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Trial record 1 of 1 for:    ANBL 1821
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Irinotecan Hydrochloride, Temozolomide, and Dinutuximab With or Without Eflornithine in Treating Patients With Relapsed or Refractory Neuroblastoma

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ClinicalTrials.gov Identifier: NCT03794349
Recruitment Status : Not yet recruiting
First Posted : January 7, 2019
Last Update Posted : January 7, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:
This phase II trial studies how well irinotecan hydrochloride, 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.

Condition or disease Intervention/treatment Phase
Ganglioneuroblastoma Recurrent Neuroblastoma Refractory Neuroblastoma Biological: Dinutuximab Drug: Eflornithine Drug: Irinotecan Biological: Sargramostim Drug: Temozolomide Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine whether administration of eflornithine (DFMO) in combination with dinutuximab, irinotecan hydrochloride (irinotecan) and temozolomide results in an improved response rate compared to dinutuximab, irinotecan and temozolomide in patients with relapsed or refractory neuroblastoma and therefore is a therapeutic regimen worthy of further testing in patients with newly-diagnosed high-risk neuroblastoma.

SECONDARY OBJECTIVES:

I. To compare progression-free survival and overall survival between patients receiving dinutuximab, irinotecan and temozolomide with and without the addition of DFMO.

II. To define the toxicity profile of DFMO administered with dinutuximab, irinotecan and temozolomide.

EXPLORATORY OBJECTIVES:

I. To characterize the immune and cytokine profiles of patients treated with DFMO/chemotherapy/dinutuximab combination and correlate with response to therapy.

II. To evaluate GD2 levels in tumor cells from patient bone marrow samples and correlate with response to therapy.

III. To explore whether the addition of DFMO to the dinutuximab and chemotherapy backbone affects pain as determined by patient report and opiate usage.

OUTLINE: Patients are randomized to 1 of 2 regimens.

REGIMEN A: Patients receive temozolomide orally (PO), via nasogastric (NG), or gastric (G) tube on days 1-5, irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1-5, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim subcutaneously (SC) or IV over 2 hours on days 6-12 of a 28-day cycle. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

REGIMEN B: 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 intravenously (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 repeats 28 for cycle 1 and then every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and periodically for 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 95 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Randomized Study of Irinotecan/Temozolomide/Dinutuximab With or Without Eflornithine (DFMO) in Children With Relapsed, Refractory or Progressive Neuroblastoma
Estimated Study Start Date : May 1, 2019
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : March 31, 2022


Arm Intervention/treatment
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 28-day cycle. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Dinutuximab
Given IV
Other Names:
  • Ch 14.18UTC
  • Ch14.18
  • MOAB Ch14.18
  • monoclonal antibody Ch14.18
  • Unituxin

Drug: Irinotecan
Given IV

Biological: Sargramostim
Given SC or IV
Other Names:
  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin

Drug: Temozolomide
Given PO or via NG or G tube
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac

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 repeats 28 for cycle 1 and then every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
Biological: Dinutuximab
Given IV
Other Names:
  • Ch 14.18UTC
  • Ch14.18
  • MOAB Ch14.18
  • monoclonal antibody Ch14.18
  • Unituxin

Drug: Eflornithine
Given PO or via NG or G tube
Other Names:
  • Alpha-Difluoromethylornithine
  • DFMO
  • difluoromethylornithine
  • Difluromethylornithine

Drug: Irinotecan
Given IV

Biological: Sargramostim
Given SC or IV
Other Names:
  • 23-L-Leucinecolony-Stimulating Factor 2
  • DRG-0012
  • Leukine
  • Prokine
  • rhu GM-CFS
  • Sagramostim
  • Sargramostatin

Drug: Temozolomide
Given PO or via NG or G tube
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac




Primary Outcome Measures :
  1. Response rate [ Time Frame: Up to 6 cycles (Each cycle is 21 days, with the exception of Regimen B Cycle 1 which is 28 days) ]
    Measured per revised International Neuroblastoma Response Criteria. Will be assessed by a one-sided continuity-corrected test of proportions with pooled variance to compare the response rates after 6 cycles in the two regimens, and the futility and efficacy monitoring rules. The response rate after 6 cycles will be calculated on each regimen, including placement of a 95% confidence interval. If the response rate on Regimen B is significantly better, then it will be considered a therapeutic regimen worthy of further testing in patients with newly-diagnosed high-risk neuroblastoma.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From the time of randomization to the occurrence of relapse, progressive disease, or death, assessed up to 5 years ]
    Kaplan-Meier curves of PFS will be generated by regimen and compared using log-rank tests.

  2. Overall survival (OS) [ Time Frame: From time of randomization to death, assessed up to 5 years ]
    Kaplan-Meier curves of OS will be generated by regimen and compared using log-rank tests.

  3. Futility or efficacy (Regimen B): A one-sided O'Brien-Fleming group-sequential boundary will be used to monitor [ Time Frame: Up to 5 years ]
    Futility monitoring will be performed. A one-sided O'Brien-Fleming group-sequential boundary will be used to monitor for efficacy of Regimen B if the sample size is increased to 148 eligible patients.

  4. Incidence of adverse events >= 3 (Arm B) [ Time Frame: Up to 5 years ]
    Assessed with Common Terminology Criteria for Adverse Events version 5.0.


Other Outcome Measures:
  1. Immune and cytokine profiles [ Time Frame: Up to 6 cycles (Each cycle is 21 days, with the exception of Regimen B Cycle 1 which is 28 days) ]
    Will be assessed by exploring the relationship between response (responder versus [vs.] non-responder) after 6 cycles on Regimen B with serum cytokine levels (IL1, IL6, tumor necrosis factor [TNF]-alpha, IFN-gamma, etc.), tumor resident immune cells (natural killer [NK] cells, tumor-associated macrophages [TAMS], tumor infiltrating lymphocyte [TILS]), and critical immune cell suppressing proteins (B7H3, PDL-1) using Fisher's exact test for categorical and Wilcoxon rank-sum test for continuous factors.

  2. GD2 levels in tumor cells from bone marrow samples [ Time Frame: Up to 5 years ]
    Will be correlated with response (responder vs. non-responder) after 6 cycles using Fisher?s exact test for categorical and the Wilcoxon rank-sum test for continuous factors.

  3. Patient reported pain and opiate usage [ Time Frame: Up to 5 years ]
    The occurrence of pain on each regimen as reported by patient report and opiate use will be descriptively summarized. Descriptive and summary statistics will be used to describe the scores from the Faces Pain Scale-Revised during the dinutuximab infusion and on day 1 with irinotecan and temozolomide alone for each arm separately. Confidence intervals will be constructed for the mean and frequency estimates. The day 1 patient reported outcome data are expected to be similar between the 2 regimens, while differences during or after completion of treatment may be observed.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    • Measurable tumor on magnetic resonance imaging (MRI) or computed tomography (CT) scan obtained within 3 weeks prior to study entry. 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 obtained within 3 weeks prior to study entry 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.
  • At least 7 days must have elapsed since the completion of therapy with a non-myelosuppressive biologic agent or retinoid.
  • 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 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)
    • 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)
    • 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.

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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03794349


Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Margaret Macy Children's Oncology Group

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Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT03794349     History of Changes
Other Study ID Numbers: ANBL1821
NCI-2018-03377 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ANBL1821 ( Other Identifier: Childrens Oncology Group )
ANBL1821 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: January 7, 2019    Key Record Dates
Last Update Posted: January 7, 2019
Last Verified: December 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
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Neuroblastoma
Ganglioneuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Irinotecan
Temozolomide
Eflornithine
Ch14.18 monoclonal antibody
Sargramostim
Antibodies, Monoclonal
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Immunologic Factors
Physiological Effects of Drugs
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents