Treatment With Dinutuximab, Sargramostim (GM-CSF), and Isotretinoin in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma (NBL)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    40
  • sponsor
    Children's Oncology Group
Updated on 25 May 2022

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 effect 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.

Description

PRIMARY OBJECTIVE:

I. To determine the feasibility of administering dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the frontline Post-Consolidation setting in patients with high-risk neuroblastoma who have undergone Induction and Consolidation therapy with tandem high-dose chemotherapy with stem cell rescue (ASCT).

SECONDARY OBJECTIVES:

I. To describe the toxicity profile of dinutuximab, GM-CSF, and isotretinoin in combination with irinotecan and temozolomide in the Post-Consolidation setting.

II. To describe the event-free survival and overall survival of patients who receive dinutuximab in combination with irinotecan and temozolomide, GM-CSF, and isotretinoinin the Post-Consolidation setting.

EXPLORATORY OBJECTIVES:

I. To describe the toxicity profiles associated with chemo-immunotherapy in the Post-Consolidation setting according to the type of prior therapy.

II. To describe response to chemo-immunotherapy in the Post-Consolidation setting using the revised International Neuroblastoma Risk Classification (INRC) in patients with evaluable or measurable disease at study entry.

III. To characterize immune and cytokine profiles in patients receiving Post-Consolidation chemo-immunotherapy.

IV. To bank serial blood samples to investigate the relationship between factors related to the tumor, host, and immune environment and clinical outcomes in patients treated with chemo-immunotherapy.

OUTLINE

Patients receive temozolomide orally (PO) or via enteral tube daily and irinotecan intravenously (IV) over 90 minutes daily on days 1-5, dinutuximab IV over 10-20 hours daily on days 2-5, sargramostim subcutaneously (SC) or IV over 2 hours daily on days 6-12, and isotretinoin PO twice daily (BID) on days 8-21. 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.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 15, 18, 24, 30, 36, 42, 48, 54, and 60 months.

Details
Condition Ganglioneuroblastoma, Nodular, High Risk Neuroblastoma
Treatment isotretinoin, Temozolomide, Irinotecan, sargramostim, Dinutuximab
Clinical Study IdentifierNCT04385277
SponsorChildren's Oncology Group
Last Modified on25 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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
Prior therapy
All patients must have completed high-risk Induction therapy with 4-6 cycles of chemotherapy
but subsequently found to meet criteria will also be eligible
After completion of Induction therapy, patients may have received no more than 4 cycles of bridging chemotherapy or chemo-immunotherapy prior to ASCT
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
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
and Lansky for patients =< 16 years
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
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)
Patients must not have received long-acting myeloid growth factors (e.g., Neulasta)
months to < 1 year: 0.5 (male and female)
to < 2 years: 0.6 (male and female)
within 14 days of entry on this study. Seven days must have elapsed since
to < 6 years: 0.8 (male and female)
administration of a short-acting myeloid growth factor
to < 10 years: 1 (male and female)
to < 13 years: 1.2 (male and female)
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
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
Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
echocardiogram or radionuclide angiogram

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 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
Patients may not have received additional systemic cancer-directed therapy following
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
completion of the last planned high-dose chemotherapy with ASCT prior to
enrollment on this trial
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 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
Patients on any other immunosuppressive medications (e.g., cyclosporine, tacrolimus)
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
are not eligible. However, prior or planned concomitant treatment with
Lactating females who plan to breastfeed their infants
eculizumab is permitted (e.g., treatment of TA-TMA)
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
Patients must not have received drugs that are strong inducers or inhibitors of CYP3A4
within 7 days prior to study enrollment
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