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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT04385277




Registration number
NCT04385277
Ethics application status
Date submitted
8/05/2020
Date registered
12/05/2020
Date last updated
21/11/2023

Titles & IDs
Public title
Treatment With Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma (NBL)
Scientific title
A Pilot Study of Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma
Secondary ID [1] 0 0
NCI-2020-02950
Secondary ID [2] 0 0
ANBL19P1
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ganglioneuroblastoma, Nodular 0 0
Neuroblastoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Neuroendocrine tumour (NET)
Cancer 0 0 0 0
Children's - Other
Cancer 0 0 0 0
Children's - Brain
Cancer 0 0 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Surgery - Biospecimen Collection
Treatment: Surgery - Bone Marrow Aspiration
Treatment: Surgery - Bone Marrow Biopsy
Treatment: Surgery - Computed Tomography
Other interventions - Dinutuximab
Treatment: Surgery - FDG-Positron Emission Tomography
Treatment: Other - Iobenguane I-123
Treatment: Drugs - Irinotecan
Treatment: Drugs - Isotretinoin
Treatment: Surgery - Magnetic Resonance Imaging
Treatment: Surgery - Multigated Acquisition Scan
Other interventions - Sargramostim
Treatment: Drugs - Temozolomide

Experimental: Treatment (temozolomide, irinotecan, dinutuximab) - Patients receive temozolomide PO or via enteral tube daily and irinotecan IV over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim SC or IV over 2 hours daily on days 6-12, and isotretinoin PO BID on days 8-21. Patients undergo MUGA during screening. Patients also undergo MRI, or CT, I23I-MIBG, or FDG-PET, BM aspiration, and BM biopsy on study. Treatment repeats every 28 days for up to 5 cycles (up to 6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.


Treatment: Surgery: Biospecimen Collection
Correlative studies

Treatment: Surgery: Bone Marrow Aspiration
Undergo BM aspiration

Treatment: Surgery: Bone Marrow Biopsy
Undergo BM biopsy

Treatment: Surgery: Computed Tomography
Undergo CT

Other interventions: Dinutuximab
Given IV

Treatment: Surgery: FDG-Positron Emission Tomography
Undergo FDG-PET

Treatment: Other: Iobenguane I-123
Undergo 123I-MIBG

Treatment: Drugs: Irinotecan
Given IV

Treatment: Drugs: Isotretinoin
Given PO

Treatment: Surgery: Magnetic Resonance Imaging
Undergo MRI

Treatment: Surgery: Multigated Acquisition Scan
Undergo MUGA

Other interventions: Sargramostim
Given SC or IV

Treatment: Drugs: Temozolomide
Given PO or via enteral tube
Intervention code [1] 0 0
Treatment: Surgery
Intervention code [2] 0 0
Other interventions
Intervention code [3] 0 0
Treatment: Other
Intervention code [4] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Proportion of patients who complete 5 cycles of dinutuximab + chemotherapy without progressive disease (PD)
Timepoint [1] 0 0
Within 30 weeks from the date of first treatment
Secondary outcome [1] 0 0
Event-free survival (EFS)
Timepoint [1] 0 0
From the time of start of protocol therapy to the occurrence of disease relapse or progression, secondary malignancy, or death, assessed up to 60 months
Secondary outcome [2] 0 0
Overall survival (OS)
Timepoint [2] 0 0
From the time of start of protocol therapy to death, assessed up to 60 months

Eligibility
Key inclusion criteria
- Patients must be < 31 years of age at the time of enrollment.

- 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 at the time of diagnosis)
and have been designated as having high-risk disease based on Children's Oncology
Group (COG) risk classification. The following disease groups are eligible:

- Patients with International Neuroblastoma Risk Group (INRG) Stage M disease with
any 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 at the time of diagnosis regardless of biologic features; OR

- Age 365-547 days at the time of diagnosis with tumors with unfavorable
histology and/or deoxyribonucleic acid (DNA) index = 1

- Patients with INRG Stage MS disease with MYCN amplification

- Patients with INRG Stage L2 disease with 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 at the time of diagnosis with MYCN non-amplified tumors with
unfavorable histology

- Note: Patients observed or patients 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 criteria will also be eligible

- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years

- Prior therapy

- All patients must have completed high-risk Induction therapy with 4-6 cycles of
chemotherapy

- After completion of Induction therapy, patients may have received no more than 4
cycles of bridging chemotherapy or chemo-immunotherapy prior to ASCT

- Patients cannot have previously progressed on immunotherapy with dinutuximab or
other anti-GD2 monoclonal antibody

- All patients must have had undergone surgical resection of their primary tumor as
part of frontline therapy. Exceptions to this requirement include patients who
had a complete response to Induction chemotherapy, patients with no identifiable
primary tumor, and patients for whom the institutional surgical team determined
that potential risks outweighed potential benefits of resection

- All patients must have undergone tandem high-dose chemotherapy with ASCT as part
of Consolidation

- Patients must enroll between day +56 and day +200 from the peripheral blood stem
cell (PBSC) infusion following the last dose of high-dose chemotherapy during
Consolidation

- All patients must have undergone external beam radiation therapy. Exceptions to
this requirement include patients who had no identifiable primary tumor and no
persistent metastatic disease at the end of Induction. For patients who received
radiotherapy, at least 7 days must have elapsed between completion of
radiotherapy and enrollment on this study

- Patients must not have received long-acting myeloid growth factors (e.g., Neulasta)
within 14 days of entry on this study. Seven days must have elapsed since
administration of a short-acting myeloid growth factor

- Peripheral absolute neutrophil count (ANC) >= 750/uL

- Platelet count >= 50,000/uL (transfusion independent for >= 7 days)

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2, or a serum creatinine based on age/gender as follows:

- Age: Maximum Serum Creatinine (mg/dL)

- 6 months to < 1 year: 0.5 (male and female)

- 1 to < 2 years: 0.6 (male and female)

- 2 to < 6 years: 0.8 (male and female)

- 6 to < 10 years: 1 (male and female)

- 10 to < 13 years: 1.2 (male and female)

- 13 to < 16 years: 1.5 (male), 1.4 (female)

- >= 16 years: 1.7 (male), 1.4 (female)

- Note: Patients with history of transplant associated-thrombotic
microangiopathy (TA-TMA) must have a creatinine clearance or radioisotope
GFR at baseline to assess renal function and must meet the above criteria

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

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
ULN for age (=< 225 U/L)

- 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

- Absence of dyspnea at rest

- If pulmonary function tests (PFTs) are performed, forced expiratory volume in 1 second
(FEV1)/forced vital capacity (FVC) must be > 60%

- No clinical evidence of active central nervous system (CNS) disease at the time of
study enrollment

- Patients with seizure disorder may be enrolled if on non-enzyme-inducing
anticonvulsants and well controlled

- CNS toxicity from prior therapy =< grade 2
Minimum age
No limit
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Patients must not have had progressive disease (PD) per the revised International
Neuroblastoma Risk Criteria (INRC) since the initial diagnosis of high-risk
neuroblastoma

- Exception: Progressive disease within the first 2 cycles of Induction
chemotherapy consisting of cyclophosphamide and topotecan is allowed. Patients
with progression subsequent to initial cyclophosphamide and topotecan cycles are
excluded

- Patients may not have received additional systemic cancer-directed therapy following
completion of the last planned high-dose chemotherapy with ASCT prior to enrollment on
this trial

- Patients may not have received iodine-131 (131I)-metaiodobenzylguanidine (MIBG)
therapy at any time prior to enrollment on this trial

- Patients who received single (rather than tandem) high-dose chemotherapy with ASCT are
excluded

- Patients cannot be receiving other ongoing anticancer therapy

- Patients who were enrolled onto ANBL1531 AND underwent arm assignment are not
eligible. Patients who enrolled onto ANBL1531 who declined second consent may be
eligible for ANBL19P1 if all other criteria are met

- Patients enrolled onto ANBL17P1 are not eligible

- Patients must have been off pharmacologic doses of systemic steroids for at least 7
days prior to enrollment

- Patients who require or are likely to require pharmacologic doses of systemic
corticosteroids while receiving treatment on this study are ineligible. The only
exception is for patients known to require 2 mg/kg or less of hydrocortisone (or an
equivalent dose of an alternative corticosteroid) as premedication for blood product
administration in order to avoid allergic transfusion reactions

- Note: The use of conventional doses of inhaled steroids for the treatment of
asthma is permitted, as is the use of physiologic doses of steroids for patients
with known adrenal insufficiency

- Patients on any other immunosuppressive medications (e.g., cyclosporine, tacrolimus)
are not eligible. However, prior or planned concomitant treatment with eculizumab is
permitted (e.g., treatment of TA-TMA)

- Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, valproic acid, or carbamazepine for at least 7 days prior to study
enrollment

- Note: Patients receiving non-enzyme inducing anticonvulsants such as gabapentin
or levetiracetam are eligible

- Patients must not have received drugs that are strong inducers or inhibitors of CYP3A4
within 7 days prior to study enrollment

- Patients must not have been diagnosed with myelodysplastic syndrome or with any
malignancy other than neuroblastoma

- Patients with symptoms of congestive heart failure are not eligible

- Patients with moderate or large pericardial effusions are not eligible

- Patients must not have >= grade 2 diarrhea

- Patients must not have uncontrolled infection

- Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required discontinuation of the anti-GD2 therapy are not eligible

- Patients with a significant intercurrent illness (any ongoing serious medical problem
unrelated to cancer or its treatment) that is not covered by the detailed exclusion
criteria and that is expected to interfere with the action of study agents or to
significantly increase the severity of the toxicities experienced from study treatment
are not eligible

- 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

- 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

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
31/12/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
26/09/2024
Actual
Sample size
Target
Accrual to date
Final
34
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC,WA
Recruitment hospital [1] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [4] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
3052 - Parkville
Recruitment postcode(s) [4] 0 0
6009 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Arkansas
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
Colorado
Country [5] 0 0
United States of America
State/province [5] 0 0
Connecticut
Country [6] 0 0
United States of America
State/province [6] 0 0
Delaware
Country [7] 0 0
United States of America
State/province [7] 0 0
District of Columbia
Country [8] 0 0
United States of America
State/province [8] 0 0
Florida
Country [9] 0 0
United States of America
State/province [9] 0 0
Georgia
Country [10] 0 0
United States of America
State/province [10] 0 0
Idaho
Country [11] 0 0
United States of America
State/province [11] 0 0
Illinois
Country [12] 0 0
United States of America
State/province [12] 0 0
Indiana
Country [13] 0 0
United States of America
State/province [13] 0 0
Iowa
Country [14] 0 0
United States of America
State/province [14] 0 0
Kentucky
Country [15] 0 0
United States of America
State/province [15] 0 0
Louisiana
Country [16] 0 0
United States of America
State/province [16] 0 0
Maryland
Country [17] 0 0
United States of America
State/province [17] 0 0
Massachusetts
Country [18] 0 0
United States of America
State/province [18] 0 0
Michigan
Country [19] 0 0
United States of America
State/province [19] 0 0
Minnesota
Country [20] 0 0
United States of America
State/province [20] 0 0
Mississippi
Country [21] 0 0
United States of America
State/province [21] 0 0
Missouri
Country [22] 0 0
United States of America
State/province [22] 0 0
Nebraska
Country [23] 0 0
United States of America
State/province [23] 0 0
New Jersey
Country [24] 0 0
United States of America
State/province [24] 0 0
New York
Country [25] 0 0
United States of America
State/province [25] 0 0
North Carolina
Country [26] 0 0
United States of America
State/province [26] 0 0
North Dakota
Country [27] 0 0
United States of America
State/province [27] 0 0
Ohio
Country [28] 0 0
United States of America
State/province [28] 0 0
Oklahoma
Country [29] 0 0
United States of America
State/province [29] 0 0
Pennsylvania
Country [30] 0 0
United States of America
State/province [30] 0 0
Tennessee
Country [31] 0 0
United States of America
State/province [31] 0 0
Texas
Country [32] 0 0
United States of America
State/province [32] 0 0
Utah
Country [33] 0 0
United States of America
State/province [33] 0 0
Virginia
Country [34] 0 0
United States of America
State/province [34] 0 0
Washington
Country [35] 0 0
Canada
State/province [35] 0 0
Nova Scotia
Country [36] 0 0
New Zealand
State/province [36] 0 0
Auckland
Country [37] 0 0
New Zealand
State/province [37] 0 0
Christchurch

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This phase II trial studies if dinutuximab, GM-CSF, isotretinoin in combination with
irinotecan, and temozolomide (chemo-immunotherapy) can be given safely to patients with
high-risk neuroblastoma after Consolidation therapy (which usually consists of two autologous
stem cell transplants and radiation) who have not experienced worsening or recurrence of
their disease. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike
chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby
healthy cells. Sargramostim helps the body produce normal infection-fighting white blood
cells. Isotretinoin helps the neuroblastoma cells become more mature. These 3 drugs (standard
immunotherapy) are already given to patients with high-risk neuroblastoma after Consolidation
because they have been proven to be beneficial in this setting. Chemotherapy drugs, such as
irinotecan and temozolomide, work in different ways to stop the growth of tumor cells, either
by killing the cells, by stopping them from dividing, or by stopping them from spreading.
They may also affect how well immunotherapy works on neuroblastoma cells. Giving
chemo-immunotherapy after intensive therapy may work better in treating patients with
high-risk neuroblastoma compared to standard immunotherapy.
Trial website
https://clinicaltrials.gov/ct2/show/NCT04385277
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Ami V Desai
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT04385277