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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01701479
Recruitment Status : Active, not recruiting
First Posted : October 5, 2012
Last Update Posted : July 14, 2020
Sponsor:
Collaborators:
University Medicine Greifswald
St. Anna Children's Hospital, Vienna
Hospital Universitario La Fe
Istituto Giannina Gaslini
Gustave Roussy, Cancer Campus, Grand Paris
Schneider Children's Medical Center, Israel
Great Ormond Street Hospital for Children NHS Foundation Trust
University Hospital, Toulouse
Johann Wolfgang Goethe University Hospital
Jena University Hospital
Children's University Hospital, Ireland
University Hospital Tuebingen
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Alder Hey Children's NHS Foundation Trust
University Hospitals Bristol NHS Foundation Trust
Newcastle-upon-Tyne Hospitals NHS Trust
The Leeds Teaching Hospitals NHS Trust
NHS Greater Glasgow and Clyde
Medical University of Graz
Medical University Innsbruck
Centre Leon Berard
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
University Hospital Southampton NHS Foundation Trust
Institut Curie
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Information provided by (Responsible Party):
St. Anna Kinderkrebsforschung

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Neuroblastoma Drug: ch14.18/CHO Drug: Aldesleukin Drug: Isotretinoin Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 288 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The patients will be randomised to immunotherapy with isotretinoin (13-cis-RA) and ch14.18/CHO, with or without aldesleukin (IL-2).
Masking: None (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
Study Start Date : January 2012
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: Experimental arm

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.

Drug: ch14.18/CHO
Other Name: Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary cells

Drug: Aldesleukin
Other Names:
  • Proleukin
  • Interleukin-2
  • IL-2

Drug: Isotretinoin
Other Names:
  • 13-cis-Retinoic acid
  • 13-cis-RA

Active Comparator: Comparator arm

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.

Drug: ch14.18/CHO
Other Name: Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary cells

Drug: Isotretinoin
Other Names:
  • 13-cis-Retinoic acid
  • 13-cis-RA




Primary Outcome Measures :
  1. Event free survival [ Time Frame: through study completion, an average of 1 year ]

    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


Secondary Outcome Measures :
  1. Pain-toxicity endpoint [ Time Frame: through study completion, an average of 1 year ]
    assessment of pain intensity and relief by appropriate medication with a validated self-report tool (Wong-Baker Faces Pain Rating Scale, FPS-R)

  2. Efficacy endpoint [ Time Frame: through study completion, an average of 1 year ]
    validation of the correlation between activated NK cells and ch14.18/CHO level with ADCC by using serum and MNC from patients

  3. Systemic immune modulation/response [ Time Frame: through study completion, an average of 1 year ]
    repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype response (HAMA and HACA)

  4. 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 ]
  5. Determination of pharmacokinetics of ch14.18/CHO by assessing blood levels of ch14.18/CHO via ELISA (Enzyme-linked-Immunosorbent Assay) [ Time Frame: through study completion, an average of 1 year ]
    determination of the pharmacokinetics of ch14.18/CHO (ELISA analysis of ch14.18/CHO blood levels)

  6. Evaluation of anti-tumour response in patients with measureable disease [ Time Frame: through study completion, an average of 1 year ]
    Bone marrow, skeletal lesions, soft tissue lesions, lymph nodes and/or primary tumour site as measured by immunocytology, mIBG, CT and/or MRI

  7. Evaluation of impact of KIR/KIRL mismatch and Fc receptor polymorphisms on EFS (PCR sequence-specific primer technique) [ Time Frame: through study completion, an average of 1 year ]
    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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01701479


Locations
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Austria
St. Anna Kinderspital
Vienna, Austria, 1090
France
Institut Curie
Paris, France, 75248
Institut Gustave Roussy
Villejuif, France, 94805
Germany
University Children's Hospital
Greifswald, Germany, 17475
Israel
Schneider Children's Medical Centre of Israel
Petach Tikvah, Israel, 49202
Italy
Gaslini Children's Hospital
Genova, Italy, 16147
Spain
Hospital Universitario La Fe
Valencia, Spain, 46009
United Kingdom
Birmingham Children's Hospital NHS Foundation Trust
Birmingham, United Kingdom, B4 6NH
University Hospitals Bristol NHS Foundation Trust
Bristol, United Kingdom, BS2 8BJ
Leeds Teaching Hospitals NHS Trust
Leeds, United Kingdom, LS1 3EX
Alder Hey Children's NHS Foundation Trust
Liverpool, United Kingdom, L12 2AP
University College Hospitals NHS Foundation Trust
London, United Kingdom, NW1 2BU
Great Ormond Street Hospital for Children NHS Foundation Trust
London, United Kingdom, WC1N 3JH
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle, United Kingdom, NE1 4LP
Sponsors and Collaborators
St. Anna Kinderkrebsforschung
University Medicine Greifswald
St. Anna Children's Hospital, Vienna
Hospital Universitario La Fe
Istituto Giannina Gaslini
Gustave Roussy, Cancer Campus, Grand Paris
Schneider Children's Medical Center, Israel
Great Ormond Street Hospital for Children NHS Foundation Trust
University Hospital, Toulouse
Johann Wolfgang Goethe University Hospital
Jena University Hospital
Children's University Hospital, Ireland
University Hospital Tuebingen
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Alder Hey Children's NHS Foundation Trust
University Hospitals Bristol NHS Foundation Trust
Newcastle-upon-Tyne Hospitals NHS Trust
The Leeds Teaching Hospitals NHS Trust
NHS Greater Glasgow and Clyde
Medical University of Graz
Medical University Innsbruck
Centre Leon Berard
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
University Hospital Southampton NHS Foundation Trust
Institut Curie
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Investigators
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Principal Investigator: Holger Lode, MD, PhD University Medicine Greifswald
Additional Information:
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Responsible Party: St. Anna Kinderkrebsforschung
ClinicalTrials.gov Identifier: NCT01701479    
Other Study ID Numbers: 012010
2009-018077-31 ( EudraCT Number )
First Posted: October 5, 2012    Key Record Dates
Last Update Posted: July 14, 2020
Last Verified: July 2020
Keywords provided by St. Anna Kinderkrebsforschung:
Neuroblastoma
Refractory neuroblastoma
Relapsed neuroblastoma
ch14.18/CHO
Aldesleukin (IL-2)
Additional relevant MeSH terms:
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Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Aldesleukin
Interleukin-2
Ch14.18 monoclonal antibody
Isotretinoin
Physiological Effects of Drugs
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Dermatologic Agents