Overview

Dinutuximab With Chemotherapy, Surgery and Stem Cell Transplantation for the Treatment of Children With Newly Diagnosed High Risk Neuroblastoma

Status:
Recruiting
Trial end date:
2029-12-31
Target enrollment:
0
Participant gender:
All
Summary
This phase III trial tests how well the addition of dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy works for treating children with newly diagnosed high-risk neuroblastoma. Dinutuximab is a monoclonal antibody that binds to a molecule called GD2, which is found on the surface of neuroblastoma cells, but is not present on many healthy or normal cells in the body. When dinutuximab binds to the neuroblastoma cells, it helps signal the immune system to kill the tumor cells. This helps the cells of the immune system kill the cancer cells, this is a type of immunotherapy. When chemotherapy and immunotherapy are given together, during the same treatment cycle, it is called chemoimmunotherapy. This clinical trial randomly assigns patients to receive either standard chemotherapy and surgery or chemoimmunotherapy (chemotherapy plus dinutuximab) and surgery during Induction therapy. Chemotherapy drugs administered during Induction include, cyclophosphamide, topotecan, cisplatin, etoposide, vincristine, and doxorubicin. These drugs work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing or by stopping them from spreading. Upon completion of 5 cycles of Induction therapy, a disease evaluation is completed to determine how well the treatment worked. If the tumor responds to therapy, patients receive a tandem transplantation with stem cell rescue. If the tumor has little improvement or worsens, patients receive chemoimmunotherapy on Extended Induction. During Extended Induction, dinutuximab is given with irinotecan, temozolomide. Patients with a good response to therapy move on to Consolidation therapy, when very high doses of chemotherapy are given at two separate points to kill any remaining cancer cells. Following, transplant, radiation therapy is given to the site where the cancer originated (primary site) and to any other areas that are still active at the end of Induction. The final stage of therapy is Post-Consolidation. During Post-Consolidation, dinutuximab is given with isotretinoin, with the goal of maintaining the response achieved with the previous therapy. Adding dinutuximab to Induction chemotherapy along with standard of care surgical resection of the primary tumor, radiation, stem cell transplantation, and immunotherapy may be better at treating children with newly diagnosed high-risk neuroblastoma.
Phase:
Phase 3
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
National Cancer Institute (NCI)
Treatments:
Antibodies, Monoclonal
Carboplatin
Cisplatin
Cyclophosphamide
Daunorubicin
Dinutuximab
Doxorubicin
Etoposide
Etoposide phosphate
Irinotecan
Isotretinoin
Liposomal doxorubicin
Mechlorethamine
Melphalan
Nitrogen Mustard Compounds
Podophyllotoxin
Temozolomide
Thiotepa
Topotecan
Tretinoin
Vincristine
Vitamin A
Criteria
Inclusion Criteria:

- Patients must be enrolled on APEC14B1 and have consented to testing through the
Molecular Characterization Initiative (MCI), prior to enrollment on ANBL2131

- ≤ 30 years at the time of initial diagnosis with high-risk disease

- Must have a diagnosis of neuroblastoma (NBL) or ganglioneuroblastoma (nodular)
verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone
marrow with elevated urinary catecholamines

- Newly diagnosed, high risk neuroblastoma (HRNBL) defined as one of the following:

- Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or
M and MYCN amplification

- Age ≥ 547 days and INRG stage M regardless of biologic features (clinical
MYCN testing not required prior to enrollment)

- Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have
progressed to stage M without systemic chemotherapy

- Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who
have progressed to stage M without systemic chemotherapy (clinical MYCN
testing not required prior to enrollment)

- Patients must have a BSA ≥ 0.25 m^2

- No prior anti-cancer therapy except as outlined below:

- Patients initially recognized to have high-risk disease treated with
topotecan/cyclophosphamide initiated on an emergent basis and within allowed
timing, and with consent

- Patients observed or treated with a single cycle of chemotherapy per a low or
intermediate risk neuroblastoma regimen (e.g., as per ANBL0531, ANBL1232 or
similar) for what initially appeared to be non-high-risk disease but subsequently
found to meet the criteria

- Patients who received localized emergency radiation to sites of life threatening
or function-threatening disease prior to or immediately after establishment of
the definitive diagnosis

- Human immunodeficiency virus (HIV) -infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial

- A serum creatinine based on age/sex derived from the Schwartz formula for estimating
glomerular filtration rate (GFR) utilizing child length and stature data published by
the CDC or

- a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m^2 or

- a GFR ≥ 70 mL/min/1.73 m^2. GFR must be performed using direct measurement with a
nuclear blood sampling method or direct small molecule clearance method
(iothalamate or other molecule per institutional standard) Note: Estimated GFR
(eGFR) from serum creatinine, cystatin C or other estimates are not acceptable
for determining eligibility

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

- Serum glutamic pyruvic transaminase (SGPT) (Alanine aminotransferase [ALT]) ≤ 10 x
ULN*

- Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L

- Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by
echocardiogram or radionuclide angiogram

- Ability to tolerate Peripheral Blood Stem Cell (PBSC) Collection:

No known contraindication to PBSC collection. Examples of contraindications might be a
weight or size less than the collecting institution finds feasible, or a physical condition
that would limit the ability of the child to undergo apheresis catheter placement (if
necessary) and/or the apheresis procedure

Exclusion Criteria:

- Patients who are 365-546 days of age with INRG Stage M and MYCN non amplified NBL,
irrespective of additional biologic features

- Patients ≥ 547 days of age with INRG Stage L2, MYCN non-amplified NBL, regardless of
additional biologic features

- Patients with known bone marrow failure syndromes

- Patients on chronic immunosuppressive medications (e.g., tacrolimus, cyclosporine,
corticosteroids) for reasons other than prevention/treatment of allergic reactions and
adrenal replacement therapy are not eligible. Topical and inhaled corticosteroids are
acceptable

- Patients with a primary immunodeficiency syndrome who require ongoing immune globulin
replacement therapy

- Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required prior to
enrollment for female patients of childbearing potential

- Lactating females who plan to breastfeed their infants

- Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation

- All patients and/or their parents or legal guardians must sign a written informed
consent

- All institutional, food and drug administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met