NB2013-HR German (GPOH) / Dutch (DCOG) Trial

NCT02641782 | Terminated Phase 2 DMC

• 1 other identifier: Uni-Koeln-1694
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Although the five year survival rate of children with high risk neuroblastoma have increased over the last three decades from 4 to 44 % (1), neuroblastoma is the second most frequent cause for cancer related death in childhood (11 %). Most patients show good initial response rates (complete (CR) and partial remission (PR) rate 95 %), but 55 % experience a largely treatment-resistant tumor progression. Recently, a breakthrough with immunotherapy was reported by US investigators from the Children's Oncology Group (2) using the anti-ganglioside D2 (GD2) monoclonal antibody ch14.18 for tumor cell destruction and granulocyte macrophage-colony stimulating factor (GM-CSF) plus interleukin 2 (IL-2) for immunostimulation. This immune therapy resulted in an increase of 20 % Event free survival (EFS) at 2 year from randomization. However, this was associated with a high toxicity rate (pain, capillary leak syndrome). The proposed trial compares the Childrens' Oncology Group (COG) "standard of care" arm (anti-GD2 + GM-CSF + IL-2 i.v. + retinoic acid oral) with an experimental arm (anti-GD2 + GM-CSF + IL-2 s.c. + retinoic acid oral) designed to reduce toxicity. The potential benefit from this trial consists of the confirmation that the American trial design is feasible in an independent set of patients with different preceding therapy, at a different time point regarding to immune reconstitution after autologous stem cell transplantation (ASCT), the feasibility of a newly designed immunotherapy (which is hopefully less toxic) and the investigation of immune response parameters. This pilot study is the prerequisite for a consecutive randomized clinical trial comparing two immunotherapeutic approaches in a larger set of patients.

Conditions

Neuroblastoma

Keywords

High Risk Neuroblastoma

Outcome Measures

Primary Outcomes (1)

• toxic death or relevant grade 4 toxicity

  Relevant grade 4 toxicities are defined as ascites, adult respiratory distress syndrome, capillary leak syndrome, cytokine release syndrome, dyspnea, hypotension, motor neuropathy, sensory neuropathy.

  up to 7 months

Secondary Outcomes (3)

• Reduction of key side effects

  up to 7 months

• Maximum of antibody-related pain

  up to 5 months

• Comparative pharmacokinetics

  up to 2 months

Study Arms (2)

Standard Arm

ACTIVE COMPARATOR

Standard IL-2 i.v. together with antibody ch14.18, GM-CSF and retinoic acid

Drug: antibody ch14.18; Drug: GM-CSF; Drug: IL-2 i.v.; Drug: Retinoic acid

Experimental Arm

EXPERIMENTAL

IL-2 s.c. together with antibody ch14.18, GM-CSF and retinoic acid

Drug: antibody ch14.18; Drug: GM-CSF; Drug: IL-2 s.c.; Drug: Retinoic acid

Interventions

antibody ch14.18 DRUG

17.5mg/m²d 10-20h i.v, d4-7 in cycles 1,3,5 and d8-11 in cycles 2,4.

Also known as: Unituxin

Experimental Arm; Standard Arm

GM-CSF DRUG

250µg/m²xd, d1-14 s.c. or i.v (2h) in cycles 1,3,5

Also known as: Sargramostim, Leukine

Experimental Arm; Standard Arm

IL-2 i.v. DRUG

3.0 mio U/m²xd d1-4 continuous infusion i.v. and 4.5 mio U/m²xd d8-11 continuous infusion i.v. in cycles 2,4

Also known as: Proleukin

Standard Arm

IL-2 s.c. DRUG

0.06 mio U/m² i.v. test dosis for 30min. i.v. at least 2h before first subcutaneous (s.c.) application. 6 mio U/m²xd d1-5 and 8-12 s.c. in cycles 2,4

Also known as: Proleukin

Experimental Arm

Retinoic acid DRUG

160mg/m²xd b.i.d.oral d 11-24 in cycles 1,3,5,6 and d15-28 in cycles 2,4

Also known as: isotretinoin

Experimental Arm; Standard Arm

Eligibility Criteria

• Age: 18 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Established diagnosis of neuroblastoma according to the international criteria (INSS)
• High risk (HR): stage 4 over 18 months of age and oncogen MYCN (MYCN) amplified neuroblastoma of any stage and any age until 25 years (recurrent disease (Germany and The Netherlands) after re-induction chemotherapy (+/- other modalities) or newly diagnosed disease (only The Netherlands):
• Complete front-line treatment including induction chemotherapy, radioisotope (mIBG) treatment, appropriate local therapy such as surgical removal and/ or local irradiation of the primary tumor and myeloablative chemotherapy with autologous stem cell reinfusion according to the actual guidelines of the GPOH/DCOG
• achieved response status: stable disease or better (CR, VGPR, PR, SD).
• Written informed consent of parents or guardian and - if appropriate - of the patient.
• For at least two weeks prior to start of trial medication off any standard or experimental treatment no tumour surgery no immediate requirements for palliative chemotherapy, radiotherapy or surgery
• The patient may have had prior central nervous system (CNS) metastases provided 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 (assessed clinically and by MRI or CT) The patient is off steroids for four weeks prior to starting the study and will not require them during the course of the study A patient with seizure disorders may be enrolled if well controlled on anticonvulsants and if no seizures have occurred within a 6 week period prior to starting trial treatment
• HIV sero-negative and neither active nor chronic-replicative hepatitis B infection
• Laboratory testing: The patients should have adequate functions of the cor, lung, bone marrow, liver, kidney

Sponsors & Collaborators

• University of Cologne: lead

Study Sites (1)

University of Cologne

Cologne, 50924, Germany

Location

Related Publications (3)

• Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.

  PMID: 20879881 BACKGROUND

• Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Klingebiel T, Berthold F. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy. BMC Cancer. 2011 Jan 18;11:21. doi: 10.1186/1471-2407-11-21.

  PMID: 21244693 BACKGROUND

• Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Niethammer D, Berthold F. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol. 2004 Sep 1;22(17):3549-57. doi: 10.1200/JCO.2004.08.143.

  PMID: 15337804 RESULT

MeSH Terms

Conditions

Neuroblastoma

Interventions

dinutuximab; Granulocyte-Macrophage Colony-Stimulating Factor; sargramostim; aldesleukin; Tretinoin; Isotretinoin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological

Study Officials

• Frank Berthold, Prof. Dr.

  University of Cologne

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Study Record Dates

• First Submitted: December 12, 2015
• First Posted: December 29, 2015
• Study Start: November 1, 2015
• Primary Completion: December 23, 2016
• Study Completion: January 30, 2017
• Last Updated: November 4, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)