The main aim of this clinical trial is to find a way of giving ch14.18/CHO, in combination with subcutaneous aldesleukin (IL-2) and oral isotretinoin (13-cis-RA), to children and young people with primary refractory or relapsed neuroblastoma without intravenous morphine.
Although a lot of children and young people with neuroblastoma can be cured with current standard chemotherapy, sometimes, particularly at relapse the disease no longer responds to standard drugs. Therefore, there is a need to find new drug combinations which will act against neuroblastoma which no longer responds to standard drugs. Ch14.18/CHO has been shown to improve the outcome of patients with neuroblastoma. However, one of the side effects of receiving ch14.18/CHO is severe pain. High doses of intravenous morphine are needed to control the pain and this means that patients must stay in hospital. Results from other clinical trials have shown that giving ch14.18/CHO over a longer time reduces pain, yet the drug still works just as well to fight the neuroblastoma. The clinical trial aims to give ch14.18/CHO over a longer time so that intravenous morphine is not needed and that this treatment regimen can ultimately be given in an outpatient setting. Ch14.18/CHO is a monoclonal antibody. Monoclonal antibodies are made in the laboratory and are designed to bind to specific cancer cells. Ch14.18/CHO was designed to bind to neuroblastoma cells and other cancer cells that express the GD-2 antigen. The GD-2 antigen is expressed by virtually all neuroblastoma cells. An antigen is a substance that stimulates an immune response in the body by producing antibodies. Thus, when ch14.18/CHO binds to the neuroblastoma cells, the body's immune system is stimulated to attack and kill the neuroblastoma cells. Ch14.18/CHO is called chimeric, because it was genetically engineered to consist of 30% mouse-protein and of 70% human protein. Ch14.18/CHO represents a new kind of cancer therapy that, unlike chemotherapy and radiation, targets the destruction of cancer cells without destroying nearby healthy cells. There is laboratory evidence to suggest that ch14.18/CHO can activate the body's own immune cells to destroy cancer cells. These immune cells include killer cells that are activated or stimulated by aldesleukin (IL-2). Therefore this treatment is a combination of ch14.18/CHO and aldesleukin (IL-2). Aldesleukin (IL-2) is a substance that is similar to a substance made by the body in all individuals. Under normal circumstances, the body makes small amounts of aldesleukin (IL-2) that help white blood cells fight infection. It is now possible to make aldesleukin (IL-2) in the laboratory and give humans much higher doses than their own body makes. There is evidence in the laboratory and in animals that aldesleukin (IL-2) increases the anti-cancer effect of monoclonal antibodies like ch14.18/CHO. We wish to study whether aldesleukin (IL-2) can help improve the effectiveness of ch14.18/CHO in humans. In addition to ch14.18/CHO and aldesleukin (IL-2), isotretinoin (13-cis-RA) will also be given. Isotretinoin (13-cis-RA) is considered standard treatment for patients with neuroblastoma and works by induction of neuroblastoma cell death.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
288
St. Anna Kinderspital
Vienna, Austria
Institut Curie
Paris, France
Institut Gustave Roussy
Villejuif, France
Event free survival
The primary endpoint is event free survival calculated from the date of randomisation. The following will be considered as events: * disease progression or relapse * death from any cause * second neoplasm
Time frame: through study completion, an average of 1 year
Pain-toxicity endpoint
assessment of pain intensity and relief by appropriate medication with a validated self-report tool (Wong-Baker Faces Pain Rating Scale, FPS-R)
Time frame: through study completion, an average of 1 year
Efficacy endpoint
validation of the correlation between activated NK cells and ch14.18/CHO level with ADCC by using serum and MNC from patients
Time frame: through study completion, an average of 1 year
Systemic immune modulation/response
repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype response (HAMA and HACA)
Time frame: through study completion, an average of 1 year
Assessment of absolute lymphocyte counts and absolute NK cell numbers after the respective cycles as a measurement of response to s.c. aldesleukin (IL-2) in the standard treatment arm.
Time frame: through study completion, an average of 1 year
Determination of pharmacokinetics of ch14.18/CHO by assessing blood levels of ch14.18/CHO via ELISA (Enzyme-linked-Immunosorbent Assay)
determination of the pharmacokinetics of ch14.18/CHO (ELISA analysis of ch14.18/CHO blood levels)
Time frame: through study completion, an average of 1 year
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University Children's Hospital
Greifswald, Germany
Schneider Children's Medical Centre of Israel
Petach Tikvah, Israel
Gaslini Children's Hospital
Genova, Italy
Hospital Universitario La Fe
Valencia, Spain
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, United Kingdom
University Hospitals Bristol NHS Foundation Trust
Bristol, United Kingdom
Leeds Teaching Hospitals NHS Trust
Leeds, United Kingdom
...and 4 more locations
Evaluation of 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
Time frame: through study completion, an average of 1 year
Evaluation of impact of KIR/KIRL mismatch and Fc receptor polymorphisms on EFS (PCR sequence-specific primer technique)
Immunomodulation induced by the treatment will be complemented by a whole blood assay. Fc Receptor polymorphisms and KIR/KIR Ligand mismatch analysis will be done via KIR genotyping on patient DNA samples by PCR sequence-specific primer technique
Time frame: through study completion, an average of 1 year