A Phase 3 Study of 131I-Metaiodobenzylguanidine (131I-MIBG) or Crizotinib Added to Intensive Therapy for Children with Newly Diagnosed High-Risk Neuroblastoma (NBL).
Primary Aims 1.1.1 To determine in the context of a randomized trial whether the EFS of patients with newly diagnosed high-risk NBL is improved with the addition of 131I-MIBG during Induction, prior to tandem autologous stem cell transplantation (ASCT).
1.1.2 To determine whether the addition of crizotinib to intensive multimodality therapy for patients with high-risk NBL whose tumors harbor activating point mutations in or amplification of the ALK gene results in superior EFS compared to a contemporaneously treated cohort of patients whose tumors lack these ALK aberrations.
1.2 Secondary Aims 1.2.1 To describe the toxicities associated with treatment for high-risk NBL with and without the addition of 131I-MIBG or crizotinib.
1.2.2 To estimate EFS and describe toxicity in patients with newly diagnosed high risk NBL randomized to treatment with an 131I-MIBG-containing Induction prior to BuMel ASCT.
1.2.3 To describe the OS and response rates (evaluated per INRC criteria prior to ASCT and prior to post-Consolidation therapy) for patients with high-risk neuroblastoma treated with or without 131I-MIBG or crizotinib.
1.2.4 To prospectively evaluate the relationship of response rate per revised International Neuroblastoma Response Criteria (INRC) to EFS and OS in patients with high-risk NBL treated with and without the addition of 131I-MIBG or crizotinib.
1.3 Exploratory Aims 1.3.1 To evaluate whole body radiation dose, tumor factors, and host factors as potential predictors of efficacy and/or toxicity associated with 131I-MIBG therapy and transplant conditioning.
1.3.2 To determine whether the efficacy (end-Induction response, EFS, and OS) of crizotinib is associated with specific ALK mutations or ALK amplification.
1.3.3 To characterize changes in tumor markers [circulating tumor DNA, including ALK and other tumor specific genetic aberrations, and circulating GD2] over time in response to protocol therapy.
1.3.4 To correlate results of tumor and host profiling with end-Induction response and EFS.
1.3.5 To prospectively evaluate EFS for patients with MIBG non-avid high-risk NBL compared to patients with MIBG-avid high-risk NBL who are randomized to treatment without 131I-MIBG.
1.3.6 To correlate Curie scores calculated from 131I-MIBG post-treatment scans with end Induction response, EFS and OS.
1.3.7 To describe changes in image defined risk factors (IDRFs) over the course of Induction therapy, with correlation to surgical outcomes and local failure rates following primary tumor resection.
1.3.8 To define patterns of failure at time of first relapse or progression in patients with high risk NBL.
1.3.9 To determine the feasibility of prospectively monitoring adverse events using electronic health records.
1.3.10 To compare local, central, and computer assisted Curie score assignment at baseline and during therapy in patients with MIBG-avid high-risk NBL.
1.3.11 To compare late toxicities (including impaired organ function and secondary tumor occurrence) in patients treated with 131I-MIBG or crizotinib to late toxicities in patients who have not received these therapies.
- Rutgers Cancer Institute of New Jersey
- RWJBarnabas Health
- Newark Beth Israel Medical Center
Inclusion Criteria
- Patients must be enrolled on ANBL00B1 (NCT00904241) or APEC14B1 (NCT02402244) prior to
enrollment on ANBL1531 (NCT03126916)
- Patient must be >= 365 days and =< 30 years of age at diagnosis
- Patients must have a diagnosis of neuroblastoma or ganglioneuroblastoma (nodular)
verified by tumor pathology analysis or demonstration of clumps of tumor cells in bone
marrow with elevated urinary catecholamine metabolites; the following disease groups
are eligible:
- Patients with International Neuroblastoma Risk Group (INRG) stage M disease are
eligible if found to have either of the following features:
- MYCN amplification (> 4-fold increase in MYCN signals as compared to
reference signals), regardless of additional biologic features; OR
- Age > 547 days regardless of biologic features
- Patients with INRG stage MS disease with MYCN amplification
- Patients with INRG stage L2 disease with MYCN amplification
- Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS
disease who progressed to stage M without prior chemotherapy may enroll within 4
weeks of progression to stage M
- Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1
disease who progress to stage M without systemic therapy may enroll within 4
weeks of progression to stage M
- Patients initially recognized to have high-risk disease must have had no prior
systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis
and within allowed timing); 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 will also be eligible; patients who
receive localized emergency radiation to sites of life-threatening or
function-threatening disease prior to or immediately after establishment of the
definitive diagnosis will be eligible
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine based on age/sex as follows:
- 1 to < 2 years: male = 0.6; female = 0.6
- 2 to < 6 years: male = 0.8; female = 0.8
- 6 to < 10 years: male = 1; female = 1
- 10 to < 13 years: male = 1.2; female = 1.2
- 13 to < 16 years: male = 1.5; female = 1.4
- >= 16 years: male = 1.7; female = 1.4
- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, and
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
ULN; for the purposes of this study, ULN for SGPT (ALT) is 45
- Shortening fraction of >= 27% by echocardiogram, or ejection fraction of > 50% by
echocardiogram or radionuclide angiogram
- No known contraindication to peripheral blood stem cell (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 with INRG stage L2 tumors without amplification of MYCN regardless of tumor
histology (may meet criteria for high risk classification but are not eligible for
this trial)
- Patients with bone marrow failure syndromes
- Patients for whom targeted radiopharmaceutical therapy would be contraindicated due to
underlying medical disorders
- 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 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
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.