The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03794349




Registration number
NCT03794349
Ethics application status
Date submitted
2/01/2019
Date registered
7/01/2019
Date last updated
25/06/2020

Titles & IDs
Public title
Irinotecan Hydrochloride, Temozolomide, and Dinutuximab With or Without Eflornithine in Treating Patients With Relapsed or Refractory Neuroblastoma
Scientific title
A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab With or Without Eflornithine (DFMO) in Children With Relapsed, Refractory or Progressive Neuroblastoma
Secondary ID [1] 0 0
NCI-2018-03377
Secondary ID [2] 0 0
ANBL1821
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ganglioneuroblastoma 0 0
Recurrent Neuroblastoma 0 0
Refractory 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
Other interventions - Dinutuximab
Treatment: Drugs - Eflornithine
Treatment: Drugs - Eflornithine Hydrochloride
Treatment: Drugs - Irinotecan
Treatment: Drugs - Irinotecan Hydrochloride
Other interventions - Sargramostim
Treatment: Drugs - Temozolomide

Active Comparator: Regimen A (chemotherapy, dinutuximab, sargramostim) - Patients receive temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12 of a 21-day cycle. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

Experimental: Regimen B (eflornithine, chemotherapy, dinutuximab) - Patients receive eflornithine PO, via NG, or G tube on days -6 to 21 of cycle 1 and days 1-21 of subsequent cycles, temozolomide PO, via NG, or G tube on days 1-5, irinotecan hydrochloride IV over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC or IV over 2 hours on days 6-12. Treatment duration is 28 days for cycle 1 and then every 21 days in subsequent cycles for up to 17 cycles in the absence of disease progression or unacceptable toxicity.


Other interventions: Dinutuximab
Given IV

Treatment: Drugs: Eflornithine
Given PO or via NG or G tube

Treatment: Drugs: Eflornithine Hydrochloride
Given PO or via NG or G tube

Treatment: Drugs: Irinotecan
Given IV

Treatment: Drugs: Irinotecan Hydrochloride
Given IV

Other interventions: Sargramostim
Given SC or IV

Treatment: Drugs: Temozolomide
Given PO or via NG or G tube

Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Response rate - Responders are defined as patients who achieve a >= minor response (MR) per the International Neuroblastoma Response Criteria (INRC) as their best overall response by the end of 6 cycles. The response rate to treatment will be calculated among all eligible patients, including placement of a 95% confidence interval on the response rate.
Timepoint [1] 0 0
Up to the first 6 cycles of treatment
Secondary outcome [1] 0 0
Progression-free survival (PFS) - Kaplan-Meier method will be used to estimate progression-free survival (PFS). PFS time will be calculated from the time of randomization to the occurrence of relapse, progressive disease, or death. Patients without a PFS event will be censored at the time of last follow-up.
Timepoint [1] 0 0
Up to 5 years
Secondary outcome [2] 0 0
Overall survival (OS) - Kaplan-Meier method will be used to estimate overall survival (OS). OS time will be calculated from the time of randomization to the occurrence of death. Patients still alive will be censored at the time of last follow-up.
Timepoint [2] 0 0
Up to 5 years
Secondary outcome [3] 0 0
Incidence of adverse events >= Grade 3 (Regimen B) - The percentage of patients on Regimen B with at least one Grade 3 or higher toxicity will be calculated, assessed with Common Terminology Criteria for Adverse Events version 5.0.
Timepoint [3] 0 0
Up to 5 years

Eligibility
Key inclusion criteria
- Patients must have had histologic verification of neuroblastoma or
ganglioneuroblastoma or demonstration of neuroblastoma cells in the bone marrow with
elevated urinary catecholamines (i.e. > 2 x upper limit of normal [ULN]), at the time
of initial diagnosis.

- For the purposes of this study, aggressive multidrug chemotherapy is defined as
chemotherapy including 2 or more agents that must include an alkylating agent and a
platinum-containing compound. Patients must have ONE of the following:

- First episode of recurrent disease following completion of aggressive multi-drug
frontline therapy.

- First episode of progressive disease during aggressive multi-drug frontline
therapy.

- Primary resistant/refractory disease (less than partial response by International
Neuroblastoma Response Criteria [INRC]) detected at the conclusion of at least 4
cycles of aggressive multidrug induction chemotherapy on or according to a
high-risk neuroblastoma protocol (examples include A3973, ANBL0532, ANBL09P1,
ANBL12P1, ANBL1531, etc.).

- Patients must have at least ONE of the following at the time of enrollment:

- Measurable tumor on magnetic resonance imaging (MRI) or computed tomography (CT)
scan. Measurable is defined as >= 10 mm in at least one dimension on
spiral/helical CT that is metaiodobenzylguanidine (MIBG) avid or demonstrates
increased fludeoxyglucose F-18 (FDG) uptake on positron emission tomography (PET)
scan.

- MIBG-avid lesion detected on MIBG scan with positive uptake at a minimum of one
site. This site must represent disease recurrence after completion of therapy,
progressive disease on therapy, or refractory disease during induction.

- Patients with resistant/refractory soft tissue disease that is not MIBG avid or
does not demonstrate increased FDG uptake on PET scan must undergo biopsy to
document the presence of viable neuroblastoma. Biopsy is not required for
patients who have a new site of soft tissue disease (radiographic evidence of
disease progression) regardless of whether progression occurs while receiving
therapy or after completion of therapy.

- Patients with bone marrow disease only will be eligible if they have more than 5%
disease involvement (documented neuroblastoma cells) in at least one sample from
bilateral bone marrow biopsies.

- Note: Patients with elevated catecholamines (i.e. > 2 x ULN) only are NOT
eligible for this study.

- 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 of age.

- Primary refractory/resistant patients must have received at least 4 cycles of
frontline chemotherapy. Frontline therapy may also have included surgery,
chemotherapy, autologous stem cell transplantation (SCT) +/- MIBG, immunotherapy,
radiotherapy, and retinoids but must NOT have received second line therapy for
resistant/refractory, relapsed, or progressive disease. Patients who received
intensified therapy for poor induction response or refractory disease (e.g. MIBG) will
be considered to have received second line therapy and will not be eligible.

- At least 14 days must have elapsed since completion of myelosuppressive therapy.

- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced
platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of
agent.

- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and
toxicity related to prior antibody therapy must be recovered to grade =< 1.

- No interim time prior to study entry is required following prior radiation therapy
(RT) for non-target lesions. However, patients must not have received radiation for a
minimum of 4 weeks prior to study entry at the site of any lesion that will be
identified as a target lesion to measure tumor response. Lesions that have been
previously radiated cannot be used as target lesions unless there is radiographic
evidence of progression at the site following radiation or a biopsy done following
radiation shows viable neuroblastoma. Palliative radiation while on study is not
permitted.

- Patients are eligible >= 6 weeks after autologous stem cell transplants or stem cell
infusions (including stem cell infusions given as supportive care following 131 I-MIBG
therapy) as long as hematologic and other eligibility criteria have been met.

- Patients are eligible >= 6 weeks after therapeutic 131 I-MIBG provided that all other
eligibility criteria are met.

- Subjects who have previously received anti-GD2 monoclonal antibodies with or without
retinoids for biologic therapy are eligible unless they have had progressive disease
while receiving prior anti-GD2 therapy or progressed/relapsed within 3 months of
receiving anti-GD2 therapy. However, eligible patients may NOT have received anti-GD2
monoclonal antibodies in combination with chemotherapy.

- Subjects who have received autologous marrow infusions or autologous stem cell
infusions that were purged using monoclonal antibody linked to beads are eligible.

- Subjects who have previously received DFMO are eligible for this study provided they
have not had progressive disease while receiving DFMO or progressed/relapsed within 3
months of completing DFMO.

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

- For patients with solid tumors (without marrow involvement) including status post SCT:
peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to
enrollment).

- For patients with solid tumors (without marrow involvement) including status post SCT:
platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to
enrollment).

- Patients known to have bone marrow involvement with neuroblastoma are eligible
provided that minimum ANC and platelet count criteria are met. However, these patients
are not evaluable for hematological toxicity.

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

- 1 to < 2 years (male 0.6 mg/dL, female 0.6 mg/dL)

- 2 to < 6 years (male 0.8 mg/dL, female 0.8 mg/dL)

- 6 to < 10 years (male 1 mg/dL, female 1 mg/dL)

- 10 to < 13 years (male 1.2 mg/dL, female 1.2 mg/dL)

- 13 to < 16 years (male 1.5 mg/dL, female 1.4 mg/dL)

- >= 16 years (male 1.7 mg/dL, female 1.4 mg/dL) (within 7 days prior to
enrollment).

- Total bilirubin =< 1.5 x ULN for age (within 7 days prior to enrollment).

- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 5.0 x
ULN for age (=< 225 U/L). For the purpose of this study, the ULN for SGPT is 45 U/L
(within 7 days prior to enrollment).

- Shortening fraction of >= 27% by echocardiography (ECHO) (within 7 days prior to
enrollment).

- Ejection fraction of >= 50% by ECHO or gated radionuclide study (within 7 days prior
to enrollment).

- No evidence of dyspnea at rest, no exercise intolerance, no chronic oxygen
requirement, and room air pulse oximetry > 94% if there is a clinical indication for
pulse oximetry. Normal pulmonary function tests in patients who are capable of
cooperating with testing (including diffusion capacity of the lung for carbon monoxide
[DLCO)] are required if there is a clinical indication for determination. For patients
who do not have respiratory symptoms, full pulmonary function tests (PFTs) are NOT
required.

- Patients with a history of central nervous system (CNS) disease must have no clinical
or radiological evidence of active CNS disease at the time of study enrollment.

- Patients with seizure disorders may be enrolled if seizures are well controlled on
anti-convulsants.

- CNS toxicity =< grade 2.
Minimum age
1 Year
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Men and women of childbearing potential and their partners must agree to use adequate
contraception while enrolled on this study. Based on the established teratogenic
potential of alkylating agents, pregnant women will be excluded from this study.
Because of potential risks to breastfed infants due to drug metabolites that could be
excreted in breast milk, female patients who are lactating must agree to stop
breastfeeding or will otherwise be excluded from this study. Females of childbearing
potential must have a negative pregnancy test to be eligible for this study.

- Patients with only elevated catecholamines (i.e. > 2 x ULN) are NOT eligible for this
study.

- 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. 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.

- Patients must not have received prior treatment with irinotecan and temozolomide.

- Patients must not have received enzyme-inducing anticonvulsants including phenytoin,
phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.
Patients receiving non-enzyme inducing anticonvulsants such as gabapentin, valproic
acid, or levetiracetam will be eligible.

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

- 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 must not have >= grade 2 diarrhea.

- Patients who are unable to tolerate oral/nasogastric/gastrostomy medications will not
be eligible for this trial. Additionally, patients with significant malabsorption will
not be eligible for this trial.

- Patients must not have uncontrolled infection.

- Patients with a history of grade 4 allergic reactions to anti-GD2 antibodies or
reactions that required permanent 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
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
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Suspended
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA
Recruitment hospital [1] 0 0
John Hunter Children's Hospital - Hunter Regional Mail Centre
Recruitment hospital [2] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [5] 0 0
Women's and Children's Hospital-Adelaide - North Adelaide
Recruitment postcode(s) [1] 0 0
2310 - Hunter Regional Mail Centre
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
4101 - South Brisbane
Recruitment postcode(s) [5] 0 0
5006 - North Adelaide
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
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
District of Columbia
Country [7] 0 0
United States of America
State/province [7] 0 0
Florida
Country [8] 0 0
United States of America
State/province [8] 0 0
Georgia
Country [9] 0 0
United States of America
State/province [9] 0 0
Hawaii
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
Maine
Country [17] 0 0
United States of America
State/province [17] 0 0
Maryland
Country [18] 0 0
United States of America
State/province [18] 0 0
Massachusetts
Country [19] 0 0
United States of America
State/province [19] 0 0
Michigan
Country [20] 0 0
United States of America
State/province [20] 0 0
Minnesota
Country [21] 0 0
United States of America
State/province [21] 0 0
Mississippi
Country [22] 0 0
United States of America
State/province [22] 0 0
Missouri
Country [23] 0 0
United States of America
State/province [23] 0 0
Nebraska
Country [24] 0 0
United States of America
State/province [24] 0 0
New Jersey
Country [25] 0 0
United States of America
State/province [25] 0 0
New York
Country [26] 0 0
United States of America
State/province [26] 0 0
North Carolina
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
Oregon
Country [30] 0 0
United States of America
State/province [30] 0 0
Pennsylvania
Country [31] 0 0
United States of America
State/province [31] 0 0
Rhode Island
Country [32] 0 0
United States of America
State/province [32] 0 0
South Carolina
Country [33] 0 0
United States of America
State/province [33] 0 0
South Dakota
Country [34] 0 0
United States of America
State/province [34] 0 0
Tennessee
Country [35] 0 0
United States of America
State/province [35] 0 0
Texas
Country [36] 0 0
United States of America
State/province [36] 0 0
Utah
Country [37] 0 0
United States of America
State/province [37] 0 0
Vermont
Country [38] 0 0
United States of America
State/province [38] 0 0
Virginia
Country [39] 0 0
United States of America
State/province [39] 0 0
Washington
Country [40] 0 0
United States of America
State/province [40] 0 0
West Virginia
Country [41] 0 0
United States of America
State/province [41] 0 0
Wisconsin
Country [42] 0 0
Canada
State/province [42] 0 0
Manitoba
Country [43] 0 0
Canada
State/province [43] 0 0
Nova Scotia
Country [44] 0 0
Canada
State/province [44] 0 0
Quebec
Country [45] 0 0
New Zealand
State/province [45] 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 how well irinotecan hydrochloride (irinotecan), temozolomide, and
dinutuximab work with or without eflornithine in treating patients with neuroblastoma that
has come back or that isn't responding to treatment. Drugs used in chemotherapy, such as
irinotecan hydrochloride 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. Immunotherapy with monoclonal antibodies, such as dinutuximab, may induce changes
in the body's immune system and may interfere with the ability of tumor cells to grow and
spread. Eflornithine blocks the production of chemicals called polyamines that are important
in the growth of cancer cells. Giving eflornithine with irinotecan hydrochloride,
temozolomide, and dinutuximab, may work better in treating patients with relapsed or
refractory neuroblastoma.
Trial website
https://clinicaltrials.gov/show/NCT03794349
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Margaret E Macy
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/show/NCT03794349