Phase II Study of Monoclonal Antibody ch14.18/CHO Continuous Infusion in Patients With Primary Refractory or Relapsed Neuroblastoma

Study Overview
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Brief Summary
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In this trial, monoclonal anti-Disialoganglioside GD2 (GD2) antibody ch14.18/CHO will be assessed for the treatment of patients with relapsed or refractory neuroblastoma. The antibody is used as a single agent applied in a new treatment schedule associated with less side effects.

Detailed Description
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The Treatment with ch14.18 antibody has demonstrated efficacy in patients with neuroblastoma. However the treatment is associated with an on target side effect, i.e. neuropathic pain. This requires coadministration of intravenous morphine. In this clinical Trial we will evaluate a less toxic treatment regimen consisting of continuous longterm Infusion (LTI) of ch14.18/CHO administered at a dose of 10 mg/m2/day over 10 days (total dose 100 mg/m2/cycle). Patients may receive up to five 35-day cycles in absence of signs of progression.

Official Title
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Phase II Study of Monoclonal Antibody ch14.18/CHO Continuous Infusion in Patients With Primary Refractory or Relapsed Neuroblastoma

Conditions
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Neuroblastoma

Intervention / Treatment
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* Drug: dinutuximab beta


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 12 months and ≤ 21 years of age at the time of study entry Diagnosis of neuroblastoma according to the INSS criteria Tumour burden controlled by conventional therapy (except patients with early minimal bone marrow relapse) fulfilling one of the following criteria: - Primary refractory patients with stage 4 disease Relapse after primary stage 4 disease Disseminated relapse after primary localized neuroblastoma. Measurable and/or evaluable disease in any of the following sites (skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site and/or bone marrow) as measured by mIBG scan, CT, MRI and/or immunocytology Life expectancy of at least 12 weeks. Performance status greater or equal to 70% (Lansky Score or Karnofsky) Consent to the placement of a central venous line, if one has not already been placed Off any standard or experimental treatment for at least two weeks prior to start of immunotherapy (Day 1 of cycle 1) and fully recovered from the short-term major toxic effects No immediate requirements for palliative chemotherapy, radiotherapy or surgery At least 2 weeks from any tumour surgery and fully recovered from any post-surgical complications HIV sero-negative Neither active nor chronic-replicative Hepatitis B infection Females of childbearing potential must have a negative pregnancy test and must agree to use an effective birth control method during the whole study duration including the last FU visit. Female patients who are lactating must agree to stop breast-feeding. Patient may have had prior CNS metastases, provided the following criteria are all met: The patient's CNS disease has been previously treated. The patient's CNS disease has been clinically stable for four weeks prior to starting this study (assessment must be made clinically and by CT or MRI). The patient is off steroids for four weeks prior to starting trial treatment and will not require them during the course of the study. Patients with seizure disorders may be enrolled if well controlled on anticonvulsants and if no seizures have occurred within a 6 week period prior to starting trial treatment All patients and/or their parents or legal guardians must sign a written informed consent. Laboratory testing: Shortening fraction of ≥ 30% on Echocardiogram. FEV1 and FVC > 60% of the predicted by pulmonary function tests. Children unable to do PFTs should have no dyspnoea at rest and a pulse oximetry > 94% in room air. Adequate bone marrow function as defined by ANC >0.5 10^9/L, platelets ≥ 20 10^9/L and haemoglobin > 8.0 g/dL Adequate liver function, as defined by an ALT or AST < 5 x normal and a total bilirubin < 1.0 mg/dL. Adequate renal function, as defined by a serum creatinine <1.5 mg/dL or a creatinine clearance or radioisotope GFR of > 60 mL/minute/1.73 m². Exclusion Criteria: Progressive disease at the time of inclusion into the study. ADA positivity due to previous treatment with an anti-GD2 antibody (e.g. ch14.18/SP2/0, ch14.18/CHO). Previous treatment with ch14.18/CHO in this study. e) Requirement, or likely requirement, for corticosteroids or other immunosuppressive drugs. f) Concurrent treatment with any non-trial anticancer therapies. g) Patients with hypersensitivity against one component of the investigational product or against mouse proteins. h) Female patients of childbearing potential if pregnant, nursing, or not using effective contraception during the treatment period, as the potential effects of ch14.18 on the fetus have not been determined.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Long term infusion of ch14.18/CHO<br>10 day continuous Infusion of ch14.18/CHO. | Drug: dinutuximab beta<br>* Up to 5 cycles of continuous infusion of ch14.18/CHO is administered at a dose of 10 mg/m2/day over 10 days (total dose 100 mg/m2/cycle). Cycle duration: 35-days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumour activity of ch14.18/CHO continuous infusion | The response rate in patients with measurable/evaluable disease (skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site and bone marrow) as measured by Metaiodobenzylguanidine scan (MIBG), Computed tomography (CT), Magnetic Resonance Imaging (MRI) and/or immunocytology at the end of the study. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival |  | 5 years | 
| Safety and tolerability | Pain intensity and the need for appropriate medication for pain relief Adverse events, vital signs and changes in clinical laboratory assessments | 2 years | 
| Immunogenicity | Immunogenicity: Anti-Drug Antibody (ADA) | 2 years | 
| Immunophenotyping | Unit: cells/µl | 2 years | 
| Antibody dependent cellular cytotoxicity (ADCC) | Unit: % | 2 years | 
| Complement dependent cytotoxicity (CDC) | Unit: % | 2 years | 
| Whole Blood Test (WBT) | Unit: % | 2 years | 
| Cytokines | Unit: µg/ml | 2 years | 
| Clearance (CL) | Unit: l/d*m² | 2 years | 
| Volume distribution at steady state (Vdss) | Unit: l/m² | 2 years | 
| mean residence time (MRT) | Unit: days | 2 years | 
| half-life time (t1/2) | Unit: days | 2 years | 
| Area Under the Curve (AUC) | Unit: µg*d/ml | 2 years | 
| Maximum Plasma Concentration (Cmax) and Minimum Plasma Concentration (Cmin) | Unit: µg/ml | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ch14.18/CHO, neuroblastoma, long term infusion