Phase I Study of 131-I mIBG Followed by Nivolumab & Dinutuximab Beta Antibodies in Children With Relapsed/Refractory Neuroblastoma
NCT ID: NCT02914405
Last Updated: 2025-10-22
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
ACTIVE_NOT_RECRUITING
Clinical Phase
PHASE1
Total Enrollment
44 participants
Study Classification
INTERVENTIONAL
Study Start Date
2018-05-24
Study Completion Date
2025-11-30
Brief Summary
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Neuroblastoma, the most common extra-cranial solid tumour in children, remains one of the major challenges in paediatric oncology. A promising way to further improve outcome in this disease appears to be the development of adjuvant therapeutic strategies. In this research the anti-GD2 antibody, which is a standard treatment, is to be combined with 131-l Metaiodobenzylguanidine (mlBG) and anti-Programmed Cell Death Protein 1 (anti-PD1) antibody Nivolumab - the investigated drugs - with the aim of generating sustained anti-neuroblastoma immunity. In particular it will be determined the safety and tolerability of the novel combination as well as documented any evidence of efficacy in paediatric patients with relapsed and refractory high risk neuroblastoma.
This study is sponsored by the University Hospital Southampton and will take place in 4 hospitals in the United Kingdom, Germany and USA. The estimated duration of the study is 2 years, starting in December 2016.
This is an "adaptive study". Such design uses accumulating of data from the ongoing trial to modify aspects of the study (e.g. duration, number of treatments) without undermining its validity or integrity. There will be 3 cohorts of patients. As safety of Nivolumab is well established, Cohort 1 will assess its safety and tolerability in combination with 131-l mlBG. Cohort 2 will then add anti-GD2 to the drug combination, assessing safety and tolerability. Cohort 3 will escalate all 3 agents to the full 100% dose level to assure safety for expanded analyses of clinical and laboratory data at that dose level.
Patients will initially be recruited into Cohort 1. Patients must have completed at least 12 weeks of trial treatment without reaching a Dose Limiting Toxicity before a patient can be recruited to the next cohort.
A minimum of 3 evaluable patients will be treated in cohorts 1-3. Assuming the full dose combination therapy (cohort) is tolerable, 15 evaluable patients will be treated.
This study is sponsored by the University Hospital Southampton and will take place in 4 hospitals in the United Kingdom, Germany and USA. The estimated duration of the study is 2 years, starting in December 2016.
This is an "adaptive study". Such design uses accumulating of data from the ongoing trial to modify aspects of the study (e.g. duration, number of treatments) without undermining its validity or integrity. There will be 3 cohorts of patients. As safety of Nivolumab is well established, Cohort 1 will assess its safety and tolerability in combination with 131-l mlBG. Cohort 2 will then add anti-GD2 to the drug combination, assessing safety and tolerability. Cohort 3 will escalate all 3 agents to the full 100% dose level to assure safety for expanded analyses of clinical and laboratory data at that dose level.
Patients will initially be recruited into Cohort 1. Patients must have completed at least 12 weeks of trial treatment without reaching a Dose Limiting Toxicity before a patient can be recruited to the next cohort.
A minimum of 3 evaluable patients will be treated in cohorts 1-3. Assuming the full dose combination therapy (cohort) is tolerable, 15 evaluable patients will be treated.
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Detailed Description
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Conditions
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Neuroblastoma
Study Design
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Allocation Method
NA
Intervention Model
SINGLE_GROUP
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Treatment
The dose and schedule of 131-I mIBG will be constant, and the doses of ch14.18/ CHO and Nivolumab determined by cohort:
* Cohort I: 3 mg/kg Nivolumab (100% adult dose). No ch14.18/CHO. (3-6 patients)
* Cohort II: 50mg/m2/cycle ch14.18/CHO (50% established Long Term Intervention (LTI) dose) and 3 mg/kg Nivolumab (100% adult dose) (3-6 patients)
* Cohort III: 100mg/m2/cycle ch14.18/CHO (100% established LTI dose) and 3 mg/kg Nivolumab (100% adult dose) (initial 3-6 patients, expanded to 15 patient cohort if tolerated)
Group Type
EXPERIMENTAL
Nivolumab
Intervention Type
DRUG
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains consisting of 440 amino acids and 2 identical light chains. Molecular weight is 146,221 daltons.
Ch14.18/CHO
Intervention Type
DRUG
APN311 (ch14.18/CHO) is manufactured in a Good Manufacturing Practice (GMP) compliant facility of Polymun Scientific, Austria according to a state of the art aseptic manufacturing process based on a characterized and stable Chinese Hamster Ovary (CHO) cell line. After propagation of the working cell bank (WCB) in small volume vessels/bioreactors, manufacture is carried out in a 2500 L stirred tank reactor utilizing components which are free of material of animal or human origin.
Interventions
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Nivolumab
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains consisting of 440 amino acids and 2 identical light chains. Molecular weight is 146,221 daltons.
Intervention Type
DRUG
Ch14.18/CHO
APN311 (ch14.18/CHO) is manufactured in a Good Manufacturing Practice (GMP) compliant facility of Polymun Scientific, Austria according to a state of the art aseptic manufacturing process based on a characterized and stable Chinese Hamster Ovary (CHO) cell line. After propagation of the working cell bank (WCB) in small volume vessels/bioreactors, manufacture is carried out in a 2500 L stirred tank reactor utilizing components which are free of material of animal or human origin.
Intervention Type
DRUG
Other Intervention Names
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BMS-936558
MDX1106
ONO-4538
anti-PD-1) NSC#748726
IND #124729
Mouse-human chimeric monoclonal anti-GD2 Immunoglobulin G1 (IgG1) antibody
Eligibility Criteria
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Inclusion Criteria
* At study entry patients must be \> 1 year
* Relapsed or refractory high risk neuroblastoma (as defined by International Neuroblastoma Risk Group (INRG) criteria)
* MIBG avid disease on imaging within 4 weeks to study entry.
* ≥ 3 months since any myeloablative chemotherapy / stem cell rescue
* ≥ 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half lives since last dose of any monoclonal antibody therapy.
* Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky)
* Estimated life expectancy ≥ 12 weeks
* Adequate bone marrow function: Absolute Neutrophil Count (ANC) \>1.0 x 10/L, platelets, 20 x 10/L and haemoglobin \> 8.0 g/dL.
* Adequate renal function: serum creatinine \<1.5 mg/dL or a estimated creatinine clearance or radioisotope Glomerular Filtration Rate Study (GFR) of \> 60 mL/minute/1.73m2.
* Adequate cardiac function: shortening fraction of 28 % by echocardiogram.
* Adequate hepatic function: Alanine transaminase (ALT) or Aspartate transaminase (AST) \< 5 x ULN and a total bilirubin \< 1.5 x Upper Limit of Normal (ULN)
* Adequate lung function: Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) \>60% of the predicted by pulmonary function tests. Children unable to do Pulmonary Function Tests (PFTs) should have no dyspnea at rest and a pulse oximetry \>94% on room air.
* Adequate pancreatic function: serum lipase \< 1.5 x upper limit normal
* Patients may have had prior Central Nervous System (CNS) metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable prior for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema.
* Patients must consent to the placement of a central venous line, if one has not already been placed.
* Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery.
* Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
* Patients with seizure disorders may be enrolled if seizures are well controlled.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional and national requirements for clinical trials must be met.
* Expression of PD-L1 by tumour is not a pre-requisite
* Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration.
* Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy
* Relapsed or refractory high risk neuroblastoma (as defined by International Neuroblastoma Risk Group (INRG) criteria)
* MIBG avid disease on imaging within 4 weeks to study entry.
* ≥ 3 months since any myeloablative chemotherapy / stem cell rescue
* ≥ 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half lives since last dose of any monoclonal antibody therapy.
* Patients must have a performance status greater or equal 60% (Lansky Score or Karnofsky)
* Estimated life expectancy ≥ 12 weeks
* Adequate bone marrow function: Absolute Neutrophil Count (ANC) \>1.0 x 10/L, platelets, 20 x 10/L and haemoglobin \> 8.0 g/dL.
* Adequate renal function: serum creatinine \<1.5 mg/dL or a estimated creatinine clearance or radioisotope Glomerular Filtration Rate Study (GFR) of \> 60 mL/minute/1.73m2.
* Adequate cardiac function: shortening fraction of 28 % by echocardiogram.
* Adequate hepatic function: Alanine transaminase (ALT) or Aspartate transaminase (AST) \< 5 x ULN and a total bilirubin \< 1.5 x Upper Limit of Normal (ULN)
* Adequate lung function: Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) \>60% of the predicted by pulmonary function tests. Children unable to do Pulmonary Function Tests (PFTs) should have no dyspnea at rest and a pulse oximetry \>94% on room air.
* Adequate pancreatic function: serum lipase \< 1.5 x upper limit normal
* Patients may have had prior Central Nervous System (CNS) metastasis at point of entry to study, but patients with mIBG avid parenchymal brain lesions will be excluded. All CNS disease must be treated and stable prior for at least 4 weeks prior to starting trial 131-I mIBG therapy (see section 4). Patients with extra-axial disease (e.g. skull (bone) metastasis that do not invade the dura) may be enrolled providing there is no evidence of brain oedema.
* Patients must consent to the placement of a central venous line, if one has not already been placed.
* Patients must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery.
* Females of childbearing potential must have a negative pregnancy test. Patients of childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.
* Patients with seizure disorders may be enrolled if seizures are well controlled.
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional and national requirements for clinical trials must be met.
* Expression of PD-L1 by tumour is not a pre-requisite
* Parents or carers willing and able to comply with radiation safety measures needed for 131-I mIBG administration.
* Patient must be judged capable of tolerating isolation procedures associated with 131-I-mIBG therapy
Exclusion Criteria
* Patients who have previously received ch14.18 (CHO or SP2/0) will not be excluded unless they have had severe or life threatening toxicity necessitating withdrawal of treatment previously or if they have a strong/neutralizing Human Antichimeric Antibody (HACA) (≥ 10 μg/ml)
* Patients who have had previous 131-I mIBG therapy will not be excluded
* Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study
* Previous allogeneic stem cell transplant or solid organ transplant
* Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
* Patients receiving systemic corticosteroids (other than physiological replacement) or other immunosuppressive agents within 14 days prior to study entry
* Unable to maintain platelets ≥ 50 x 109/l without transfusion
* HIV or Hepatitis B or C infection
* Patients with significant intercurrent illnesses and/or any of the following:
* Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance.
* Patients with significant psychiatric disabilities or uncontrolled seizure disorders.
* Patients with active infections.
* Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade \>2) are ineligible.
* Patients with clinically significant, symptomatic, pleural effusions.
* Patients who require, or are likely to require, corticosteroid or other immunosuppressive drugs.
* Patients who have had previous 131-I mIBG therapy will not be excluded
* Patients previously treated with Nivolumab or any other PD-1 or PD-L1 targeting antibodies will be excluded from the study
* Previous allogeneic stem cell transplant or solid organ transplant
* Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
* Patients receiving systemic corticosteroids (other than physiological replacement) or other immunosuppressive agents within 14 days prior to study entry
* Unable to maintain platelets ≥ 50 x 109/l without transfusion
* HIV or Hepatitis B or C infection
* Patients with significant intercurrent illnesses and/or any of the following:
* Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance.
* Patients with significant psychiatric disabilities or uncontrolled seizure disorders.
* Patients with active infections.
* Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade \>2) are ineligible.
* Patients with clinically significant, symptomatic, pleural effusions.
* Patients who require, or are likely to require, corticosteroid or other immunosuppressive drugs.
Minimum Eligible Age
1 Year
Maximum Eligible Age
99 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
Yes
Sponsors
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University College London Hospitals
OTHER
Sponsor Role
collaborator
University of Wisconsin, Madison
OTHER
Sponsor Role
collaborator
University Hospital Greifswald
OTHER
Sponsor Role
collaborator
Solving Kids' Cancer US/EU
UNKNOWN
Sponsor Role
collaborator
Joining Against Cancer in Kids
UNKNOWN
Sponsor Role
collaborator
The Band of Parents
UNKNOWN
Sponsor Role
collaborator
University Hospital Southampton NHS Foundation Trust
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Juliet Gray
Role: PRINCIPAL_INVESTIGATOR
Consultant Paediatric Oncologist
Locations
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University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics; American Family Children's Hospital
Madison, Wisconsin, United States
Site Status
University Hospital Southampton NHS Foundation Trust
Southampton, Hampshire, United Kingdom
Site Status
University College London Hospital
London, London, United Kingdom
Site Status
Countries
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United States
United Kingdom
References
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RESULT
Matthay KK, Quach A, Huberty J, Franc BL, Hawkins RA, Jackson H, Groshen S, Shusterman S, Yanik G, Veatch J, Brophy P, Villablanca JG, Maris JM. Iodine-131--metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol. 2009 Mar 1;27(7):1020-5. doi: 10.1200/JCO.2007.15.7628. Epub 2009 Jan 26.
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RESULT
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RESULT
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RESULT
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RESULT
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RESULT
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RESULT
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RESULT
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RESULT
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RESULT
Albertini MR, Hank JA, Schiller JH, Khorsand M, Borchert AA, Gan J, Bechhofer R, Storer B, Reisfeld RA, Sondel PM. Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients. Clin Cancer Res. 1997 Aug;3(8):1277-88.
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RESULT
Ozkaynak MF, Sondel PM, Krailo MD, Gan J, Javorsky B, Reisfeld RA, Matthay KK, Reaman GH, Seeger RC. Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children's Cancer Group Study. J Clin Oncol. 2000 Dec 15;18(24):4077-85. doi: 10.1200/JCO.2000.18.24.4077.
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RESULT
Gilman AL, Ozkaynak MF, Matthay KK, Krailo M, Yu AL, Gan J, Sternberg A, Hank JA, Seeger R, Reaman GH, Sondel PM. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol. 2009 Jan 1;27(1):85-91. doi: 10.1200/JCO.2006.10.3564. Epub 2008 Dec 1.
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RESULT
Ladenstein R, Potschger U, Siabalis D, Garaventa A, Bergeron C, Lewis IJ, Stein J, Kohler J, Shaw PJ, Holter W, Pistoia V, Michon J. Dose finding study for the use of subcutaneous recombinant interleukin-2 to augment natural killer cell numbers in an outpatient setting for stage 4 neuroblastoma after megatherapy and autologous stem-cell reinfusion. J Clin Oncol. 2011 Feb 1;29(4):441-8. doi: 10.1200/JCO.2009.23.5465. Epub 2010 Dec 13.
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RESULT
Siebert N, Eger C, Seidel D, Juttner M, Zumpe M, Wegner D, Kietz S, Ehlert K, Veal GJ, Siegmund W, Weiss M, Loibner H, Ladenstein R, Lode HN. Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2. MAbs. 2016;8(3):604-16. doi: 10.1080/19420862.2015.1130196. Epub 2016 Jan 19.
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Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
2016-002221-11
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
RHM CHI0811
Identifier Type: -
Identifier Source: org_study_id
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