Neuroblastoma | Therapy for Children With Advanced Stage Neuroblastoma
Neuroblastoma research study
What is the primary objective of this study?
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).
Who is eligible to participate?
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.
Which medical condition, disease, disorder, syndrome, illness, or injury is researched?
Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.
Drug:cyclophosphamideGiven intravenously (IV)
Procedure:peripheral blood stem cell harvestFollowing 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.
Procedure:surgical resectionThe 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.
Biological:peripheral blood stem cell transplantationTransplantation of previously harvested peripheral blood stem cells.
Biological:natural killer cell infusionNatural 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.
Radiation:radiation therapyRadiation 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-CSFGiven subcutaneously (SQ)
Biological:G-CSFGiven subcutaneously (SQ)
Biological:interleukin-2Given by continuous infusion during MRD maintenance, and SQ during induction.
Drug:IsotretinoinGiven orally (PO)
Device:CliniMACSThe 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.
Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.
TreatmentParticipants 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.
Start Date: July 5, 2013
Completed Date: July 2021
Phase: Phase 2
Primary Outcome: Number of participants with complete or partial response
Secondary Outcome: Feasibility of delivering hu14.18K322A to 6 cycles of induction therapy
Study sponsors, principal investigator, and references
Principal Investigator: Wayne L. Furman, MD
Lead Sponsor: St. Jude Children's Research Hospital
Collaborator: Cookies for Kids' Cancer