Phase I Study of 131-I mIBG Followed by Nivolumab & Dinutuximab Beta Antibodies in Children With Relapsed/Refractory Neuroblastoma

NCT02914405 | Active Not Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: RHM CHI08112016-002221-11
• Study Type: interventional
• Target: 44
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

Neuroblastoma

Keywords

131-I-mIBG therapy; ch14.18/CHO; Nivolumab; MiniVan

Outcome Measures

Primary Outcomes (1)

• Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients

  • To determine the safety and tolerability of the novel combination of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients, assessed by nature, frequency, severity and timing of adverse events, including serious adverse events and immune related adverse events during administration of ch14.18/CHO

  2 Years

Secondary Outcomes (3)

• Anti-tumour response in patients with measureable disease as measured by immunocytology, MIBG, CT and/or MRI in patients receiving 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma

  2 Years

• Anti-tumour response in patients with measureable disease as measured by immunocytology, MIBG, CT and/or MRI in patients receiving 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma

  2 Years

• KIR/KIR-Ligand genotype, FcγR genotype

  2 Years

Study Arms (1)

Treatment

EXPERIMENTAL

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)

Drug: Nivolumab; Drug: Ch14.18/CHO

Interventions

Nivolumab 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.

Also known as: BMS-936558, MDX1106, ONO-4538, anti-PD-1) NSC#748726, IND #124729

Treatment

Ch14.18/CHO 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.

Also known as: Mouse-human chimeric monoclonal anti-GD2 Immunoglobulin G1 (IgG1) antibody

Treatment

Eligibility Criteria

• Age: 1 Year - 99 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital Southampton NHS Foundation Trust: lead
• University College London Hospitals: collaborator
• University of Wisconsin, Madison: collaborator
• University Hospital Greifswald: collaborator
• Solving Kids' Cancer US/EU: collaborator
• Joining Against Cancer in Kids: collaborator
• The Band of Parents: collaborator

Study Sites (3)

University of Wisconsin Carbone Cancer Center; UW Hospital and Clinics; American Family Children's Hospital

Madison, Wisconsin, 53792, United States

Location

University Hospital Southampton NHS Foundation Trust

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

University College London Hospital

London, London, NW1 2BU, United Kingdom

Location

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• Yang RK, Kalogriopoulos NA, Rakhmilevich AL, Ranheim EA, Seo S, Kim K, Alderson KL, Gan J, Reisfeld RA, Gillies SD, Hank JA, Sondel PM. Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the hu14.18 antibody increases intratumoral CD8+ T and NK cells and improves survival. Cancer Immunol Immunother. 2013 Aug;62(8):1303-13. doi: 10.1007/s00262-013-1430-x. Epub 2013 May 10.

  PMID: 23661160 RESULT

• Williams EL, Dunn SN, James S, Johnson PW, Cragg MS, Glennie MJ, Gray JC. Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model. Clin Cancer Res. 2013 Jul 1;19(13):3545-55. doi: 10.1158/1078-0432.CCR-12-3226. Epub 2013 May 6.

  PMID: 23649004 RESULT

• Zernikow B, Hechler T. Pain therapy in children and adolescents. Dtsch Arztebl Int. 2008 Jul;105(28-29):511-21; quiz 521-2. doi: 10.3238/arztebl.2008.0511. Epub 2008 Jul 14.

  PMID: 19626208 RESULT

MeSH Terms

Conditions

Neuroblastoma

Interventions

Nivolumab; Immunoglobulin G; Antibodies

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)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes

Study Officials

• Juliet Gray

  Consultant Paediatric Oncologist

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2016
• First Posted: September 26, 2016
• Study Start: May 24, 2018
• Primary Completion: June 30, 2025
• Study Completion (Estimated): September 30, 2026
• Last Updated: April 28, 2026

Record last verified: 2026-04

Locations

US (1); GB (2)