| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Neuroblastoma is the most common extra-cranial solid tumour in children |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029260 |
| E.1.2 | Term | Neuroblastoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the safety and tolerability of the novel combination of 131-I-mIBG, Dinutuximab beta and Nivolumab in children with relapsed neuroblastoma. |
|
| E.2.2 | Secondary objectives of the trial |
To document any evidence of benefit (tumour responses) of 131-I-mIBG, Dinutuximab beta and Nivolumab in children with relapsed and refractory high risk neuroblastoma (time to progression, objective response rate)
To provide a descriptive analysis of any associations between particular inherited immune receptor types (KIR/KIR-Ligand genotype, FcγR genotype) and response to the trial treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• At study entry patients must be > 1 year
• Relapsed or refractory high risk neuroblastoma (as defined by 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, see Appendix 1: Performance Scales)
• Estimated life expectancy ≥ 12 weeks
• Adequate bone marrow function: ANC >1.0 x 109/L, platelets ≥50 x 109/L and haemoglobin > 8.0 g/dL
• Adequate renal function: serum creatinine <1.5 mg/dL or a estimated creatinine clearance or radioisotope GFR of > 60 mL/minute/1.73m2
• Adequate cardiac function: shortening fraction of ≥ 28 % by echocardiogram
• Adequate hepatic function: ALT or AST < 5 x ULN and a total bilirubin < 1.5 x ULN
• Adequate lung function: FEV1 and FVC >60% of predicted by pulmonary function tests. Children unable to do 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 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
• 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 to avoid pregnancy for 5 months after last dose of trial medication. Female patients who are lactating must agree to stop breast-feeding. Male patients who are sexually active must be instructed to use contraception throughout treatment and for a period of 7 months after last dose of trial medication.
• 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
• Patients who have previously received Dinutuximab beta (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
• At least 1 x 106 /Kg autologous stem cells stored and available if needed
• Patients and/or their parents or legal guardians must agree that no standard or experimental anti-tumour treatment, except when specified in the protocol, is allowed any time during the study treatment.
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|
| E.4 | Principal exclusion criteria |
• 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. Local steroid treatments (e.g. dermal, mucosal, inhaled) are allowed.
• Unable to maintain platelets ≥ 50 x 109/L without transfusion
• HIV or Hepatitis B or C infection
• Patients who have had major surgery (e.g laparotomy or thoracotomy) within the past 2 weeks.
• Patients with significant intercurrent illnesses and/or any of the following:
o Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm disturbance.
o Patients with significant psychiatric disabilities or uncontrolled seizure disorders.
o Patients with active infections, or active peptic ulcers, unless these conditions are corrected or controlled.
o Patients with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade >2) are ineligible.
o Patients with clinically significant, symptomatic, pleural effusions. Patients with uncontrolled hypertension
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary outcome is toxicity (adverse events, pain) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary endpoints for this trial are:
• Anti-tumour response in patients with measureable disease (bone marrow, skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site) as measured by immunocytology, MIBG, CT and/or MRI
• Fcϒ receptor geneotype (-2A (H131R), -3A (V158F) and -3B (NA1/NA2) and KIR / KIR ligand genotype
• Serum concentration of ch14.18/CHO, pre-infusion and end of infusion (cycle 1, 3 and 5)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First study of this combinaton of agents (Phase 1) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Germany |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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