Therapy for Children With Advanced Stage Neuroblastoma
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|ClinicalTrials.gov Identifier: NCT01857934|
Recruitment Status : Recruiting
First Posted : May 20, 2013
Last Update Posted : December 20, 2017
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.
- 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.
- 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).
|Condition or disease||Intervention/treatment||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 Device: CliniMACS||Phase 2|
The phases of the study are:
- Screening phase: Tests and evaluations will be done before treatment starts.
- 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.
- 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.
- Maintenance/MRD treatment phase: With immune therapy in addition to the standard treatment with the drug isotretinoin.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||210 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma|
|Actual Study Start Date :||July 5, 2013|
|Estimated Primary Completion Date :||January 2021|
|Estimated Study Completion Date :||July 2021|
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.
Given intravenously (IV)
Other Name: Cytoxan(R)
Other Name: Hycamtin(R)
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.
Other Name: Platinol-AQ(R)
Other Name: Adriamycin(R)
Other Name: Oncovin(R)
Other Name: Busulfex(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. In the event there is not a suitable parental donor, consenting participants will receive an additional course of hu14.18K322A.
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.
Given subcutaneously (SQ)
Given subcutaneously (SQ)
Other Name: Mesnex(R)
Other Name: Keppra
Given by continuous infusion during MRD maintenance, and SQ during induction.
Given orally (PO)
Other Name: 13-cis retinoic acid
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.
Other Name: Cell Selection System
- Number of participants with complete or partial response [ Time Frame: after two initial courses of chemotherapy (approximately 6 weeks after enrollment) ]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.
- Event-free survival (EFS) [ Time Frame: 3 years after last participant enrollment ]EFS will be estimated for patients with newly diagnosed high-risk neuroblastoma treated with the addition of hu4.18K322A to each phase of treatment.
- Feasibility of delivering hu14.18K322A to 6 cycles of induction therapy [ Time Frame: After 6 cycles of induction therapy (approximately 24 weeks after enrollment) ]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 due to toxicity or has disease progression during the induction therapy, unless delay is a result of non-medical issues (e.g. not due to protocol toxicity).
- Local failure rate [ Time Frame: End of study - about 4- 5 years ]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) ]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) ]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).
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01857934
|Contact: Wayne L. Furman, MDfirstname.lastname@example.org|
|United States, Tennessee|
|St. Jude Children's Research Hospital||Recruiting|
|Memphis, Tennessee, United States, 38105|
|Contact: Wayne L. Furman, MD 866-278-5833 email@example.com|
|Principal Investigator: Wayne L. Furman, MD|
|Principal Investigator:||Wayne L. Furman, MD||St. Jude Children's Research Hospital|