Title
MiNivAN; A Phase 1 study of 131-I mIBG followed by Nivolumab and Dinutuximab beta Antibodies in children with relapsed/refractory Neuroblastoma

Description
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.

Objective
Primary Outcome Measures:

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

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)


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)


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

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)

Key Eligibility
At study entry patients must be greater than 1 year of age

Relapsed or refractory high risk neuroblastoma (as defined by INRG criteria)

MIBG avid disease on imaging within 4 weeks to study entry

Greater than or equal to 3 months since any myeloablative chemotherapy / stem cell rescue

Greater than or equal to 42 days since any other immunotherapy e.g. tumour vaccines. At least 3 half-lives since last dose of any monoclonal antibody therapy

Must have a performance status greater or equal 60% (Lansky Score or Karnofsky Performance Scales)

Estimated life expectancy greater than or equal to 12 weeks

Adequate bone marrow, renal, cardiac,hepatic, lung and pancreatic function as defined by the protocol

May have had prior 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 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

Must consent to the placement of a central venous line, if one has not already been placed

Must have no immediate requirements for palliative chemotherapy, radiotherapy or surgery

Can not be pregnant or breast feeding and male and female of childbearing potential must agree to adequate birth control as defined by the protocol

Patients with seizure disorders may be enrolled if seizures are well controlled

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

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

Patients who have had previous 131-I mIBG therapy will not be excluded

Autologous stem cells stored and available if needed as defined by the protocol

EXCLUSION

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. Local steroid treatments (e.g. dermal, mucosal, inhaled) are allowed

Unable to maintain platelets without transfusion as defined by the protocol

HIV or Hepatitis B or C infection

Symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance

Significant psychiatric disabilities or uncontrolled seizure disorders

Active infections, or active peptic ulcers, unless these conditions are corrected or controlled

Clinically significant neurologic deficit or objective peripheral neuropathy (Grade greater than 2) are ineligible

Clinically significant, symptomatic, pleural effusions. Patients with uncontrolled hypertension

Applicable Disease Sites
Colon and Rectum; Endocrine cancers; Gastrointestinal cancers, other; Genitourinary cancers, other; Hematologic cancers, other; Ill-Defined Sites; Kidney; Liver; Lung; Melanoma/Skin cancer; Pancreas; Sarcoma; Stomach; Thyroid

Participating Institutions
UW Health University Hospital