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). |
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Condition | Neuroblastoma |
Intervention | 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 | Phase 2 |
Sponsor | St. Jude Children's Research Hospital |
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 |
Tracking Information[ + expand ][ + ]
First Received Date | May 16, 2013 |
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Last Updated Date | January 10, 2014 |
Start Date | May 2013 |
Estimated Primary Completion Date | June 2019 |
Current 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. |
Current Secondary Outcome Measures |
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Descriptive Information[ + expand ][ + ]
Brief Title | Therapy for Children With Advanced Stage Neuroblastoma |
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Official Title | Neuroblastoma 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 Type | Interventional |
Study Phase | Phase 2 |
Study Design | Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment |
Condition | Neuroblastoma |
Intervention | Drug: cyclophosphamide Given intravenously (IV) Other Names: Cytoxan(R)Drug: topotecan Given IV Other Names: Hycamtin(R)Biological: hu14.18K322A Given IV Other Names:
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:
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:
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:
Given subcutaneously (SQ) Other Names:
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:
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 Status | Recruiting |
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Estimated Enrollment | 42 |
Estimated Completion Date | June 2019 |
Estimated Primary Completion Date | September 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. |
Gender | Both |
Ages | N/A |
Accepts Healthy Volunteers | No |
Contacts | Contact: Wayne L. Furman, MD 866-278-5833 info@stjude.org |
Location Countries | United States |
Administrative Information[ + expand ][ + ]
NCT Number | NCT01857934 |
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Other Study ID Numbers | NB2012 |
Has Data Monitoring Committee | No |
Information Provided By | St. Jude Children's Research Hospital |
Study Sponsor | St. Jude Children's Research Hospital |
Collaborators | Cookies for Kids' Cancer |
Investigators | Principal Investigator: Wayne L. Furman, MD St. Jude Children's Research Hospital |
Verification Date | January 2014 |
Locations[ + expand ][ + ]
St. Jude Children's Research Hospital | Memphis, Tennessee, United States, 38105 Contact: Wayne L. Furman, MD | 866-278-5833 | info@stjude.orgPrincipal Investigator: Wayne L. Furman, MD Recruiting |
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