Clinical Trials /

Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas

NCT02304458

Description:

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.

Related Conditions:
  • Ewing Sarcoma
  • Peripheral Primitive Neuroectodermal Tumor
  • Rhabdomyosarcoma
Recruiting Status:

Suspended

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas
  • Official Title: A Phase 1/2 Study of Nivolumab in Children, Adolescents, and Young Adults With Recurrent or Refractory Solid Tumors as a Single Agent and in Combination With Ipilimumab

Clinical Trial IDs

  • ORG STUDY ID: NCI-2014-01222
  • SECONDARY ID: NCI-2014-01222
  • SECONDARY ID: ADVL1412
  • SECONDARY ID: ADVL1412
  • SECONDARY ID: UM1CA097452
  • NCT ID: NCT02304458

Conditions

  • 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

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (nivolumab, ipilimumab)

Purpose

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). Monoclonal antibodies, such as nivolumab and ipilimumab, may block tumor growth in different ways by targeting certain cells. 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 FoundationOne
      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 60 minutes on days 1 and 15. Courses 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 courses in the absence of disease progression or
      unacceptable toxicity.

      MAINTENANCE: Patients receive nivolumab IV as in Part A. Courses 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 courses in the absence of disease
      progression or unacceptable toxicity.

      MAINTENANCE: Patients receive nivolumab IV over 60 minutes on days 1 and 15. Courses repeat
      every 28 days in the absence of disease progression or unacceptable toxicity.

      PART E: Participants receive nivolumab IV over 60 minutes on day 1 and ipilimumab IV over 90
      minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of
      disease progression or unacceptable toxicity. Participants then receive nivolumab IV over 60
      minutes on days 1 and 15. Courses 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nivolumab, ipilimumab)ExperimentalSee Detailed Description
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Parts A & C: patients must be >= 12 months and < 18 years of age at the time of study
             enrollment

          -  Parts B1-B6, B8, D1-D6, E3, E4: patients must be >= 12 months and =< 30 years of age
             at the time of study enrollment

          -  Part B7: patients must be >= 12 months and < 18 years of age at the time of study
             enrollment

          -  Patients must have had histologic verification of malignancy at original diagnosis or
             relapse

               -  Parts A & C: patients with recurrent or refractory solid tumors, without central
                  nervous system (CNS) tumors or known CNS metastases, are eligible; note: CNS
                  imaging for patients without a known history of CNS disease is only required if
                  clinically indicated

               -  Part B1: patients with relapsed or refractory neuroblastoma

               -  Part B2: patients with relapsed or refractory osteosarcoma

               -  Part B3: patients with relapsed or refractory rhabdomyosarcoma

               -  Part B4: patients with relapsed or refractory Ewing sarcoma or peripheral
                  primitive neuroectodermal tumor (PNET)

               -  Part B5: patients with relapsed or refractory Hodgkin lymphoma

               -  Part B6: patients with relapsed or refractory non-Hodgkin lymphoma

               -  Part B7: patients with unresectable melanoma or metastatic melanoma or relapsed
                  melanoma or refractory melanoma

               -  Part B8: Patients with relapsed or refractory neuroblastoma (MIBG evaluable
                  disease without Response Evaluation Criteria in Solid Tumors [RECIST] measurable
                  lesion)

               -  Once the dose-escalation portion of Part A is completed, cohorts that are open
                  concurrently for eligible patients (including Parts B and C and potential
                  pharmacokinetic [PK] expansion cohorts) may be selected at the treating
                  physician's discretion pending slot availability; in the event a disease group
                  cohort in Part B is completed after the initial stage of Simon's optimal
                  two-stage design, for selected disease cohorts, a corresponding cohort in the
                  same disease group for select disease types will be open in Part D:

               -  Part D1: Patients with relapsed or refractory neuroblastoma

               -  Part D2: Patients with relapsed or refractory osteosarcoma

               -  Part D3: Patients with relapsed or refractory rhabdomyosarcoma

               -  Part D4: Patients with relapsed or refractory Ewing sarcoma or peripheral PNET

               -  Part D5: Patients with relapsed or refractory non-Hodgkin lymphoma

               -  Part D6: Patients with relapsed or refractory neuroblastoma (MIBG evaluable
                  disease without RECIST measurable lesion)

               -  Part E3: Patients with relapsed or refractory rhabdomyosarcoma

               -  Part E4: Patients with relapsed or refractory Ewing sarcoma or peripheral PNET

          -  Parts A & C: patients must have either measurable or evaluable disease

          -  Parts B, D & E: patients must have measurable disease for Parts B1-B6, D1-D5, E3 and
             E4; melanoma patients in Part B7 must have either measurable or evaluable disease;
             neuroblastoma patients in Parts B8 and D6 must be evaluable for MIBG response without
             evidence of RECIST measurable lesions

          -  Patient's current disease state must be one for which there is no known curative
             therapy or therapy proven to prolong survival with an acceptable quality of life

          -  Karnofsky >= 50% for patients > 16 years of age and Lansky >= 60 for patients =< 16
             years of age; patients who are unable to walk because of paralysis, but who are up in
             a wheelchair, will be considered ambulatory for the purpose of assessing the
             performance score

          -  Patients must have fully recovered from the acute toxic effects of all prior
             anti-cancer therapy and must meet the following minimum duration from prior
             anti-cancer directed therapy prior to enrollment; if after the required timeframe, the
             defined eligibility criteria are met, e.g. blood count criteria, the patient is
             considered to have recovered adequately

               -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive

                    -  At least 21 days after the last dose of cytotoxic or myelosuppressive
                       chemotherapy (42 days if prior nitrosourea)

               -  Hematopoietic growth factors: At least 14 days after the last dose of a
                  long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth
                  factor; for agents that have known adverse events occurring beyond 7 days after
                  administration, this period must be extended beyond the time during which adverse
                  events are known to occur; the duration of this interval must be discussed with
                  the study chair

               -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
                  reduced platelet or absolute neutrophil count [ANC] counts): At least 7 days
                  after the last dose of agent

               -  Interleukins, interferons and cytokines (other than hematopoietic growth
                  factors): >= 21 days after the completion of interleukins, interferon or
                  cytokines (other than hematopoietic growth factors)

               -  Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
                  and toxicity related to prior antibody therapy must be recovered to grade =< 1

               -  External beam radiation therapy (XRT)/external beam irradiation including
                  protons: >= 14 days after local XRT; >= 150 days after total body irradiation
                  (TBI), craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if
                  other substantial bone marrow (BM) radiation.

               -  Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days
                  must have elapsed since systemically administered radiopharmaceutical therapy

               -  Stem cell infusion (with or without TBI):

                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
                       cell infusion including donor lymphocyte infusion (DLI) or boost infusion:
                       >= 100 days after infusion, no evidence of graft versus host disease (GVHD)
                       and no requirement for immunosuppression

                    -  Autologous stem cell infusion including boost infusion: >= 42 days

               -  Cellular therapy: >= 42 days must have elapsed since the completion of any type
                  of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic
                  cells, etc.)

               -  Patients must not have received prior exposure to nivolumab; for patients
                  enrolled in parts C, D and E, patients must not have received prior nivolumab or
                  ipilimumab

          -  For patients with solid tumors without known bone marrow involvement:

          -  Peripheral absolute neutrophil count (ANC) >= 750/mm^3

          -  Platelet count >= 75,000/mm^3 (transfusion independent, defined as not receiving
             platelet transfusions for at least 7 days prior to enrollment)

          -  Patients with known bone marrow metastatic disease will be eligible for study provided
             they meet the blood counts above (may receive transfusions provided they are not known
             to be refractory to red cell or platelet transfusions); these patients will not be
             evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients with a
             solid tumor must be evaluable for hematologic toxicity, for Parts A and C; if
             dose-limiting hematologic toxicity is observed on either Part A or C, all subsequent
             patients enrolled must be evaluable for hematologic toxicity on that Part

          -  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 1 to < 2 years: maximum serum creatinine (mg/dL) 0.6 for males and females

               -  Age 2 to < 6 years: 0.8 for males and females

               -  Age 6 to < 10 years: 1 for males and females

               -  Age 10 to < 13 years: 1.2 for males and females

               -  Age 13 to < 16 years: 1.5 for males and 1.4 for females

               -  Age >= 16 years: 1.7 for males and 1.4 for females

          -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
             age

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
             U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

          -  No evidence of dyspnea at rest, no exercise intolerance due to pulmonary
             insufficiency, and a pulse oximetry > 92% while breathing room air

          -  Serum lipase =< ULN at baseline; patients with glucose intolerance should be on a
             stable regimen and be monitored

          -  All patients and/or their parents or legally authorized representatives must sign a
             written informed consent; assent, when appropriate, will be obtained according to
             institutional guidelines

          -  Tissue blocks or slides must be sent for all patients; if tissue blocks or slides are
             unavailable, the study chair must be notified prior to enrollment

        Exclusion Criteria:

          -  Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
             must be obtained in girls who are post-menarchal; women of childbearing potential
             (WOCBP) receiving nivolumab will be instructed to adhere to contraception for a period
             of 5 months after the last dose of nivolumab; men receiving nivolumab and who are
             sexually active with WOCBP will be instructed to adhere to contraception for a period
             of 7 months after the last dose of nivolumab

          -  Patients requiring daily systemic corticosteroids are not eligible; patients must not
             have received systemic corticosteroids within 7 days prior to enrollment; if used to
             modify immune adverse events related to prior therapy, >= 14 days must have elapsed
             since last dose of corticosteroid; Note: use of topical or inhaled corticosteroids
             will not render a patient ineligible

          -  Patients who are currently receiving another investigational drug are not eligible

          -  Patients who are currently receiving other anti-cancer agents are not eligible

          -  Patients with CNS tumors or known CNS metastases will be excluded from this trial;
             patients with a history of CNS metastases that have been previously treated may enroll
             if sequential imaging shows not evidence for active disease; patients with extra axial
             disease (e.g. skull [bone] metastasis that do not invade the dura) may enroll if there
             is no evidence for CNS edema associated with the lesion

          -  Patients with a history of any grade autoimmune disorder are not eligible;
             asymptomatic laboratory abnormalities (e.g. antinuclear antibody [ANA], rheumatoid
             factor, altered thyroid function studies) will not render a patient ineligible in the
             absence of a diagnosis of an autoimmune disorder

          -  Patients with >= grade 2 hypothyroidism due to history of autoimmunity are not
             eligible; note: hypothyroidism due to previous irradiation on thyroidectomy will not
             impact eligibility

          -  Patients who have an uncontrolled infection are not eligible

          -  Patients with a history of congestive heart failure (CHF) or are at risk because of
             underlying cardiovascular disease or exposure to cardiotoxic drugs must have adequate
             cardiac function as clinically indicated:

               -  Corrected QT interval (QTC) =< 480 msec

               -  Shortening fraction of >= 27% by echocardiogram or ejection fraction of >= 50% by
                  gated radionuclide study

          -  Patients with known human immunodeficiency virus (HIV) or hepatitis B or C are
             excluded

          -  Patients who have received prior solid organ transplantation are not eligible

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible

          -  Patients who have received prior anti-PD1 directed therapy (monoclonal antibody [mAb]
             or small molecule) are not eligible

          -  Parts C, D, and E: patients who have received prior ipilimumab are not eligible
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of nivolumab (Phase I)
Time Frame:28 days
Safety Issue:
Description:Defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity graded by Common Terminology Criteria for Adverse Events version 5.0.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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