ADVL1412: 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

Why are we doing this research?

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:

  • 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.
  • Determine if systemic nivolumab exposure in children is similar to the systemic exposure in adults following a 3 mg/kg dose.
  • 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.
  • Assess antitumor effects of nivolumab across selected childhood solid tumors in six expansion cohorts; neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.
  • 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.
  • Assess immunogenicity of nivolumab alone and in combination with ipilimumab by measuring anti-drug antibody (ADA) levels.

Secondary Objectives:

  • 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.
  • Explore whether correlations exist between programmed death ligand 1 (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: neuroblastoma RAS Viral [V-Ras] oncogene homolog [NRAS], v-raf murine sarcoma viral oncogene homolog B [BRAF], mitogen-activated protein kinase kinase 1 [MEK], v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog [KIT], platelet-derived growth factor [PDGF], tumor protein p53 [TP53], retinoblastoma 1 [RB1] and breast cancer 1, early onset [BRCA1], v-akt murine thymoma viral oncogene homolog [Akt] phosphorylation, interleukin [IL]-17 or PD-L1).

Study Type: Interventional

Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 12 Months to 30 Years

ELIGIBILITY CRITERIA

Inclusion Criteria:

  • Parts A & C: patients must be >= 12 months and =< 18 years of age at the time of study enrollment
  • Part B: patients must be >= 12 months and =< 30 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 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 PK expansion cohorts) may be selected at the treating physician's discretion pending slot availability
  • Parts A & C: patients must have either measurable or evaluable disease
  • Part B: patients must have measurable disease
  • 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
  • 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
  • At least 7 days after the last dose of a biologic agent; 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
  • At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines
  • At least 3 half-lives of the antibody after the last dose of a monoclonal antibody
  • At least 14 days after local palliative external beam radiation therapy (XRT) (small port); at least 150 days must have elapsed if prior total-body irradiation (TBI), craniospinal XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other substantial bone marrow (BM) radiation
  • No evidence of active graft vs. host disease and at least 56 days must have elapsed after transplant or stem cell infusion; patients with prior allogeneic transplants are not eligible
  • Patients must not have received prior exposure to nivolumab; for patients enrolled in Part C, 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 upper limit of normal (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; 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 in Parts A, B, and C; 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; females of childbearing potential must be willing to adhere to effective contraception during and for 23 weeks after the last dose of nivolumab; males who are sexually active with women of childbearing potential must be willing to adhere to effective contraception during and for 31 weeks 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; 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 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 monoclonal antibody (mAb) therapy are not eligible

Part C: patients who have received prior ipilimumab are not eligible

Ages

  • From 1 to 30 years old

Conditions

  • Lymphoma Hodgkin Relapse
  • Lymphoma Non Hodgkin Relapse
  • Sarcoma Osteosarcoma Relapse
  • Sarcoma Ewing Relapse
  • Sarcoma Rhabdomyosarcoma Relapse
  • Neuroblastoma Relapse - Refractory
  • Liver Relapse - Refractory
  • Kidney Relapse - Refractory
  • Solid Tumor Retinoblastoma Relapse - Refractory
  • Solid Tumor Melanoma Relapse - Refractory
  • Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Solid Tumors - All Other
  • Adult - Lymphoma Hodgkin Relapse
  • Adult - Lymphoma Non Hodgkin Relapse
  • Adult - Sarcoma Osteosarcoma Relapse
  • Adult - Sarcoma Rhabdomyosarcoma Relapse
  • Adult - Sarcoma Ewing Relapse
  • Adult - Neuroblastoma Relapse - Refractory
  • Adult - Liver Relapse - Refractory
  • Adult - Kidney Relapse - Refractory
  • Adult - Solid Tumor Retinoblastoma Relapse - Refractory
  • Adult - Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Adult - Solid Tumors - All Other

Contact

For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati OH 45229-3039
Phone: 513-636-2799

Email: cancer@cchmc.org