ch14.18/CHO Bridging Study
ch14.18/CHO Bridging Study
The purpose of this study is to assess the safety, pharmacokinetic and activity profiles of
 the ch14.18 antibody produced in cells of hamster origin (ch14.18/CHO).
Anti-ganglioside GD2 antibody ch14.18 is a monoclonal antibody specifically recognizing the
 target antigen GD2, which is expressed on virtually all neuroblastoma tumours. This antibody
 is a chimeric protein and consists to 30% of mouse variable light and heavy chain and to 70%
 of human constant heavy and light chain. Ch 14.18 has already been tested in stage 4
 neuroblastoma patients in phase I/II clinical trials with encouraging response rates.
 Therefore, the European SIOP neuroblastoma group designed a Phase III protocol to test the
 efficacy of ch14.18 immunotherapy in a randomised trial.

 However, the ch14.18 antibody for this Phase III trial was recloned and produced in Chinese
 hamster ovary (CHO) cells in contrast to ch14.18 antibody used for previous clinical trials,
 which was produced in murine, non-secreting myeloma cells (SP2/0). Although the antibody-gene
 transfer into CHO and SP2/0 was done with exactly the same plasmid assuring an identical
 protein sequence, changes in the glycosylation of the final protein product may occur since
 the glycosylation pattern varies between different production cell lines. Glycosylation is
 important for the immunological effector function of the antibody and the pharmacokinetics in
 patients. Therefore, this change is considered to be a major change in production requiring
 the reassessment of the new product in a Phase I clinical trial.

 The primary objective of this trial is the re-evaluation of toxicity of the new ch14.18/CHO
 antibody. This is ultimately followed by the secondary objectives including the determination
 of pharmacokinetics and immunostimulation in patients receiving ch14.18/CHO therapy. This
 involves particularly the determination of activation of immune effector cells and complement
 during and after application of ch14.18/CHO. Subsequently, we will evaluate the clinical
 effect of this treatment on the course of the disease.

 The nature of this phase I trial is a bridging study for a medicinal product subjected to a
 major change in production according to the guidelines provided by the "Committee for
 Proprietary Medicinal Products" (CPMP) of the "European Agency for the Evaluation of
 Medicinal Products (EMEA) (Document Number CPMP/BWP/3207/00).
Inclusion Criteria:

 -  Patients must be <= 21 years of age.

 -  Patients must be diagnosed with neuroblastoma according to the INSS criteria.

 -  Disease must be considered refractory to conventional therapy including patients:

 -  over 1 year of age and presenting as stage 4 disease which have been refractory to
 first line chemotherapy

 -  over 1 year with recurrent disease after multi-agent chemotherapy (including any stage
 and biological pattern)

 -  If the patient history meets the above criteria, any disease states except overt
 progressing disease at the time of antibody treatment renders the patients eligible
 for this study.

 -  Patients may not have developed human anti-chimeric antibody due to pre-treatment with
 ch14.18/SP2/0.

 -  Patients must have a performance status greater or equal 70% (Lansky Score).

 -  Patients must have an estimated life expectancy of at least 12 weeks.

 -  Patients must consent to the placement of a central venous line (Broviac or Hickman
 catheter), if one has not already been placed, or a stable IV anticipated to last for
 the 5 days required to administer the 5 infusions each month

 -  Patients must have fully recovered the toxic effects of any prior therapy.

 -  Patients must have no immediate requirements for palliative chemotherapy, radiotherapy
 or surgery.

 -  Patients may have had prior CNS metastasis providing, 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 scan), and the patient is off steroids for CNS disease for four weeks prior to
 starting on study and during the course of the study. Patients with seizure disorders
 may be enrolled if on anti-convulsants and are well controlled.

 -  Patients should have a shortening fraction of >= 27% by Echocardiogram or ejection
 function of >50% by gated radionuclide study.

 -  Patients should have 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.

 -  All patients must have adequate bone marrow function as defined by ANC >1000/uL,
 platelets >= 75,000/uL and haemoglobin >= 9.0 gm/dL. Transfusions are permitted to
 meet these platelet and haemoglobin criteria.

 -  Patients must have adequate liver function, as defined by an ALT or AST < 5 x normal
 and a total bilirubin < 1.0 mg/dL.

 -  Patients must have adequate renal function, as defined by a serum creatinin <= 1.5
 mg/dL or a creatinin clearance or radioisotope GFR of >= 60 mL/minute.

 -  All patients and/or their parents or legal guardians must sign a written informed
 consent

 -  All institutional and national requirements for human studies must be met.

 Exclusion Criteria:

 -  Patients who have received chemotherapeutic agents (standard or experimental),
 radiation therapy, or other immunosuppressive therapy within three weeks prior to
 study.

 -  Females of childbearing potential will be excluded if they are 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.

 -  Patients with significant intercurrent illnesses

 -  Patients with symptoms of congestive heart failure or uncontrolled cardiac rhythm
 disturbance.

 -  Patients with significant psychiatric disabilities or uncontrolled seizure disorders.

 -  Patients with active infections or active peptic ulcer, unless these conditions are
 corrected or controlled.

 -  Patients with a clinically significant neurologic deficit or objective peripheral
 neuropathy (Grade >= 2) are ineligible.

 -  Patients with clinically significant, symptomatic, pleural effusions.

 -  Patients who require, or are likely to require, corticosteroid or other
 immunosuppressive drugs for intercurrent disease.

 -  Patients who have had major surgery, i.e. laparotomy or thoracotomy) within the past
 two weeks.

 -  Patients with organ allografts, including bone marrow or haematopoietic stem cells.
 Patients receiving prior autologous bone marrow or stem cell reinfusions are eligible.

 -  Patients must be tested for HIV and Hepatitis B Surface (HBS) Ag and excluded, if
 positive, as this may influence the ability of the immune system to be stimulated by
 this treatment.