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

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.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

Site-responsible Investigators:

Contacts:

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: 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)

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

  -  Parts B & D: patients must have measurable disease for Parts B1-B6 and D1-D5;
     melanoma patients in Part B7 must have either measurable or evaluable disease;
     neuroblastoma patients in Part 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

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

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

  -  At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta)
     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 ANC counts): At least 7 days after the last dose of agent

  -  ≥ 21 days after the completion of interleukins, interferon or cytokines (other than
     hematopoetic growth factors)

  -  ≥ 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

  -  ≥ 14 days after local palliative external beam radiation therapy (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

  -  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

  -  Patients must not have received prior exposure to nivolumab; for patients enrolled in
     Parts C and D, 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; males and females of childbearing
     potential must be willing to adhere to effective contraception during and for 5 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 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 and D: patients who have received prior ipilimumab are not eligible