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

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02304458
First Posted: December 2, 2014
Last Update Posted: December 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
November 26, 2014
December 2, 2014
December 12, 2017
February 2, 2015
October 31, 2020   (Final data collection date for primary outcome measure)
  • Maximum tolerated dose of nivolumab (Phase I) [ Time Frame: 28 days ]
    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 4.0.
  • Recommended phase 2 dose of nivolumab plus ipilimumab (Part C) [ Time Frame: Up to 30 days ]
    A descriptive summary of all toxicities will be reported.
  • Response rate of nivolumab combined with ipilimumab in expanded cohorts of patients with neuroblastoma, osteosarcoma, rhabdomyosarcomas, Ewing sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma (Part D) [ Time Frame: Up to 5 years ]
    Defined as either complete response, partial response, stable disease, or progressive disease, according to the Response Evaluation Criteria in Solid Tumors. Disease response will be reported descriptively.
  • Response rate of nivolumab combined with ipilimumab, defined as either complete response, partial response, stable disease, or progressive disease, according to the Response Evaluation Criteria in Solid Tumors (Part D) [ Time Frame: Up to 5 years ]
    Response rates will be calculated as the percent of patients whose best response is a complete response or partial response and confidence intervals will be constructed according to the method of Chang. Will be reported descriptively.
  • Response rate of nivolumab in expanded cohorts of patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma, and non-Hodgkin lymphoma (Part B) [ Time Frame: Up to 5 years ]
    Disease response will be reported descriptively.
  • Response rate of nivolumab, defined as either complete response, partial response, stable disease, or progressive disease, according to the Response Evaluation Criteria in Solid Tumors (Part B) [ Time Frame: Up to 5 years ]
    Response rates will be calculated as the percent of patients whose best response is a complete response or partial response and confidence intervals will be constructed according to the method of Chang. Will be reported descriptively.
  • Maximum tolerated dose of nivolumab, defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicity (Phase I) [ Time Frame: 28 days ]
  • Response rate of nivolumab, defined as either complete response (CR), partial response (PR), stable disease, or progressive disease, according to the Response Evaluation Criteria in Solid Tumors (Part B) [ Time Frame: Up to 2 years ]
    Response rates will be calculated as the percent of patients whose best response is a CR or PR and confidence intervals will be constructed according to the method of Chang. Will be reported descriptively.
  • RP2D of nivolumab plus ipilimumab (Part C) [ Time Frame: Up to 30 days ]
    A descriptive summary of all toxicities will be reported.
Complete list of historical versions of study NCT02304458 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
  • Biomarker expression analysis [ Time Frame: Baseline ]
    Will be evaluated for association with outcome, overall and by tumor type. All of these analyses will be descriptive and exploratory and hypotheses generating in nature.
  • PD-L1 expression [ Time Frame: Baseline ]
    Analyzed in an exploratory fashion, both using a binary scale and using a continuous scale to evaluate whether there are correlations between PD-L1 expression and antitumor effects.
  • Pharmacodynamic analysis, as determined by degree of PD1 occupancy rate on peripheral blood T cells [ Time Frame: Days 1, 2, 4, 8, and 15 of course 1 ]
    Evaluated pre- and post-therapy using flow cytometry. Human anti-human antibody analyses will be measured by Bristol-Myers-Squibb.
  • Pharmacokinetic parameters of nivolumab [ Time Frame: Days 1, 2, 4, 8, and 15 of course 1, days 1, 2, 4, and 8 of course 2, and day 1 of course 4 (Parts A & B); within 30 min prior to start of nivolumab infusion and immediately prior to ipilimumab on day 1 of courses 1-4 (Part C) ]
    The pharmacokinetic parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
  • Pharmacokinetic (PK) parameters of nivolumab [ Time Frame: Days 1, 2, 4, 8, and 15 of course 1, days 1, 2, 4, and 8 of course 2, and day 1 of course 4 (Parts A & B); within 30 min prior to start of nivolumab infusion and immediately prior to ipilimumab on day 1 of courses 1-4 (Part C) ]
    The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
  • Pharmacodynamic analysis, as determined by degree of PD1 occupancy rate on peripheral blood T cells [ Time Frame: Days 1, 2, 4, 8, and 15 of course 1 ]
    Evaluated pre- and post-therapy using flow cytometry. Human anti-human antibody analyses will be measured by Bristol-Myers-Squibb.
  • PD-L1 expression [ Time Frame: Baseline ]
    Analyzed in an exploratory fashion, both using a binary scale (> 5% or < 5% of tumor tissue) and using a continuous scale to evaluate whether there are correlations between PD-L1 expression and antitumor effects.
 
Nivolumab With or Without Ipilimumab in Treating Younger Patients With Recurrent or Refractory Solid Tumors or Sarcomas
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
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.

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 (Part D).

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).

OUTLINE: This is a phase I, dose-escalation study of nivolumab followed by a phase II study.

PART A: 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: Patients with neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or melanoma receive nivolumab as in Part A.

PART C:

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:

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.

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.

Interventional
Phase 1
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • 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 Hodgkin Lymphoma
  • Refractory Malignant Solid Neoplasm
  • Refractory Non-Hodgkin Lymphoma
  • 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
  • Biological: Ipilimumab
    Given IV
    Other Names:
    • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
    • BMS-734016
    • MDX-010
    • MDX-CTLA4
    • Yervoy
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Nivolumab
    Given IV
    Other Names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Other: Pharmacological Study
    Correlative studies
Experimental: Treatment (nivolumab, ipilimumab)
See Detailed Description
Interventions:
  • Biological: Ipilimumab
  • Other: Laboratory Biomarker Analysis
  • Biological: Nivolumab
  • Other: Pharmacological Study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
352
Not Provided
October 31, 2020   (Final data collection date for primary outcome measure)

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 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 hematopoetic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoetic 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 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; 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 and D: patients who have received prior ipilimumab are not eligible
Sexes Eligible for Study: All
12 Months to 30 Years   (Child, Adult)
No
Canada,   United States
 
 
NCT02304458
NCI-2014-01222
NCI-2014-01222 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1412
ADVL1412 ( Other Identifier: COG Phase I Consortium )
ADVL1412 ( Other Identifier: CTEP )
UM1CA097452 ( U.S. NIH Grant/Contract )
No
Not Provided
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Crystal Mackall COG Phase I Consortium
National Cancer Institute (NCI)
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP