Clinical Trials /

Treatment With Dinutuximab in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma

NCT04385277

Description:

This phase II trial studies how well dinutuximab, irinotecan, and temozolomide after intensive therapy works in treating patients with high-risk neuroblastoma. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby healthy cells. 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. Giving dinutuximab together with irinotecan and temozolomide after intensive therapy may work better in treating patients with high-risk neuroblastoma compared to dinutuximab alone.

Related Conditions:
  • Ganglioneuroblastoma, Nodular
  • Neuroblastoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Treatment With Dinutuximab in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma
  • Official Title: A Pilot Study of Dinutuximab in Combination With Irinotecan and Temozolomide in the Post-Consolidation Setting for High-Risk Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: ANBL19P1
  • SECONDARY ID: NCI-2020-02950
  • SECONDARY ID: ANBL19P1
  • SECONDARY ID: ANBL19P1
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04385277

Conditions

  • Ganglioneuroblastoma, Nodular
  • High-Risk Neuroblastoma

Interventions

DrugSynonymsArms
DinutuximabCh 14.18UTC, Ch14.18, MOAB Ch14.18, monoclonal antibody Ch14.18, UnituxinTreatment (temozolomide, irinotecan, dinutuximab)
IrinotecanTreatment (temozolomide, irinotecan, dinutuximab)
Isotretinoin13-cis retinoic acid, 13-cis-Retinoate, 13-cis-Retinoic Acid, 13-cis-Vitamin A Acid, 13-cRA, Absorica, Accure, Accutane, Amnesteem, cis-Retinoic Acid, Cistane, Claravis, Isotretinoinum, Isotrex, Isotrexin, Myorisan, Neovitamin A, Neovitamin A Acid, Oratane, Retinoicacid-13-cis, Ro 4-3780, Ro-4-3780, Roaccutan, Roaccutane, Roacutan, Sotret, ZENATANETreatment (temozolomide, irinotecan, dinutuximab)
Sargramostim23-L-Leucinecolony-Stimulating Factor 2, DRG-0012, Leukine, Prokine, rhu GM-CFS, Sagramostim, SargramostatinTreatment (temozolomide, irinotecan, dinutuximab)
TemozolomideCCRG-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, TMZTreatment (temozolomide, irinotecan, dinutuximab)

Purpose

This phase II trial studies how well dinutuximab, irinotecan, and temozolomide after intensive therapy works in treating patients with high-risk neuroblastoma. Dinutuximab represents a kind of cancer therapy called immunotherapy. Unlike chemotherapy and radiation, dinutuximab targets the cancer cells without destroying nearby healthy cells. 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. Giving dinutuximab together with irinotecan and temozolomide after intensive therapy may work better in treating patients with high-risk neuroblastoma compared to dinutuximab alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the feasibility of administering dinutuximab 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.

      SECONDARY OBJECTIVES:

      I. To describe the toxicity profile of dinutuximab 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 in 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (temozolomide, irinotecan, dinutuximab)ExperimentalPatients 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. Treatment repeats every 28 days for 5 cycles (6 cycles for isotretinoin only) in the absence of disease progression or unacceptable toxicity.
  • Dinutuximab
  • Irinotecan
  • Isotretinoin
  • Sargramostim
  • Temozolomide

Eligibility Criteria

        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 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

          -  All patients must have completed high-risk Induction therapy (a minimum of 4 cycles of
             chemotherapy and surgical resection of primary tumor) and Consolidation (single or
             tandem high-dose chemotherapy with autologous stem cell transplant [ASCT] and
             radiotherapy). Notes:

               -  Requirement for preceding radiotherapy may be waived for patients with
                  unidentifiable primary tumors and no persistent metastatic disease

               -  Requirement for preceding surgical resection of primary tumor may be waived for
                  patients who have a complete response to Induction chemotherapy or for patients
                  in whom the institutional surgeon determined that potential risks outweighed
                  potential benefits of resection

               -  Patients may have received additional therapy (including but not limited to
                  irinotecan and temozolomide with or without sargramostim [GM-CSF] + dinutuximab
                  or 131I MIBG) prior to ASCT, however, they cannot have progressed on
                  immunotherapy with dinutuximab or other anti-GD2 monoclonal antibody

          -  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

        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 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
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Proportion of patients who complete 5 cycles of dinutuximab + chemotherapy without progressive disease (PD)
Time Frame:Within 30 weeks from the date of first treatment
Safety Issue:
Description:Will be assessed by estimation of the feasibility therapy completion rate together with a 95% Wilson confidence interval (CI) The therapy will be deemed feasible if the 95% CI placed on the percentage of patients that complete at least 5 cycles of dinutuximab + chemotherapy without PD within 30 weeks contains 75% and the interim monitoring rules for feasibility and excessive toxicity are not triggered.

Secondary Outcome Measures

Measure:Event-free survival (EFS)
Time Frame: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
Safety Issue:
Description:EFS Kaplan-Meier curves and estimates will be generated.
Measure:Overall survival (OS)
Time Frame:From the time of start of protocol therapy to death, assessed up to 60 months
Safety Issue:
Description:OS Kaplan-Meier curves and estimates will be generated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Children's Oncology Group

Last Updated

May 8, 2020