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

Study Overview
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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.

Official Title
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A Phase I Study of 131-1 mIBG Followed by Nivolumab and Dinutuximab Beta in Children With Relapsed/Refractory Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: Nivolumab
* Drug: Ch14.18/CHO


Participation Criteria
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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 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.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>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<br>* 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.<br>* Other names: IND #124729;Drug: Ch14.18/CHO<br>* 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.<br>* Other names: Mouse-human chimeric monoclonal anti-GD2 Immunoglobulin G1 (IgG1) antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 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 | 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) | 2 Years | 
| KIR/KIR-Ligand genotype, FcγR genotype | To provide descriptive analysis of any associations between KIR/KIR-Ligand genotype, FcγR genotype and response | 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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131-I-mIBG therapy, ch14.18/CHO, Nivolumab, MiniVan