchicago.edu   
United States, Massachusetts
Children's Hospital Boston Recruiting
Boston, Massachusetts, United States, 02115
Contact: Suzanne Shusterman, MD    617-632-4901    suzanne_shusterman@dfci.harvard.edu   
United States, Michigan
C.S Mott Children's Hospital Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Rajen Mody, MD       rmody@umich.edu   
United States, North Carolina
University of North Carolina Active, not recruiting
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Cincinnati Children's Hospital Medical Center 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 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 Recruiting
Fort Worth, Texas, United States, 76104
Contact: Meaghan Granger, MD    682-885-4007      
United States, Washington
Children's Hospital and Regional Medical Center - Seattle Recruiting
Seattle, Washington, United States, 98105
Contact: Navin Pinto, MD    206-987-5783    navin.pinto@seattlechildrens.org   
Sponsors and Collaborators
New Approaches to Neuroblastoma Therapy Consortium
United Therapeutics
Investigators
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Study Chair: Thomas Cash, MD Children's Healthcare of Atlanta
Study Director: Araz Marachelian, MD, MS Children's Hospital Los Angeles
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Responsible Party: New Approaches to Neuroblastoma Therapy Consortium
ClinicalTrials.gov Identifier: NCT03332667    
Other Study ID Numbers: NANT2017-01
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: May 11, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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
Vorinostat
3-Iodobenzylguanidine
Dinutuximab
Sargramostim
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Radiopharmaceuticals