Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas
Condition: Metastatic Melanoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Hodgkin Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Melanoma; Recurrent Neuroblastoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Osteosarcoma; Recurrent Rhabdomyosarcoma; Refractory Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Refractory Hodgkin Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Melanoma; Refractory Neuroblastoma; Refractory Non-Hodgkin Lymphoma; Refractory Osteosarcoma; Refractory Rhabdomyosarcoma; Stage III Cutaneous Melanoma AJCC v7; Stage IIIA Cutaneous Melanoma AJCC v7; Stage IIIB Cutaneous Melanoma AJCC v7; Stage IIIC Cutaneous Melanoma AJCC v7; Stage IV Cutaneous Melanoma AJCC v6 and v7; Unresectable Melanoma
MeSH terms: Lymphoma; Neoplasms; Melanoma; Sarcoma; Lymphoma, Non-Hodgkin; Hodgkin Disease; Neuroblastoma; Osteosarcoma; Rhabdomyosarcoma; Skin Neoplasms; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Recurrence
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This phase I/II trial studies the side effects and best dose of nivolumab when given with or
      without ipilimumab to see how well they work in treating younger patients with solid tumors
      or sarcomas that have come back (recurrent) or do not respond to treatment (refractory).
      Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the
      body's immune system attack the cancer, and may interfere with the ability of tumor cells to
      grow and spread. It is not yet known whether nivolumab works better alone or with ipilimumab
      in treating patients with recurrent or refractory solid tumors or sarcomas.
    

Detailed description: 
      PRIMARY OBJECTIVES:

      I. Determine the tolerability, and define and describe the toxicities of nivolumab
      administered as a single agent in children with relapsed or refractory solid tumors at the
      adult recommended dose of 3 mg/kg.

      II. Determine if systemic nivolumab exposure in children is similar to the systemic exposure
      in adults following a 3 mg/kg dose.

      III. Determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and
      define and describe the toxicities of nivolumab plus ipilimumab administered to children with
      relapsed or refractory solid tumors.

      IV. Assess antitumor effects of nivolumab across selected childhood solid tumors in seven
      expansion cohorts (Parts B1-B6, B8); neuroblastoma (2 cohorts: measurable disease,
      metaiodobenzylguanidine [MIBG] positive only non-measurable disease), osteosarcoma,
      rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.

      V. Assess antitumor effects of nivolumab in combination with ipilimumab across selected
      childhood solid tumors in two dose combinations (Part D and Part E).

      VI. Characterize the pharmacokinetics of nivolumab alone and in combination with ipilimumab,
      including area under the curve (AUC), concentration maximum (Cmax), concentration minimum
      (Cmin), using intensive sampling.

      VII. Assess immunogenicity of nivolumab alone and in combination with ipilimumab by measuring
      anti-drug antibody (ADA) levels.

      SECONDARY OBJECTIVES:

      I. Conduct exploratory studies of the phenotypic and functional effects of nivolumab (alone
      and in combination with ipilimumab), as well as changes in antibodies to previously
      vaccinated viruses, in serum samples.

      II. Explore whether correlations exist between PD-L1 expression on tumor and antitumor
      effects of nivolumab (alone and in combination with ipilimumab) in pediatric solid tumors and
      to conduct exploratory studies of potential tumor associated biomarkers of response in tumor
      tissue (at least five out of the following markers: NRAS, BRAF, MEK, KIT, PDGF, TP53, RB1 and
      BRCA1, Akt phosphorylation, IL-17 or PD-L1).

      III. Explore presence of tumor infiltrating lymphocytes and their association with antitumor
      effects of nivolumab (alone and in combination with ipilimumab).

      IV. Conduct exploratory studies of the effect of nivolumab (alone or in combination with
      ipilimumab) on cytokine levels in serum samples.

      V. For Part E, determine tumor mutational burden of diagnostic specimens using
      FoundationOneCDx testing to explore immune- related gene expression or mutation and its
      association with antitumor response to nivolumab in combination with ipilimumab.

      OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study.

      PART A (COMPLETED): Patients with recurrent or refractory solid tumors receive nivolumab
      intravenously (IV) over 30 minutes on days 1 and 15. Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      PART B (COMPLETED): Patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing
      sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or melanoma receive nivolumab as in Part A.

      PART C (COMPLETED):

      INDUCTION: Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on
      day 1. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or
      unacceptable toxicity.

      MAINTENANCE: Patients receive nivolumab IV as in Part A. Cycles repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      PART D (COMPLETED):

      INDUCTION: Patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma,
      Hodgkin lymphoma, non-Hodgkin lymphoma, or melanoma receive nivolumab IV and ipilimumab IV as
      in Part C. Treatment repeats every 21 days for 4 cycles in the absence of disease progression
      or unacceptable toxicity.

      MAINTENANCE: Patients receive nivolumab IV over 30 minutes on days 1 and 15. Cycles repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      PART E: Patients receive nivolumab IV over 30 minutes on day 1 and ipilimumab IV over 90
      minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of
      disease progression or unacceptable toxicity. Patients then receive nivolumab IV over 30
      minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression
      or unacceptable toxicity.

      After completion of study treatment, patients are followed up at approximately 100 days,
      every 6 months for up to 24 months, and then annually for up to 60 months.
    

Intervention name(s): Ipilimumab; Laboratory Biomarker Analysis; Nivolumab; Pharmacological Study
Intervention type(s): Biological; Other; Biological; Other
Intervention description(s): Given IV; Correlative studies; Given IV; Correlative studies
Other intervention name(s): Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; Ipilimumab Biosimilar CS1002; MDX-010; MDX-CTLA4; Yervoy; BMS-936558; CMAB819; MDX-1106; NIVO; Nivolumab Biosimilar CMAB819; ONO-4538; Opdivo
Intervention MeSH terms: Nivolumab; Ipilimumab
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment