Description:
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).
Title
- Brief Title: Therapy for Children With Advanced Stage Neuroblastoma
- Official Title: Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma
Clinical Trial IDs
- ORG STUDY ID:
NB2012
- SECONDARY ID:
NCI-2013-00034
- NCT ID:
NCT01857934
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| cyclophosphamide | Cytoxan(R) | Treatment |
| topotecan | Hycamtin(R) | Treatment |
| hu14.18K322A | humanized anti-GD2 antibody, monoclonal antibody, dinutuximab | Treatment |
| cisplatin | Platinol-AQ(R) | Treatment |
| etoposide | VP16, Vepesid(R), Etopophos(R) | Treatment |
| doxorubicin | Adriamycin(R) | Treatment |
| vincristine | Oncovin(R) | Treatment |
| busulfan | Busulfex(R) | Treatment |
| melphalan | L-phenylalanine mustard, Phenylalanine mustard, L-PAM, L-sarcolysin, Alkeran(R) | Treatment |
| peripheral blood stem cell transplantation | PBSCT | Treatment |
| natural killer cell infusion | NK cell infusion | Treatment |
| GM-CSF | sargramostim, Leukine(R), granulocyte macrophage colony stimulating factor | Treatment |
| G-CSF | Granulocyte colony stimulating factor, Neupogen(R), Filgrastim | Treatment |
| mesna | Mesnex(R) | Treatment |
| levetiracetam | Keppra | Treatment |
| interleukin-2 | IL-2, aldesleukin, Proleukin(R) | Treatment |
| Isotretinoin | 13-cis retinoic acid | Treatment |
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.
- 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).
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.
4. Maintenance/MRD treatment phase: With immune therapy in addition to the standard
treatment with the drug isotretinoin.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Treatment | Experimental | 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. | - cyclophosphamide
- topotecan
- hu14.18K322A
- cisplatin
- etoposide
- doxorubicin
- vincristine
- busulfan
- melphalan
- peripheral blood stem cell transplantation
- natural killer cell infusion
- GM-CSF
- G-CSF
- mesna
- levetiracetam
- interleukin-2
- Isotretinoin
|
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.
| Maximum Eligible Age: | 18 Years |
| Minimum Eligible Age: | N/A |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Number of participants with complete or partial response |
| Time Frame: | after two initial courses of chemotherapy (approximately 6 weeks after enrollment) |
| Safety Issue: | |
| Description: | 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
| Measure: | Feasibility of delivering hu14.18K322A to 6 cycles of induction therapy |
| Time Frame: | After 6 cycles of induction therapy (approximately 24 weeks after enrollment) |
| Safety Issue: | |
| Description: | 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). |
| Measure: | Local failure rate |
| Time Frame: | End of study - about 4- 5 years |
| Safety Issue: | |
| Description: | Local failure is defined as relapse or progression of disease at the primary site. |
| Measure: | 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Dose limiting toxicity (DLT) |
| Time Frame: | During the second MRD treatment cycle (approximately 8-12 months after enrollment) |
| Safety Issue: | |
| Description: | 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). |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | St. Jude Children's Research Hospital |
Trial Keywords
- Anti-GD2 monoclonal antibody
- hu14.18K322A
- High-risk neuroblastoma
- Phase II
- Allogeneic NK cells
Last Updated
February 24, 2021
