Clinical Trials /

Dinutuximab, Sargramostim, and Combination Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing Stem Cell Transplant

NCT03786783

Description:

This phase II trial studies the side effects and how well dinutuximab and sargramostim work with combination chemotherapy in patients with high-risk neuroblastoma undergoing stem cell transplant. 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. Sargramostim helps the body produce normal infection-fighting white blood cells. Giving chemotherapy before a stem cell transplant, with drugs such as cisplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, thiotepa, melphalan, etoposide, carboplatin, topotecan, and isotretinoin, helps kill any cancer cells that are in the body and helps make room in a patient's bone marrow for new blood-forming cells (stem cells). Giving dinutuximab and sargramostim with combination chemotherapy may work better than combination chemotherapy alone in treating patients with high-risk neuroblastoma undergoing stem cell transplant.

Related Conditions:
  • Ganglioneuroblastoma
  • Neuroblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Dinutuximab, Sargramostim, and Combination Chemotherapy in Treating Patients With Newly Diagnosed High-Risk Neuroblastoma Undergoing Stem Cell Transplant
  • Official Title: A Pilot Induction Regimen Incorporating Chimeric 14.18 Antibody (ch14.18, Dinutuximab) (NSC# 764038) and Sargramostim (GM-CSF) for the Treatment of Newly Diagnosed High-Risk Neuroblastoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-03732
  • SECONDARY ID: NCI-2018-03732
  • SECONDARY ID: ANBL17P1
  • SECONDARY ID: ANBL17P1
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03786783

Conditions

  • Ganglioneuroblastoma
  • High-Risk Neuroblastoma

Interventions

DrugSynonymsArms
Aldesleukin125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, recombinant human interleukin-2Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
Dexrazoxane2, 6-Piperazinedione, 4,4''-propylenedi-, (P)- (8CI), 2,6-Piperazinedione, 4, 4''-(1-methyl-1,2-ethanediyl)bis-, (S)- (9CI), ADR-529, ICRF-187, Razoxane (+)-form, Soluble ICRF (L-isomer)Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
DinutuximabCh 14.18UTC, Ch14.18, MOAB Ch14.18, monoclonal antibody Ch14.18, UnituxinTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
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(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
MelphalanAlanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
Sargramostim23-L-Leucinecolony-Stimulating Factor 2, DRG-0012, Leukine, Prokine, rhu GM-CFS, Sagramostim, SargramostatinTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
Thiotepa1,1'',1''''-Phosphinothioylidynetrisaziridine, Girostan, N,N'', N''''-Triethylenethiophosphoramide, Oncotiotepa, STEPA, Tepadina, TESPA, Tespamin, Tespamine, Thio-Tepa, Thiofosfamide, Thiofozil, Thiophosphamide, Thiophosphoramide, Thiotef, Tifosyl, TIO TEF, Tio-tef, Triethylene Thiophosphoramide, Triethylenethiophosphoramide, Tris(1-aziridinyl)phosphine sulfide, TSPA, WR 45312Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
TopotecanHycamptamine, Topotecan LactoneTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)
VincristineLeurocristine, VCR, VincrystineTreatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)

Purpose

This phase II trial studies the side effects and how well dinutuximab and sargramostim work with combination chemotherapy in patients with high-risk neuroblastoma undergoing stem cell transplant. 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. Sargramostim helps the body produce normal infection-fighting white blood cells. Giving chemotherapy before a stem cell transplant, with drugs such as cisplatin, etoposide, vincristine, doxorubicin, cyclophosphamide, thiotepa, melphalan, etoposide, carboplatin, topotecan, and isotretinoin, helps kill any cancer cells that are in the body and helps make room in a patient's bone marrow for new blood-forming cells (stem cells). Giving dinutuximab and sargramostim with combination chemotherapy may work better in treating patients with high-risk neuroblastoma undergoing stem cell transplant.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the feasibility and tolerability of administering ch14.18 (dinutuximab) and
      sargramostim (GM-CSF) in combination with a multi-agent chemotherapy regimen during cycles
      3-5 of the Induction phase for patients with newly-diagnosed high-risk neuroblastoma.

      SECONDARY OBJECTIVES:

      I. To describe the response rates, event-free survival (EFS) and overall survival (OS) for
      patients receiving the combination of standard Induction chemotherapy and ch14.18
      (dinutuximab) followed by tandem transplant, radiation therapy, and post-consolidation
      immunotherapy.

      EXPLORATORY OBJECTIVES:

      I. To describe the clinical relevance of naturally occurring anti-glycan antibodies in
      patients receiving ch14.18 (dinutuximab).

      II. To describe the clinical relevance of natural killer (NK) receptor NKp30 isoforms in
      patients receiving ch14.18 (dinutuximab).

      III. To describe the association between host factors, including human anti-chimeric
      antibodies (HACA), and response to protocol therapy.

      IV. To describe the immune environment (gene expression; immune effector cells, activities
      and signaling molecules; immune target expression) during and following treatment.

      V. To describe the association between levels of circulating GD2, and tumor cell GD2
      expression with response to therapy.

      OUTLINE:

      INDUCTION CYCLES 1-2 (21 days): Patients receive cyclophosphamide intravenously (IV) over
      15-30 minutes and topotecan IV over 30 minutes on days 1-5. Treatment repeats every 21 days
      for 2 cycles in the absence of disease progression or unacceptable toxicity.

      INDUCTION CYCLE 3: Patients receive cisplatin IV over 1 hour on days 1-3, etoposide IV over 2
      hours on days 1-3, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim
      subcutaneously (SC) on day 6 or 7 of a 21-day cycle.

      INDUCTION CYCLE 4: Patients receive vincristine IV over 1 minute on day 1, doxorubicin IV
      over 1-15 minutes on days 1-2, cyclophosphamide IV over 1 hour on days 1-2, dinutuximab IV
      over 10-20 hours on days 2-5, and sargramostim SC on day 6 or 7 of a 21-day cycle.

      INDUCTION CYCLE 5: Patients receive cisplatin IV over 1 hour on days 1-3, etoposide IV over 2
      hours on days 1-3, dinutuximab IV over 10-20 hours on days 2-5, and sargramostim SC on day 6
      or 7 of a 21-day cycle.

      Patients may undergo surgery after the fifth cycle of Induction at the discretion of treating
      doctor. Patients with stable disease or better tumor response at the end of Induction proceed
      to Consolidation. Consolidation treatments begin between 4 and 6 weeks from the start date of
      Induction chemotherapy cycle 5. For patients who have surgical resection delayed until after
      Induction chemotherapy cycle 5, Consolidation starts within 4 weeks from the date of surgery.

      CONSOLIDATION #1: Patients receive thiotepa IV over 2 hours on days -7 to -5 and
      cyclophosphamide IV over 1 hour on days -5 to -2. Patients then undergo autologous stem cell
      transplant (ASCT) on day 0.

      CONSOLIDATION #2: Patients receive melphalan IV over 30 minutes on days -7 to -5, etoposide
      IV over 24 hours on days -7 to -4, and carboplatin IV over 24 hours on days -7 to -4.
      Patients then undergo ASCT on day 0.

      RADIATION THERAPY: Beginning 42-80 days following Consolidation #2, patients receive external
      beam radiation therapy (EBRT) daily for up to 20 days.

      Patients then receive post-Consolidation therapy starting 1 week following radiation therapy.

      POST-CONSOLIDATION CYCLES 1, 3, AND 5: Patients receive sargramostim SC on days 1-14,
      dinutuximab IV over 10-20 hours on days 4-7, and isotretinoin orally (PO) twice daily (BID)
      on days 11-24. Treatment repeats every 24 days in the absence of disease progression or
      unacceptable toxicity.

      POST-CONSOLIDATION CYCLES 2 AND 4: Patients receive aldesleukin IV continuously over 96 hours
      on days 1-4 and 8-11, dinutuximab IV over 10-20 hours on days 8-11, and isotretinoin PO BID
      on days 15-28. Treatment repeats every 32 days in the absence of disease progression or
      unacceptable toxicity.

      POST-CONSOLIDATION CYCLE 6: Patients receive isotretinoin PO BID on days 15-28 of a 28-day
      cycle

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

Trial Arms

NameTypeDescriptionInterventions
Treatment(chemotherapy, dinutuximab, sargramostim, ASCT, EBRT)ExperimentalSee Detailed Description
  • Aldesleukin
  • Carboplatin
  • Cisplatin
  • Cyclophosphamide
  • Dexrazoxane
  • Dinutuximab
  • Doxorubicin
  • Etoposide
  • Isotretinoin
  • Melphalan
  • Sargramostim
  • Thiotepa
  • Topotecan
  • Vincristine

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must be enrolled on ANBL00B1 or APEC14B1 prior to enrollment on ANBL17P1.

          -  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. The following disease groups
             are eligible:

               -  Patients with International Neuroblastoma Risk Group (INRG) stage M disease are
                  eligible if found to have either of the following features:

                    -  MYCN amplification (> 4-fold increase in MYCN signals as compared to
                       reference signals), regardless of age or additional biologic features; OR

                    -  Age > 547 days regardless of biologic features;

               -  Patients with INRG stage MS disease with MYCN amplification

               -  Patients with INRG stage L2 disease with MYCN amplification

               -  Patients > 547 days of age initially diagnosed with INRG stage L1, L2 or MS
                  disease who progress to stage M without prior chemotherapy may enroll within 4
                  weeks of progression to stage M.

               -  Patients >= 365 days of age initially diagnosed with MYCN amplified INRG stage L1
                  disease who progress to stage M without systemic therapy may enroll within 4
                  weeks of progression to stage M.

          -  Patients initially recognized to have high-risk disease must have had no prior
             systemic therapy (other than topotecan/cyclophosphamide initiated on an emergent basis
             and within allowed timing as described).

          -  Patients observed or 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
             the criteria will also be eligible.

          -  Patients who receive localized emergency radiation to sites of life-threatening or
             function-threatening disease prior to or immediately after establishment of the
             definitive diagnosis will be eligible.

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

               -  Age 1 month to < 6 months (male 0.4 mg/dL, female 0.4 mg/dL)

               -  Age 6 months to < 1 year (male 0.5 mg/dL, female 0.5 mg/dL)

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

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

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

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

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

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

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

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 10 x
             ULN. For the purposes of this study, ULN for ALT is 45 IU/L (within 7 days prior to
             enrollment).

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

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

          -  No known contraindication to peripheral blood stem cell (PBSC) collection. Examples of
             contraindications might be a weight or size less than the collecting institution finds
             feasible, or a physical condition that would limit the ability of the child to undergo
             apheresis catheter placement (if necessary) and/or the apheresis procedure.

          -  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.

        Exclusion Criteria:

          -  Patients >18 months of age with INRG stage L2, MYCN non-amplified, regardless of
             additional biologic features.

          -  Patients with bone marrow failure syndromes.

          -  Patients that are >= 12 and =< 18 months of age with INRG stage M and all 3 favorable
             biologic features (i.e., non-amplified MYCN, favorable pathology, and deoxyribonucleic
             acid [DNA] index > 1) are not eligible.

          -  Patients on immunosuppressive medications (e.g. tacrolimus, cyclosporine,
             corticosteroids for reasons other than prevention/treatment of allergic reactions,
             adrenal replacement therapy, etc.) are not eligible.

          -  Female patients who are pregnant are ineligible 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 during study therapy and for two months after the last
             dose of ch14.18 (dinutuximab) are not eligible.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 63 days
Safety Issue:
Description:Assessed with National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. A one-sided Pocock group-sequential boundary with a sample size of 42 will be used to monitor the number of patients who experience at least one unacceptable toxicity during cycle 3-5 of induction. Will be assessed by the unacceptable toxicity monitoring rule and by the estimation of the combined toxic death and unacceptable toxicity rate together with a 95% confidence interval (CI).

Secondary Outcome Measures

Measure:Response rate
Time Frame:Up to 5 years
Safety Issue:
Description:Response will be determined using the revised International Neuroblastoma Response Criteria. Response rate will be calculated as the percentage of eligible patients with at least a partial response (PR) or better at the end of Induction and will also be considered in determining whether the regimen is worth further study. Will be calculated, including placement of a 95% CI on the response rate.
Measure:Event-free survival
Time Frame:From study enrollment to the occurrence of disease relapse or progression, secondary malignancy, or death, assessed from baseline up to 5 years
Safety Issue:
Description:Kaplan-Meier curves will be generated.
Measure:Overall survival
Time Frame:From study enrollment to death, assessed from baseline up to 5 years
Safety Issue:
Description:Kaplan-Meier curves will be generated.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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