Therapy for Children With Advanced Stage Neuroblastoma
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|ClinicalTrials.gov Identifier: NCT01857934|
Recruitment Status : Active, not recruiting
First Posted : May 20, 2013
Results First Posted : February 24, 2023
Last Update Posted : February 24, 2023
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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.
- Maintenance/MRD treatment phase: With immune therapy in addition to the standard treatment with the drug isotretinoin.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||153 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|
|Actual Primary Completion Date :||October 21, 2021|
|Estimated Study Completion Date :||December 2023|
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
- Overall Response Rate [Complete Response + Very Good Partial Response + Partial Response (CR + VGPR + PR)] [ Time Frame: After two initial courses of chemotherapy (approximately 6 weeks after enrollment) ]Per the 1993 INRC: measurable tumor defined as product of the longest x widest perpendicular diameter, elevated catecholamine levels and tumor cels in bone marrow. Complete Response (CR)-no evidence of primary tumor or metastases. Very Good Partial Response (VGPR)->90% reduction of primary tumor; no metastases; no new bone lesions, all pre-existing lesions improved. Partial Response (PR)-50-90% reduction of primary tumor; >50% reduction in measurable sites of metastases; 0-1 bone marrow samples with tumor; number of positive bone sites decreased by >50%. Mixed Response (MR)->50% reduction of any measurable lesion with <50% reduction in other sites; no new lesions; <25% increase in any existing lesion. No Response (NR)-no new lesions; <50% reduction but <25% increase in an any existing lesion. No Response (NR)-no new lesions; <50% reduction but <25% increase in any existing legions. Progressive Disease (PD)-any new/increased measurable lesion by >25%; previous negative marrow positive.
- Event-free Survival (EFS) [ Time Frame: 3 years, from time of enrollment ]EFS was estimated as time to relapse, progressive disease, secondary neoplasm, or death from any cause from enrollment. The EFS was estimated by Kaplan-Meier method
- Feasibility of Delivering hu14.18K322A to 6 Cycles of Induction Therapy [ Time Frame: After 6 cycles of induction therapy (approximately 24 weeks after enrollment) ]The study is designed to monitor the feasibility of delivering hu14.18K332A to 6 cycles of Induction chemotherapy. The feasibility of Induction therapy for this study will be to target no worse than 75%. A patient was considered as a "failure" for the 6 cycles of Induction therapy if the patient failed to complete Induction therapy within 155 days since treatment initiation due to toxicity or disease progression, unless the delay was a result of non-medical issues (e.g. not due to protocol toxicity). The proportion of patients who successfully received hu14.18K322A with 6 cycles of induction chemotherapy was estimated together with a 95% confidence interval. The response rate (CR + VGPR + PR) to 6 cycles of Induction chemoimmunotherapy was estimated together with the 95% confidence intervals
- Local Failure Rate and Pattern of Failure [ Time Frame: Up to 3 years ]Local failure is defined as relapse or progression of disease at the primary site. The cumulative incidence of local failure will be estimated; competing events will include distant failure or death prior to local failure.
- Dose Limiting Toxicity (DLT) or Severe (Grade 3 or 4) VOD With hu14.18K322A With Allogeneic NK Cells in Consolidation [ Time Frame: During the recovery phase after busulfan/melphalan and PBSC rescue (approximately 24-26 weeks after enrollment) ]Number of patients who experience an unacceptable dose limiting toxicity (per CTCAE v 4.0) including the following toxicities: 1) toxicity requiring the use of pressors, including Grade 4 acute capillary leak syndrome or Grade3 and 4 hypotension; 2) Toxicity requiring ventilation support, including Grade 4 respiratory toxicity; 3) Grade 3 or 4 neurotoxicity with MRI evidence of new CNS thrombi, infarction or bleeding in any subject receiving the hu14.18K322A with NK cell combination; 4) Failure of recovery of ANC > 500/mm3 by day 35 after PBSC infusion. Number of patients who experience Grade 3 or Grade 4 (per Common Toxicity Criteria v 4.0) veno occlusive disease (VOD).
- Dose Limiting Toxicity (DLT) [ Time Frame: During MRD treatment cycle (approximately 8-12 months after enrollment) ]Number of patients who experience an unacceptable dose limiting toxicity (per CTCAE v 4.0) including the following toxicities: 1) Toxicity requiring the use of pressors, including Grade 4 acute capillary leak syndrome or Grade 3 and 4 hypotension; 2) Toxicity requiring ventilation support, including Grade 4 respiratory toxicity; 3) Grade 3 or 4 neurotoxicity with MRI evidence of new CNS thrombi, infarction or bleeding.
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|Ages Eligible for Study:||up to 18 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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:
- 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
- Age > 18 months (> 547 days) with unfavorable pathology, regardless of MYCN status
INSS stage 4 and:
- MYCN amplification, regardless of age or additional biologic features
- Age > 18 months (> 547 days) regardless of biologic features
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01857934
|United States, Tennessee|
|St. Jude Children's Research Hospital|
|Memphis, Tennessee, United States, 38105|
|Principal Investigator:||Sara M. Federico, MD||St. Jude Children's Research Hospital|
Documents provided by St. Jude Children's Research Hospital:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||St. Jude Children's Research Hospital|
|Other Study ID Numbers:||
NCI-2013-00034 ( Registry Identifier: NCI Clinical Trial Registration Program )
|First Posted:||May 20, 2013 Key Record Dates|
|Results First Posted:||February 24, 2023|
|Last Update Posted:||February 24, 2023|
|Last Verified:||February 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||Yes|
|Device Product Not Approved or Cleared by U.S. FDA:||Yes|
Anti-GD2 monoclonal antibody
Allogeneic NK cells
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue