MIBG With Dinutuximab +/- Vorinostat

NCT03332667 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: NANT2017-012P01CA217959
• Study Type: interventional
• Target: 45
• Locations: 1 country
• Sites: 12

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.

Conditions

Neuroblastoma

Outcome Measures

Primary Outcomes (4)

• MTD/RP2D Determination Cohort A

  Proportion of patients with Course 1 DLT in Cohort A

  All toxicities from enrollment until completion of course 1 (Day 56)

• MTD/RP2D Determination Cohort B

  Proportion of patients with Course 1 DLT in Cohort B

  All toxicities from enrollment until completion of course 1 (Day 56)

• Describe Non-Hematological Toxicities Cohort A

  Proportion of patients with any grade 3 or greater non-hematological toxicities in Cohort A

  All toxicities from enrollment through 30 days following end of protocol therapy, up to 5 months

• Describe Non Hematological Toxicities Cohort B

  Proportion of patients with any grade 3 or greater non-hematological toxicities in Cohort B

  All toxicities from enrollment through 30 days following end of protocol therapy, up to 5 months

Secondary Outcomes (2)

• Overall Response Cohort A

  From Day 1 of protocol therapy through 30 days following end of protocol therapy, up to 5 months

• Overall Response Cohort B

  From Day 1 of protocol therapy through 30 days following end of protocol therapy, up to 5 months

Study Arms (4)

Cohort A DL1

EXPERIMENTAL

Patients will receive 131I-MIBG on day 1 at 12 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. 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; Drug: Dinutuximab; Drug: Sargramostim; Drug: Potassium Iodide

Cohort A DL2

EXPERIMENTAL

Patients will receive 131I-MIBG on day 1 at 15 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. 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; Drug: Dinutuximab; Drug: Sargramostim; Drug: Potassium Iodide

Cohort A DL3

EXPERIMENTAL

Patients will receive 131I-MIBG on day 1 at 18 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. 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; Drug: Dinutuximab; Drug: Sargramostim; Drug: Potassium Iodide

Cohort B DL4

EXPERIMENTAL

Vorinostat will be given on days 0-13 at 180 mg/m2/dose. Patients will receive 131I-MIBG on day 1 at 18 mCi/kg/dose. Dinutuximab is given intravenously on days 8-11 and 29-32 of therapy at 17.5 mg/m2/dose. 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; Drug: Dinutuximab; Drug: Vorinostat; Drug: Sargramostim; Drug: Potassium Iodide

Interventions

131I-MIBG RADIATION

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

Also known as: 131I-Metaiodobenzylguanidine, Iobenguane sulfate, m-Iodobenzylguanidine sulfate, MIBG

Cohort A DL1; Cohort A DL2; Cohort A DL3; Cohort B DL4

Dinutuximab DRUG

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.

Also known as: Chimeric Monoclonal Antibody 14.18, MAB Ch 14.18, Unituxin, Ch14.18

Cohort A DL1; Cohort A DL2; Cohort A DL3; Cohort B DL4

Vorinostat DRUG

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

Also known as: Zolina

Cohort B DL4

Sargramostim DRUG

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

Cohort A DL1; Cohort A DL2; Cohort A DL3; Cohort B DL4

Potassium Iodide DRUG

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

Cohort A DL1; Cohort A DL2; Cohort A DL3; Cohort B DL4

Eligibility Criteria

• Age: 1 Year - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.
• All patients must have at least one of the following
• Recurrent/progressive disease: after the diagnosis of high risk neuroblastoma at any time prior to enrollment regardless of response to frontline therapy
• 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.
• 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.
• 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:
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• New Approaches to Neuroblastoma Therapy Consortium: lead
• United Therapeutics: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90027-0700, United States

Location

UCSF Helen Diller Family Comprehensive Cancer Center

San Francisco, California, 94143, United States

Location

Children Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus

Atlanta, Georgia, 30322, United States

Location

University of Chicago, Comer Children's Hospital

Chicago, Illinois, 60637, United States

Location

Children's Hospital Boston

Boston, Massachusetts, 02115, United States

Location

C.S Mott Children's Hospital

Ann Arbor, Michigan, 48109, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229-3039, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4318, United States

Location

Cook Children's Healthcare System

Fort Worth, Texas, 76104, United States

Location

Children's Hospital and Regional Medical Center - Seattle

Seattle, Washington, 98105, United States

Location

Related Publications (1)

• Cash T, Marachelian A, DuBois SG, Chi YY, Baregamyan A, Groshen SG, Jonus HC, Shamirian A, Crowley M, Goodarzian F, Acharya PT, Pawel B, Erbe AK, Shahi A, Zaborek J, Kennedy E, Asgharzadeh S, Villablanca JG, Pinto N, Weiss BD, Mosse YP, Desai AV, Macy ME, Granger M, Vo KT, Sondel PM, Matthay KK, Park JR, Goldsmith KC. Phase I Study of 131I-Metaiodobenzylguanidine With Dinutuximab +/- Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy Trial. J Clin Oncol. 2025 Aug;43(22):2490-2501. doi: 10.1200/JCO-24-02612. Epub 2025 Jun 23.

  PMID: 40549985 DERIVED

MeSH Terms

Conditions

Neuroblastoma

Interventions

3-Iodobenzylguanidine; dinutuximab; Vorinostat; sargramostim; Potassium Iodide

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Guanidines; Amidines; Organic Chemicals; Iodobenzenes; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Hydrocarbons, Iodinated; Hydrocarbons, Halogenated; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Iodides; Iodine Compounds; Inorganic Chemicals; Potassium Compounds

Results Point of Contact

• Title: NANT Medical Director
• Organization: New Advances in Neuroblastoma Therapy

nantops@chla.usc.edu

3233615687

Study Officials

• Thomas Cash, MD

  Children's Healthcare of Atlanta

  STUDY CHAIR

• Araz Marachelian, MD, MS

  Children's Hospital Los Angeles

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 2, 2017
• First Posted: November 6, 2017
• Study Start: September 12, 2018
• Primary Completion: February 23, 2024
• Study Completion: February 23, 2024
• Last Updated: April 16, 2025
• Results First Posted: April 16, 2025

Record last verified: 2025-03

Locations

US (12)