Therapy for Children With Advanced Stage Neuroblastoma

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Therapy for Children With Advanced Stage Neuroblastoma

Study Purpose

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).

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	N/A - 18 Years
Gender	All

More Inclusion & Exclusion Criteria

PARTICIPANT

Inclusion Criteria:

- 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: 1.

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. 2. Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status.

- INSS stage 4 and: 1.

MYCN amplification, regardless of age or additional biologic features. 2. Age > 18 months (> 547 days) regardless of biologic features. 3. 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).

- Written, informed consent according to institutional guidelines.

PARTICIPANT

Exclusion Criteria:

- 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).

DONOR

Inclusion Criteria:

- Potential donor is a biologic parent.

- Potential donor is at least 18 years of age.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT01857934
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	St. Jude Children's Research Hospital
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Sara M. Federico, MD
Principal Investigator Affiliation	St. Jude Children's Research Hospital
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Active, not recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Neuroblastoma
Study Website:	View Trial Website

Additional Details

The phases of the study are: 1. Screening phase: Tests and evaluations will be done before treatment starts. 2. Induction phase: Includes chemotherapy plus hu14.18K322A mAb. Participants will also have surgery during this part of the study to remove as much tumor as possible. 3. Consolidation/Intensification phase: Includes high doses of chemotherapy and blood stem cell transplantation with additional, experimental "minimal residual disease" (MRD) treatment. Participants will also get radiation treatment to all sites of the tumor(s) after recovery from the stem cell transplant. 4. Maintenance/MRD treatment phase: With immune therapy in addition to the standard treatment with the drug isotretinoin.

Arms & Interventions

Arms

Experimental: Treatment

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.

Interventions

Drug: - cyclophosphamide

Given intravenously (IV)

Drug: - topotecan

Given IV

Biological: - hu14.18K322A

Given IV

Procedure: - peripheral blood stem cell harvest

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.

Procedure: - surgical resection

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.

Drug: - cisplatin

Given IV

Drug: - etoposide

Given IV

Drug: - doxorubicin

Given IV

Drug: - vincristine

Given IV

Drug: - busulfan

Given IV

Drug: - melphalan

Given IV

Biological: - peripheral blood stem cell transplantation

Transplantation of previously harvested peripheral blood stem cells.

Biological: - natural killer cell infusion

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.

Radiation: - radiation therapy

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.

Biological: - GM-CSF

Given subcutaneously (SQ)

Biological: - G-CSF

Given subcutaneously (SQ)

Drug: - mesna

Given IV

Drug: - levetiracetam

Given IV

Biological: - interleukin-2

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

Drug: - Isotretinoin

Given orally (PO)

Device: - CliniMACS

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.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

St. Jude Children's Research Hospital, Memphis, Tennessee

Status

Address

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105

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