Long Term Continuous Infusion ch14.18/CHO Plus s.c. Aldesleukin (IL-2) (LTI)
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.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I/II Dose Schedule Finding Study of ch14.18/CHO Continuous Infusion Combined With Subcutaneous Aldesleukin (IL-2) in Patients With Primary Refractory or Relapsed Neuroblastoma|
- Efficacy endpoint [ Time Frame: day 15 of first cycle ] [ Designated as safety issue: No ]
On day 15 of the first cycle in ≥ 80% of patients:
- an increase of 500% and/or an absolute minimum increase to ≥100 cells/mcLof the CD16/CD56 positive activated NK cells, AND
- a measurable ch14.18/CHO level of at least 1 µg/ml.
- Pain-toxicity endpoint [ Time Frame: Day 5 of ch14.18/CHO infusion cycle 1 ] [ Designated as safety issue: Yes ]i.v. morphine free ch14.18/CHO infusion schedule after the first 5 days during the first cycle in >= 80% of patients
- ADCC and activated NK cell concentrations [ Designated as safety issue: No ]ADCC and activated NK cell concentrations above baseline levels in ≥ 80% of patients.
- Soluble IL-2 receptor and CDC [ Designated as safety issue: No ]Appearance of soluble IL-2 receptor and CDC.
- HAMA and HACA [ Designated as safety issue: No ]Detection of anti-idiotype response by appearance of HAMA and HACA.
- Absolute lymphocyte count [ Designated as safety issue: No ]Increase of absolute lymphocyte counts by 50% over baseline.
- Absolute NK cell numbers [ Designated as safety issue: No ]Increase of absolute NK cell numbers >1000 cells/mcL in ≥80% of patients.
- Ch14.18/CHO concentrations [ Designated as safety issue: No ]
- Anti-tumour response [ Designated as safety issue: No ]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.
- Confirmation cohort [ Designated as safety issue: No ]Once the dose finding stage is completed we will recruit a further 20 patients to the same dose level to confirm the primary and secondary endpoints.
|Study Start Date:||November 2010|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
Experimental: dose schedule finding ch14.18/CHO
Subcutaneous aldesleukin (IL-2) will be given at a dose of 6 x 106 IU/m2/day in two 5 day blocks (days 1-5 and 8-12).
A continuous infusion of ch14.18/CHO is started on day 8. The duration of the infusion is dependent on the assigned infusion schedule. The duration will range from 10 to 21 days. Three dose levels will be considered with respect to daily dose (7 mg/m2, 10 mg/m2, 15 mg/m2), which relates to total doses of 100 mg/m2,150 mg/m2 and 210 mg/m2.
Patients will receive isotretinoin (13-cis-RA) 160 mg/m²/day divided into two equal doses given orally twice a day for 14 days after the completion of the ch14.18/CHO infusion. The starting day is dependent on the duration of ch14.18/CHO infusion and may be either day 19, 23, 24 or 30.
Other Name: Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary cellsDrug: Aldesleukin
Other Names:Drug: Isotretinoin
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.
|Contact: Ruth Ladenstein, MDfirstname.lastname@example.org|
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|Principal Investigator:||Holger Lode, MD, PhD||Universitätsmedizin Greifswald|