Therapy for Children With Advanced Stage Neuroblastoma

NCT01857934 | Completed Phase 2 Results FDA Drug FDA Device

• 2 other identifiers: NB2012NCI-2013-00034
• Study Type: interventional
• Target: 153
• Locations: 1 country
• Sites: 1

Brief Summary

Neuroblastoma is the most common extracranial solid tumor in childhood, with nearly 50% of patients presenting with widespread metastatic disease. The current treatment for this group of high-risk patients includes intensive multi-agent chemotherapy (induction) followed by myeloablative therapy with stem-cell rescue (consolidation) and then treatment of minimal residual disease (MRD) with isotretinoin. Recently a new standard of care was established by enhancing the treatment of MRD with the addition of a monoclonal antibody (ch14.18) which targets a tumor-associated antigen, the disialoganglioside GD2, which is uniformly expressed by neuroblasts. Despite improvement in 2-year event-free survival (EFS) of 20%, more than one-third of children with high-risk neuroblastoma (HR defined in) still cannot be cured by this approach. Therefore, novel therapeutic approaches are needed for this subset of patients. This study will be a pilot Phase II study of a unique anti-disialoganglioside (anti-GD2) monoclonal antibody (mAb) called hu14.18K322A, given with induction chemotherapy. PRIMARY OBJECTIVE:

• To study the efficacy \[response: complete remission + partial remission (CR+PR)\] to two initial courses of cyclophosphamide and topotecan combined with hu14.18K322A (4 doses/course followed by GM-CSF) in previously untreated children with high-risk neuroblastoma.
• To estimate the event-free survival of patients with newly diagnosed high-risk neuroblastoma treated with the addition of hu14.18K322A to treatment. SECONDARY OBJECTIVES:
• To study the feasibility of delivering hu14.18K322A to 6 cycles induction chemotherapy and describe the antitumor activity (CR+PR) of this 6 course induction therapy.
• To estimate local control and pattern of failure associated with focal intensity modulated or proton beam radiation therapy dose delivery in high-risk abdominal neuroblastoma.
• To describe the tolerability of four doses of hu14.18K322A with allogeneic natural killer (NK) cells from an acceptable parent, in the immediate post-transplant period \[day +2 - +5 after peripheral blood stem cell (PBSC) infusion\] in consenting participants.
• To describe the tolerability of hu14.18K322A with interleukin-2 and GM-CSF as treatment for minimal residual disease (MRD).

Conditions

Neuroblastoma

Keywords

Anti-GD2 monoclonal antibody; hu14.18K322A; High-risk neuroblastoma; Phase II; Allogeneic NK cells

Outcome Measures

Primary Outcomes (2)

• Overall Response Rate [Complete Response + Very Good Partial Response + Partial Response (CR + VGPR + PR)]

  Per the 1993 INRC: measurable tumor defined as product of the longest x widest perpendicular diameter, elevated catecholamine levels and tumor cels in bone marrow. Complete Response (CR)-no evidence of primary tumor or metastases. Very Good Partial Response (VGPR)-\>90% reduction of primary tumor; no metastases; no new bone lesions, all pre-existing lesions improved. Partial Response (PR)-50-90% reduction of primary tumor; \>50% reduction in measurable sites of metastases; 0-1 bone marrow samples with tumor; number of positive bone sites decreased by \>50%. Mixed Response (MR)-\>50% reduction of any measurable lesion with \<50% reduction in other sites; no new lesions; \<25% increase in any existing lesion. No Response (NR)-no new lesions; \<50% reduction but \<25% increase in an any existing lesion. No Response (NR)-no new lesions; \<50% reduction but \<25% increase in any existing legions. Progressive Disease (PD)-any new/increased measurable lesion by \>25%; previous negative marrow positive.

  After two initial courses of chemotherapy (approximately 6 weeks after enrollment)

• Event-free Survival (EFS)

  EFS was estimated as time to relapse, progressive disease, secondary neoplasm, or death from any cause from enrollment. The EFS was estimated by Kaplan-Meier method

  3 years, from time of enrollment

Secondary Outcomes (4)

• Feasibility of Delivering hu14.18K322A to 6 Cycles of Induction Therapy

  After 6 cycles of induction therapy (approximately 24 weeks after enrollment)

• Local Failure Rate and Pattern of Failure

  Up to 3 years

• Dose Limiting Toxicity (DLT) or Severe (Grade 3 or 4) VOD With hu14.18K322A With Allogeneic NK Cells in Consolidation

  During the recovery phase after busulfan/melphalan and PBSC rescue (approximately 24-26 weeks after enrollment)

• Dose Limiting Toxicity (DLT)

  During MRD treatment cycle (approximately 8-12 months after enrollment)

Study Arms (1)

Treatment

EXPERIMENTAL

Participants receive IV hu14.18K322A with each course of chemotherapy (cyclophosphamide, topotecan, cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide). Mesna will be given prior to and after cyclophosphamide infusion. Peripheral blood stem cell harvest (PBSC) and surgical resection of primary tumor will be performed, if feasible. Intensification therapy includes busulfan, melphalan, and levetiracetam with peripheral blood stem cell transplantation. A course of hu14.18K322A with natural killer cell infusion will be given to consenting participants. Radiation therapy will follow PBSC transplant with the exception of any patient requiring emergent radiotherapy. MRD treatment includes hu14.18K322A, G-CSF, GM-CSF, interleukin-2 and isotretinoin. Cells for infusion are prepared using the CliniMACS System.

Drug: cyclophosphamide; Drug: topotecan; Biological: hu14.18K322A; Procedure: peripheral blood stem cell harvest; Procedure: surgical resection; Drug: cisplatin; Drug: etoposide; Drug: doxorubicin; Drug: vincristine; Drug: busulfan; Drug: melphalan; Biological: peripheral blood stem cell transplantation; Biological: natural killer cell infusion; Radiation: radiation therapy; Biological: GM-CSF; Biological: G-CSF; Drug: mesna; Drug: levetiracetam; Biological: interleukin-2; Drug: Isotretinoin; Device: CliniMACS

Interventions

cyclophosphamide DRUG

Given intravenously (IV)

Also known as: Cytoxan(R)

Treatment

topotecan DRUG

Given IV

Also known as: Hycamtin(R)

Treatment

hu14.18K322A BIOLOGICAL

Given IV

Also known as: humanized anti-GD2 antibody, monoclonal antibody, dinutuximab

Treatment

peripheral blood stem cell harvest PROCEDURE

Following evaluation and approval by a member of the transplant staff and completion of the consent form by the participant, collection of peripheral blood stem cells (PBSC) may take place.

Also known as: PBSCH

Treatment

surgical resection PROCEDURE

The primary tumor will be resected surgically following two initial courses of chemotherapy, if feasible. Patients who are unable to have their primary tumor resected after the initial two courses of induction chemotherapy will undergo surgery for resection of the primary tumor mass and careful lymph node staging.

Treatment

cisplatin DRUG

Given IV

Also known as: Platinol-AQ(R)

Treatment

etoposide DRUG

Given IV

Also known as: VP16, Vepesid(R), Etopophos(R)

Treatment

doxorubicin DRUG

Given IV

Also known as: Adriamycin(R)

Treatment

vincristine DRUG

Given IV

Also known as: Oncovin(R)

Treatment

busulfan DRUG

Given IV

Also known as: Busulfex(R)

Treatment

melphalan DRUG

Given IV

Also known as: L-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran(R)

Treatment

peripheral blood stem cell transplantation BIOLOGICAL

Transplantation of previously harvested peripheral blood stem cells.

Also known as: PBSCT

Treatment

natural killer cell infusion BIOLOGICAL

Natural killer (NK) cells obtained from a suitable donor will be given together with hu14.18K322A prior to early hematopoietic cell recovery. In the event there is not a suitable parental donor, consenting participants will receive an additional course of hu14.18K322A.

Also known as: NK cell infusion

Treatment

radiation therapy RADIATION

Radiation therapy to the primary and metastatic disease sites will follow peripheral blood stem cell transplant with the exception of any patient requiring emergent radiotherapy. External beam radiotherapy will be delivered to the primary site and select metastatic and bulky nodal sites.

Treatment

GM-CSF BIOLOGICAL

Given subcutaneously (SQ)

Also known as: sargramostim, Leukine(R), granulocyte macrophage colony stimulating factor

Treatment

G-CSF BIOLOGICAL

Given subcutaneously (SQ)

Also known as: Granulocyte colony stimulating factor, Neupogen(R), Filgrastim

Treatment

mesna DRUG

Given IV

Also known as: Mesnex(R)

Treatment

levetiracetam DRUG

Given IV

Also known as: Keppra

Treatment

interleukin-2 BIOLOGICAL

Given by continuous infusion during MRD maintenance, and SQ during induction.

Also known as: IL-2, aldesleukin, Proleukin(R)

Treatment

Isotretinoin DRUG

Given orally (PO)

Also known as: 13-cis retinoic acid

Treatment

CliniMACS DEVICE

The mechanism of action of the CliniMACS Cell Selection System is based on magnetic-activated cell sorting (MACS). The CliniMACS device is a powerful tool for the isolation of many cell types from heterogeneous cell mixtures, (e.g. apheresis products). These can then be separated in a magnetic field using an immunomagnetic label specific for the cell type of interest, such as CD3+ human T cells.

Also known as: Cell Selection System

Treatment

Eligibility Criteria

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

You may qualify if:

• Participants \<19 years of age (eligible until 19th birthday).
• Newly diagnosed, advanced stage, high-risk neuroblastoma defined as one of the following:
• Children \< 1 year with International Neuroblastoma Staging System (INSS) stage 2a, 2b, 3, 4 or 4S disease AND MYCN amplification (\>10 copies, or greater than four-fold increase in MYCN signal as compared to reference signal).
• INSS 2a or 2b disease AND MYCN amplification, regardless of age or additional biologic features
• INSS stage 3 AND:
• MYCN amplification (\>10 copies, or greater than four-fold increase in MYCN signal as compared to reference signal, regardless of age or additional biologic features
• Age \> 18 months (\> 547 days) with unfavorable pathology, regardless of MYCN status
• INSS stage 4 and:
• MYCN amplification, regardless of age or additional biologic features
• Age \> 18 months (\> 547 days) regardless of biologic features
• Age 12 - 18 months (365 - 547 days) with any of the following three unfavorable biologic features (MYCN amplification, unfavorable pathology and/or DNA index =1) or any biologic feature that is indeterminant/unknown
• Children at least 365 days initially diagnosed with: INSS stage 1, 2, 4S who progressed to a stage 4 without interval chemotherapy.
• Histologic proof of neuroblastoma or positive bone marrow for tumor cells with increased urine catecholamines.
• Adequate renal and hepatic function (serum creatinine \<3 x upper limit of normal for age, AST\< 3 x upper limit of normal).
• No prior therapy, unless an emergency situation requires local tumor treatment (discuss with principal investigator).

You may not qualify if:

• Any evidence, as judged by the investigator, of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease).
• Pregnant or breast feeding (female of child-bearing potential).
• Children with INSS 4 disease, age \<18 months with all 3 favorable biologic features (non-amplified MYCN, favorable pathology and DNA index \>1).
• Potential donor is a biologic parent
• Potential donor is at least 18 years of age.

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead
• Cookies for Kids' Cancer: collaborator
• CURE Childhood Cancer, Inc.: collaborator

Study Sites (1)

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105, United States

Location

Related Publications (2)

• Furman WL, McCarville B, Shulkin BL, Davidoff A, Krasin M, Hsu CW, Pan H, Wu J, Brennan R, Bishop MW, Helmig S, Stewart E, Navid F, Triplett B, Santana V, Santiago T, Hank JA, Gillies SD, Yu A, Sondel PM, Leung WH, Pappo A, Federico SM. Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol. 2022 Feb 1;40(4):335-344. doi: 10.1200/JCO.21.01375. Epub 2021 Dec 6.

  PMID: 34871104 DERIVED

• Nguyen R, Sahr N, Sykes A, McCarville MB, Federico SM, Sooter A, Cullins D, Rooney B, Janssen WE, Talleur AC, Triplett BM, Anthony G, Dyer MA, Pappo AS, Leung WH, Furman WL. Longitudinal NK cell kinetics and cytotoxicity in children with neuroblastoma enrolled in a clinical phase II trial. J Immunother Cancer. 2020 Mar;8(1):e000176. doi: 10.1136/jitc-2019-000176.

  PMID: 32221013 DERIVED

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude

MeSH Terms

Conditions

Neuroblastoma

Interventions

Cyclophosphamide; Topotecan; Hu14.18K322A monoclonal antibody; humanized 3F8 anti-GD2 monoclonal antibody; Antibodies, Monoclonal; dinutuximab; Cisplatin; Etoposide; Doxorubicin; Vincristine; Busulfan; Melphalan; Peripheral Blood Stem Cell Transplantation; Radiotherapy; Granulocyte-Macrophage Colony-Stimulating Factor; sargramostim; Granulocyte Colony-Stimulating Factor; Filgrastim; Mesna; Levetiracetam; Interleukin-2; aldesleukin; 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)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Camptothecin; Alkaloids; Heterocyclic Compounds; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Sulfhydryl Compounds; Acetamides; Amides; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Interleukins; Lymphokines; Retinoids; Carotenoids; Polyenes; Alkenes; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Terpenes; Pigments, Biological

Results Point of Contact

• Title: Sara M. Federico, MD
• Organization: St. Jude Children's Research Hospital

referralinfo@stjude.org

866-278-5833

Study Officials

• Sara M. Federico, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2013
• First Posted: May 20, 2013
• Study Start: July 5, 2013
• Primary Completion: October 21, 2021
• Study Completion: December 31, 2025
• Last Updated: April 16, 2026
• Results First Posted: February 24, 2023

Record last verified: 2026-04

Locations

US (1)