Long Term Continuous Infusion ch14.18/CHO Plus s.c. Aldesleukin (IL-2)

Condition(s) targeted: Neuroblastoma

Intervention: ch14.18/CHO (Drug); Aldesleukin (Drug); Isotretinoin (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: St. Anna Kinderkrebsforschung

Official(s) and/or principal investigator(s):
Holger Lode, MD, PhD, Principal Investigator, Affiliation: Universitätsmedizin Greifswald

Overall contact:
Ruth Ladenstein, MD, Phone: +43-1-40470-4750, Email: ruth.ladenstein@ccri.at

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.

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

Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Efficacy endpoint

Pain-toxicity endpoint

Secondary outcome:

ADCC and activated NK cell concentrations

Soluble IL-2 receptor and CDC

HAMA and HACA

Absolute lymphocyte count

Absolute NK cell numbers

Ch14.18/CHO concentrations

Anti-tumour response

Confirmation cohort

Detailed description: 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.

Minimum age: 1 Year. Maximum age: 21 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- At study entry patients must be > 1 year but <= 21 years of age. NOTE: Patients >21

years but <= 45 years of age, fulfilling the remaining criteria, may be enrolled in the study. These patients will be analysed separately and will not be included in the dose finding schedule algorithm. The purpose for inclusion of the older patients is to enable the collection of tolerability data.

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

- Must have received at least one previous high dose treatment followed by stem cell

rescue after conventional therapy.

- Must fulfil one of the following criteria:

- Patients with stage 4 neuroblastoma on the current high-risk SIOPEN trial

(HR-NBL-1/SIOPEN) either with primary refractory disease having had more than two front-line treatments or patients ineligible for the R2 randomization due to major delays after completed high-dose treatments.

- Treated and responding relapse after primary stage 4 disease, without signs of

progression at study entry

- Treated and responding disseminated relapse after primary localized neuroblastoma

without signs of progression at study entry.

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

Karnofsky, see Appendix 1: performance Scales , page 91)

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

- Patients must consent to the placement of a central venous line, if one has not

already been placed.

- Patients must be off any standard or experimental treatments for at least two weeks

prior to study entry and be fully recovered from the short term major toxic effects.

- Patients must have no immediate requirements for palliative chemotherapy,

radiotherapy or surgery.

- At least 4 weeks after major surgery (e. g. laporotomy or thoracotomy) and fully

recovered from any post-surgical complications.

- HIV and Hepatitis B negative.

- Females of childbearing potential must have a negative pregnancy test. Patients of

childbearing potential must agree to use an effective birth control method. Female patients who are lactating must agree to stop breast-feeding.

- Patients may have had prior CNS metastasis providing 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 scan),

- 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 anticonvulsants and are well

controlled.

- 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.

- Laboratory Testing:

- Patients should have a shortening fraction of >= 30 % by Echocardiogram.

- Patients should have FEV1 and FVC >60% of the 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 >1 10^9/L,

platelets >= 50 10^9/L and haemoglobin > 9. 0 g/dL.

- 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 creatinine <1. 5

mg/dL or a creatinine clearance or radioisotope GFR of > 60 mL/minute/1. 73m2. Exclusion Criteria:

- Patients with progressive disease

- Patients who have previously received treatment with ch14. 18/SP2/0 and/or

ch14. 18/CHO.

- Platelet transfusion dependent.

- Patients with significant intercurrent illnesses and/or any of the following:

- 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.

- 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.

- Concurrent treatment with any non-trial anticancer therapies.

Ruth Ladenstein, MD, Phone: +43-1-40470-4750, Email: ruth.ladenstein@ccri.at

St. Anna Kinderspital, Vienna 1090, Austria; Recruiting
Ruth Ladenstein, MD, Phone: +43(1)40470-4750, Email: ruth.ladenstein@ccri.at
Ruth Ladenstein, MD, Principal Investigator

Institut Curie, Paris 75248, France; Recruiting
Jean Michon, MD, Phone: +33-1-44-35-4550, Email: jean.michon@curie.net
Jean Michon, MD, Principal Investigator
Daniel Orbach, MD, Sub-Investigator

Institut Gustave Roussy, Villejuif 94805, France; Recruiting
Dominique Valteau-Couanet, MD, Phone: +33-1-42114872, Email: valteau@igr.fr
Dominique Valteau-Couanet, MD, Principal Investigator
Angela Digiannatale, MD, Sub-Investigator

University Children's Hospital, Greifswald 17475, Germany; Recruiting
Holger Lode, MD, PhD, Phone: +49 3834 866301, Email: lode@uni-greifswald.de
Holger Lode, Md, Phd, Principal Investigator

Schneider Children's Medical Centre of Israel, Petach Tikvah 49202, Israel; Recruiting
Isaac Yaniv, MD, Phone: +972-3-9253669, Email: iyaniv@clalit.org.it
Isaac Yaniv, MD, Principal Investigator
Shifra Ash, MD, Sub-Investigator

Gaslini Children's Hospital, Genova 16147, Italy; Recruiting
Alberto Garaventa, MD, Phone: +39-010-5636694-714, Email: albertogaraventa@ospedale-gaslini.ge.it
Alberto Garaventa, MD, Principal Investigator
Carla Manzitti, MD, Sub-Investigator

Hospital Universitario La Fe, Valencia 46009, Spain; Recruiting
Victoria Castel, MD, Phone: +34-96-197-3304, Email: castel_vic@gva.es
Victoria Castel, MD, Principal Investigator
Adela Canete, MD, Sub-Investigator

Birmingham Children's Hospital NHS Foundation Trust, Birmingham B4 6NH, United Kingdom; Not yet recruiting
Pamela Kearns, MBChB, MRCP (paeds), PhD, Phone: +44121 3338238, Email: p.r.kearns@bham.ac.uk
Pamela Kearns, MBChB, MRCP (paeds), PhD, Principal Investigator

University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, United Kingdom; Not yet recruiting
Helen Rees, MBBS, MRCP(Paeds), DCH, Phone: +44117 342 28815, Email: Helen.rees@uhbristol.nhs.uk
Helen Rees, MBBS, MRCP(Paeds), DCH, Principal Investigator

Leeds Teaching Hospitals NHS Trust, Leeds LS1 3EX, United Kingdom; Not yet recruiting
Martin Elliott, MBChB, MRCP, PhD, Phone: +44113 3928039, Email: Martin.elliott@leedsth.nhs.uk
Martin Elliott, MBChB, MRCP, PhD, Principal Investigator

Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, United Kingdom; Not yet recruiting
Lisa Howell, B.Med.Sci, BmBs, MRCPCH, Phone: +441512525976, Email: Lisa.howell@alderhey.nhs.uk
Lisa Howell, B.Med.Sci, BmBs, MRCPCH, Principal Investigator

Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, United Kingdom; Not yet recruiting
John Anderson, MBBS, MRCP (Paeds), PhD, Phone: +442074059200, Ext: 8832, Email: j.anderson@ich.ucl.ac.uk
John Anderson, MBBS, MRCP (Paeds), PhD, Principal Investigator

University College Hospitals NHS Foundation Trust, London NW1 2BU, United Kingdom; Not yet recruiting
Ananth Shankar, DCH, MD, MRCP, Phone: +44845 1555000, Ext: 79490, Email: ananth.shankar@uclh.nhs.uk
Ananth Shankar, DCH, MD, MRCP, Principal Investigator

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle NE1 4LP, United Kingdom; Not yet recruiting
Deborah Tweddle, MBChB (Hons), PhD, FRCPCH, Phone: +44191 2824068, Email: deborah.tweddle@nuth.nhs.uk
Deborah Tweddle, MBChB (Hons), PhD, FRCPCH, Principal Investigator

Starting date: November 2010
Last updated: October 5, 2012