Clinical trial NCT01857934: Therapy for Children With Advanced Stage Neuroblastoma
Official title: Neuroblastoma Protocol 2012: Therapy for Children With Advanced Stage High-Risk Neuroblastoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Neuroblastoma
Keywords: Anti-GD2 monoclonal antibody
hu14.18K322A
High-risk neuroblastoma
Phase II
Allogeneic NK cells
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: Cookies for Kids' Cancer
name: CURE Childhood Cancer, Inc.
First posted: 2013-05-20
Enrollment: 153
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.
* 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.

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.

Primary outcomes:
measure: Overall Response Rate [Complete Response + Very Good Partial Response + Partial Response (CR + VGPR + PR)]
timeFrame: After two initial courses of chemotherapy (approximately 6 weeks after enrollment)
measure: Event-free Survival (EFS)
timeFrame: 3 years, from time of enrollment
Secondary outcomes:
measure: Feasibility of Delivering hu14.18K322A to 6 Cycles of Induction Therapy
timeFrame: After 6 cycles of induction therapy (approximately 24 weeks after enrollment)
measure: Local Failure Rate and Pattern of Failure
timeFrame: Up to 3 years
measure: Dose Limiting Toxicity (DLT) or Severe (Grade 3 or 4) VOD With hu14.18K322A With Allogeneic NK Cells in Consolidation
timeFrame: During the recovery phase after busulfan/melphalan and PBSC rescue (approximately 24-26 weeks after enrollment)
measure: Dose Limiting Toxicity (DLT)
timeFrame: During MRD treatment cycle (approximately 8-12 months after enrollment)
Other outcomes:
Locations:
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Sara M. Federico, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Furman WL, McCarville B, Shulkin BL, Davidoff A, Krasin M, Hsu CW, Pan H, Wu J, Brennan R, Bishop MW, Helmig S, Stewart E, Navid F, Triplett B, Santana V, Santiago T, Hank JA, Gillies SD, Yu A, Sondel PM, Leung WH, Pappo A, Federico SM. Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A. J Clin Oncol. 2022 Feb 1;40(4):335-344. doi: 10.1200/JCO.21.01375. Epub 2021 Dec 6.
citation: Nguyen R, Sahr N, Sykes A, McCarville MB, Federico SM, Sooter A, Cullins D, Rooney B, Janssen WE, Talleur AC, Triplett BM, Anthony G, Dyer MA, Pappo AS, Leung WH, Furman WL. Longitudinal NK cell kinetics and cytotoxicity in children with neuroblastoma enrolled in a clinical phase II trial. J Immunother Cancer. 2020 Mar;8(1):e000176. doi: 10.1136/jitc-2019-000176.