Therapy for Children With Advanced Stage Neuroblastoma

This study is currently recruiting participants.
Verified January 2014 by St. Jude Children's Research Hospital
Sponsor:
Collaborator:
Cookies for Kids' Cancer
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier:
NCT01857934
First received: May 16, 2013
Last updated: January 10, 2014
Last verified: January 2014
  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).

Condition Intervention Phase
Neuroblastoma
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
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma

Resource links provided by NLM:


Further study details as provided by St. Jude Children's Research Hospital:

Primary Outcome Measures:
  • Number 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.


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).


Estimated Enrollment: 42
Study Start Date: May 2013
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: cyclophosphamide
Given intravenously (IV)
Other Name: Cytoxan(R)
Drug: topotecan
Given IV
Other Name: 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 Name: PBSCH
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
Other Name: Platinol-AQ(R)
Drug: etoposide
Given IV
Other Names:
  • VP16
  • Vepesid(R)
  • Etopophos(R)
Drug: doxorubicin
Given IV
Other Name: Adriamycin(R)
Drug: vincristine
Given IV
Other Name: Oncovin(R)
Drug: busulfan
Given IV
Other Name: 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 Name: PBSCT
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.
Other Name: NK cell infusion
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)
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 Name: Mesnex(R)
Drug: levetiracetam
Given IV
Other Name: Keppra
Biological: 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 Name: 13-cis retinoic acid

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.
  Eligibility

Ages Eligible for Study:   up to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01857934

Contacts
Contact: Wayne L. Furman, MD 866-278-5833 info@stjude.org

Locations
United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Wayne L. Furman, MD    866-278-5833    info@stjude.org   
Principal Investigator: Wayne L. Furman, MD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Cookies for Kids' Cancer
Investigators
Principal Investigator: Wayne L. Furman, MD St. Jude Children's Research Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT01857934     History of Changes
Other Study ID Numbers: NB2012
Study First Received: May 16, 2013
Last Updated: January 10, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by St. Jude Children's Research Hospital:
Anti-GD2 monoclonal antibody
hu14.18K322A
High-risk neuroblastoma
Phase II
Allogeneic NK cells

Additional relevant MeSH terms:
Neuroblastoma
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
Mesna
Antibodies
Antibodies, Monoclonal
Busulfan
Cyclophosphamide
Melphalan
Lenograstim
Etoposide phosphate
Cisplatin
Doxorubicin
Etoposide
Interleukin-2
Tretinoin
Vincristine
Topotecan
Etiracetam
Isotretinoin
Protective Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014