AzTrials
AzTrials

NeuroblastomaPhase 1/2LTINCT01701479

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

A Phase 1/2 study testing ch14.18/CHO, Aldesleukin and Isotretinoin in people with Neuroblastoma, run by St. Anna Kinderkrebsforschung at 14 sites in 7 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 1 year to 21 years
Conditions the study is for
Neuroblastoma
What is being tested?
ch14.18/CHO, Aldesleukin and Isotretinoin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
288 participants
Where
14 sitesin 7 countries
Study dates
Jan 2012to Dec 2020
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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
Show all 28Show fewer
  • 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.

Who cannot join

  • 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.
Show all 11Show fewer
  • 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.

Trial locations and contacts

14 sites in 7 countries.

14 sites in 7 countries

United Kingdom7 sites

  • Birmingham Children's Hospital NHS Foundation Trust

    Birmingham, B4 6NH

  • University Hospitals Bristol NHS Foundation Trust

    Bristol, BS2 8BJ

  • Leeds Teaching Hospitals NHS Trust

    Leeds, LS1 3EX

  • Alder Hey Children's NHS Foundation Trust

    Liverpool, L12 2AP

  • University College Hospitals NHS Foundation Trust

    London, NW1 2BU

  • Great Ormond Street Hospital for Children NHS Foundation Trust

    London, WC1N 3JH

  • The Newcastle upon Tyne Hospitals NHS Foundation Trust

    Newcastle, NE1 4LP

Other trials in United Kingdom

France2 sites

  • Institut Curie

    Paris, 75248

  • Institut Gustave Roussy

    Villejuif, 94805

Other trials in France

Austria1 site

  • St. Anna Kinderspital

    Vienna, 1090

Other trials in Austria

Germany1 site

  • University Children's Hospital

    Greifswald, 17475

Other trials in Germany

Israel1 site

  • Schneider Children's Medical Centre of Israel

    Petach Tikvah, 49202

Other trials in Israel

Italy1 site

  • Gaslini Children's Hospital

    Genova, 16147

Other trials in Italy

Spain1 site

  • Hospital Universitario La Fe

    Valencia, 46009

Other trials in Spain

About this study

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

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.

Read the 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.

Conditions
Neuroblastoma
Being tested
ch14.18/CHO, Aldesleukin, Isotretinoin
Keywords
Neuroblastoma, Refractory neuroblastoma, Relapsed neuroblastoma, ch14.18/CHO, Aldesleukin (IL-2)
Medical subject headings
Neuroblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ch14.18/CHODrug

    Also called Chimeric 14.18 anti-GD2 monoclonal antibody produced in Chinese hamster ovary cells

  • AldesleukinDrug

    Also called Proleukin, Interleukin-2, IL-2

  • IsotretinoinDrug

    Also called 13-cis-Retinoic acid, 13-cis-RA

Study groups in NCT01701479
Study groupRoleWhat they receive
Experimental armExperimentalSubcutaneous 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.
Receives: Drug: ch14.18/CHO; Drug: Aldesleukin; Drug: Isotretinoin
Comparator armActive comparatorA 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.
Receives: Drug: ch14.18/CHO; Drug: Isotretinoin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

    Measured: through study completion, an average of 1 year

Secondary outcomes (7)

  1. 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)

    Measured: through study completion, an average of 1 year

  2. Efficacy endpoint

    validation of the correlation between activated NK cells and ch14.18/CHO level with ADCC by using serum and MNC from patients

    Measured: through study completion, an average of 1 year

  3. Systemic immune modulation/response

    repeated analysis of NK-cell activation, soluble IL-2 receptor, ADCC, CDC and anti-idiotype response (HAMA and HACA)

    Measured: through study completion, an average of 1 year

  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.

    Measured: 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)

    determination of the pharmacokinetics of ch14.18/CHO (ELISA analysis of ch14.18/CHO blood levels)

    Measured: through study completion, an average of 1 year

  6. 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

    Measured: through study completion, an average of 1 year

  7. 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

    Measured: through study completion, an average of 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Oct 2012 (estimated)
  2. Study startJan 2012
  3. Primary completionDec 2020 (estimated)
  4. Study completionDec 2020 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
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)
Enrolment
288 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01701479
Sponsor's protocol ID
012010
Other IDs
2009-018077-31, 2009
Acronym
LTI
Status last verified
Jul 2020
First submitted
3 Oct 2012
Last updated
14 Jul 2020
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing ch14.18/CHO, Aldesleukin and Isotretinoin in people with Neuroblastoma, run by St. Anna Kinderkrebsforschung at 14 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 28 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 14 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 14 sites in United Kingdom, France, Austria, Germany, Israel and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event free survival (time frame: through study completion, an average of 1 year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01701479.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jul 2020.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Keep searching with a free account

You’ve used your 3 free searches for this session. Log in or create a free AzTrials account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in