Therapy for Children With Advanced Stage Neuroblastoma

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

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.

Sponsors & Collaborators

• Cookies for Kids' Cancer

  collaborator OTHER

• CURE Childhood Cancer, Inc.

  collaborator OTHER

• St. Jude Children's Research Hospital

  lead OTHER

Principal Investigators

• Sara M. Federico, MD · St. Jude Children's Research Hospital

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Max Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2013-07-05

Primary Completion

2021-10-21

Completion

2025-12-31

FDA Drug

Yes

FDA Device

Yes

Countries

• United States

Study Locations