Therapy for Children With Advanced Stage Neuroblastoma

St. Jude Children's Research Hospital

Status and phase: Active, not recruiting; Phase 2

Conditions: Neuroblastoma

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

Study type: Interventional

Funder types: Other

Identifiers

NCT01857934

NCI-2013-00034 (Registry Identifier)

NB2012

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 153 patients

Sex: All

Ages: Under 18 years old

Volunteers: No Healthy Volunteers

Inclusion and 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 design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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153 participants in 1 patient group

Treatment

Experimental group

Description:

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.

Treatment:

Drug: busulfan

Drug: doxorubicin

Device: CliniMACS

Biological: peripheral blood stem cell transplantation

Drug: levetiracetam

Drug: etoposide

Drug: melphalan

Drug: topotecan

Radiation: radiation therapy

Drug: cisplatin

Biological: hu14.18K322A

Biological: interleukin-2

Procedure: surgical resection

Drug: cyclophosphamide

Procedure: peripheral blood stem cell harvest

Drug: mesna

Drug: vincristine

Biological: natural killer cell infusion

Drug: Isotretinoin

Biological: G-CSF

Biological: GM-CSF