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Phase I Study of Investigational Medicinal Products in Children With Relapsed/Refractory Neuroblastoma (Inbraced)

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ClinicalTrials.gov Identifier: NCT02914405
Recruitment Status : Recruiting
First Posted : September 26, 2016
Last Update Posted : June 25, 2018
Sponsor:
Collaborators:
University College London Hospitals NHS Foundation Trust
University of Wisconsin, Madison
University Hospital Greifswald
Solving Kids' Cancer US/EU
Joining Against Cancer in Kids
The Band of Parents
Information provided by (Responsible Party):
University Hospital Southampton NHS Foundation Trust

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.


Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: Nivolumab Drug: Ch14.18/CHO Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of 131-1 Meta-iodobenzylguanidine (mIBG) Followed by Nivolumab and Chimeric 14.18 Anti-GD2 Monoclonal Antibody Produced in Chinese Hamster Ovary Cells (ch14.18/CHO) in Children With Relapsed/Refractory Neuroblastoma
Actual Study Start Date : May 24, 2018
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : May 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: 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)
Drug: 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.
Other Names:
  • BMS-936558
  • MDX1106
  • ONO-4538
  • anti-PD-1) NSC#748726
  • IND #124729

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.
Other Name: Mouse-human chimeric monoclonal anti-GD2 Immunoglobulin G1 (IgG1) antibody




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Events [Safety and tolerability] of 131-I-MIBG, ch14.18/CHO and Nivolumab in paediatric patients [ Time Frame: 2 Years ]
    • 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


Secondary Outcome Measures :
  1. 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 [ Time Frame: 2 Years ]
    To document any evidence of efficacy of 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma (time to progression)

  2. 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 [ Time Frame: 2 Years ]
    To document any evidence of efficacy of 131-I-MIBG, ch14.18/CHO and Nivolumab in patients with relapsed and refractory high risk neuroblastoma (objective response rate)

  3. KIR/KIR-Ligand genotype, FcγR genotype [ Time Frame: 2 Years ]
    To provide descriptive analysis of any associations between KIR/KIR-Ligand genotype, FcγR genotype and response



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

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 ≥ 20 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.

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): NCT02914405


Contacts
Contact: Danny Pratt +44(0)2381204989 ext 3943 danny.pratt@uhs.nhs.uk

Locations
United Kingdom
University Hospital Southampton NHS Foundation Trust Recruiting
Southampton, Hampshire, United Kingdom, SO16 6YD
Contact: Danny B Pratt    023 8120 4989 ext 3943    danny.pratt@uhs.nhs.uk   
Contact: Tom Bower    023 8120 4989 ext 3853    thomas.bower@uhs.nhs.uk   
Principal Investigator: Juliet C Gray         
University College London Hospital Recruiting
London, United Kingdom, NW1 2BU
Contact: Pamela Niem    023 447 7135    Pamela.Niem@nhs.net   
Contact: Sarah Taylor    07890 60 9229    sarah.taylor83@nhs.net   
Principal Investigator: Mark Gaze         
Sponsors and Collaborators
University Hospital Southampton NHS Foundation Trust
University College London Hospitals NHS Foundation Trust
University of Wisconsin, Madison
University Hospital Greifswald
Solving Kids' Cancer US/EU
Joining Against Cancer in Kids
The Band of Parents
Investigators
Principal Investigator: Juliet Gray Consultant Paediatric Oncologist

Publications of Results:

Other Publications:
Responsible Party: University Hospital Southampton NHS Foundation Trust
ClinicalTrials.gov Identifier: NCT02914405     History of Changes
Other Study ID Numbers: RHM CHI0811
2016-002221-11 ( EudraCT Number )
First Posted: September 26, 2016    Key Record Dates
Last Update Posted: June 25, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University Hospital Southampton NHS Foundation Trust:
131-I-mIBG therapy
ch14.18/CHO
Nivolumab

Additional relevant MeSH terms:
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
Antibodies
Antibodies, Monoclonal
Immunoglobulins
Immunoglobulin G
Nivolumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents