Therapy for Children With Advanced Stage Neuroblastoma

Overview[ - collapse ][ - ]

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. 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 intensity modulated 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).
ConditionNeuroblastoma
InterventionDrug: 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
PhasePhase 2
SponsorSt. Jude Children's Research Hospital
Responsible PartySt. Jude Children's Research Hospital
ClinicalTrials.gov IdentifierNCT01857934
First ReceivedMay 16, 2013
Last UpdatedJanuary 10, 2014
Last verifiedJanuary 2014

Tracking Information[ + expand ][ + ]

First Received DateMay 16, 2013
Last Updated DateJanuary 10, 2014
Start DateMay 2013
Estimated Primary Completion DateJune 2019
Current Primary Outcome MeasuresNumber of participants with complete or partial response [Time Frame: after two initial courses of chemotherapy (approximately 6 weeks after enrollment)] [Designated as safety issue: No]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.
Current Secondary Outcome Measures
  • Failure rate for the 6 cycles of induction therapy. [Time Frame: After 6 cycles of induction therapy (approximately 24 weeks after enrollment)] [Designated as safety issue: No]A patient will be considered as a failure for the 6 cycles of induction therapy if the patient failed to complete induction therapy within 155 days or has disease progression during the induction therapy.
  • Local failure rate [Time Frame: End of study - about 4- 5 years] [Designated as safety issue: No]Local failure is defined as relapse or progression of disease at the primary site.
  • Dose limiting toxicity (DLT) or severe (grade 3 or 4) VoD [Time Frame: During the recovery phase after busulfan/melphalan and PBSC rescue (approximately 24-26 weeks after enrollment)] [Designated as safety issue: Yes]Participants will be considered evaluable for tolerability if they receive four doses of hu14.18K322A with allogeneic NK cells in the immediate post-transplant period, or if hu14.18K322A is discontinued early for presumed toxicity.
  • Dose limiting toxicity (DLT) [Time Frame: During the second MRD treatment cycle (approximately 8-12 months after enrollment)] [Designated as safety issue: Yes]Participants will be considered evaluable for tolerability if they receive at least one dose of hu14.18K322A with course 2 of MRD treatment (the first course given with IL-2).

Descriptive Information[ + expand ][ + ]

Brief TitleTherapy for Children With Advanced Stage Neuroblastoma
Official TitleNeuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma
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.

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 intensity modulated
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).
Detailed 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.5. Maintenance/MRD treatment phase: With
immune therapy in addition to the standard treatment with the drug isotretinoin.

4. Maintenance/MRD treatment phase: With immune therapy in addition to the standard
treatment with the drug isotretinoin.
Study TypeInterventional
Study PhasePhase 2
Study DesignEndpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionNeuroblastoma
InterventionDrug: cyclophosphamide
Given intravenously (IV)
Other Names:
Cytoxan(R)Drug: topotecan
Given IV
Other Names:
Hycamtin(R)Biological: hu14.18K322A
Given IV
Other Names:
  • humanized anti-GD2 antibody
  • monoclonal antibody
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.
Other Names:
PBSCHProcedure: 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
Other Names:
Platinol-AQ(R)Drug: etoposide
Given IV
Other Names:
  • VP16
  • Vepesid(R)
  • Etopophos(R)
Drug: doxorubicin
Given IV
Other Names:
Adriamycin(R)Drug: vincristine
Given IV
Other Names:
Oncovin(R)Drug: busulfan
Given IV
Other Names:
Busulfex(R)Drug: melphalan
Given IV
Other Names:
  • L-phenylalanine mustard
  • Phenylalanine mustard
  • L-PAM
  • L-sarcolysin
  • Alkeran(R)
Biological: peripheral blood stem cell transplantation
Transplantation of previously harvested peripheral blood stem cells.
Other Names:
PBSCTBiological: 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.
Other Names:
NK cell infusionRadiation: 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)
Other Names:
  • sargramostim
  • Leukine(R)
  • granulocyte macrophage colony stimulating factor
Biological: G-CSF
Given subcutaneously (SQ)
Other Names:
  • Granulocyte colony stimulating factor
  • Neupogen(R)
  • Filgrastim
Drug: mesna
Given IV
Other Names:
Mesnex(R)Drug: levetiracetam
Given IV
Other Names:
KeppraBiological: interleukin-2
Given by continuous infusion during MRD maintenance, and SQ during induction.
Other Names:
  • IL-2
  • aldesleukin
  • Proleukin(R)
Drug: Isotretinoin
Given orally (PO)
Other Names:
13-cis retinoic acid
Study Arm (s)Experimental: Treatment
Participants receive intravenous 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.

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment42
Estimated Completion DateJune 2019
Estimated Primary Completion DateSeptember 2018
Eligibility 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.
GenderBoth
AgesN/A
Accepts Healthy VolunteersNo
ContactsContact: Wayne L. Furman, MD
866-278-5833
info@stjude.org
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT01857934
Other Study ID NumbersNB2012
Has Data Monitoring CommitteeNo
Information Provided BySt. Jude Children's Research Hospital
Study SponsorSt. Jude Children's Research Hospital
CollaboratorsCookies for Kids' Cancer
Investigators Principal Investigator: Wayne L. Furman, MD St. Jude Children's Research Hospital
Verification DateJanuary 2014

Locations[ + expand ][ + ]

St. Jude Children's Research Hospital
Memphis, Tennessee, United States, 38105
Contact: Wayne L. Furman, MD | 866-278-5833 | info@stjude.org
Principal Investigator: Wayne L. Furman, MD
Recruiting