CompletedNCT02304458Updated Oct 17, 2023Results posted

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

A Phase 1/2 interventional study of Ipilimumab and Laboratory Biomarker Analysis in Metastatic Melanoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor and Recurrent Hodgkin Lymphoma, sponsored by National Cancer Institute (NCI). Completed at 25 sites in 2 countries. Open to participants aged 12 Months to 30 Years. Per ClinicalTrials.gov, last updated 2023-10-17.

Sponsored by National Cancer Institute (NCI) · Phase 1/2, Interventional, and Treatment

Phase: Phase 1/2
Study type: Interventional
Enrollment: 140
Allocation: Not applicable
Ages: 12 Months to 30 Years
Sex: All

Study 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.

Read the 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.

Conditions studied

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

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Who can participate

Ages eligible: 12 Months to 30 Years
Sexes eligible: All
Accepts healthy volunteers: No

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
- 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]) =\< 135 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

Exclusion Criteria:

Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as there is yet no available information regarding human fetal or teratogenic toxicities; 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
Patient who have received allotransplantation 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

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 140 participants (actual)

Study arms

Experimental
Treatment (nivolumab, ipilimumab)
See Detailed Description
Biological: Ipilimumab · Other: Laboratory Biomarker Analysis · Biological: Nivolumab · Other: Pharmacological Study

Interventions

BiologicalIpilimumab
Given IV
Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, Ipilimumab Biosimilar CS1002, MDX-010, MDX-CTLA4, Yervoy
OtherLaboratory Biomarker Analysis
Correlative studies
BiologicalNivolumab
Given IV
Also known as: BMS-936558, CMAB819, MDX-1106, NIVO, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo
OtherPharmacological Study
Correlative studies

What researchers measure

Primary outcomes

Frequency of Dose Limiting Toxicities of Nivolumab as a Single Agent or in Combination With Ipilimumab
The frequency (%) of patients experiencing a dose limiting toxicity at least possibly attributable to nivolumab as a single agent or in combination with ipilimumab by study part and dose level.
Time frame: 28 days
Antitumor Effect of Nivolumab as a Single Agent or in Combination With Ipilimumab
Frequency of disease response (best overall response of partial or complete response) assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR by study part and dose level.
Time frame: Up to 5 years

Secondary outcomes

Pharmacodynamics of Nivolumab as a Single Agent or in Combination With Ipilimumab
Median (min,max) concentration by protein, study part, and dose level.
Time frame: Up to 28 days
Area Under the Drug Concentration Curve of Nivolumab as a Single Agent or in Combination With Ipilimumab
The median (min,max) of the area under the drug concentration curve for nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24,72,192, and 360 hours post-dose.
Time frame: Up to 15 days
Half-life of Nivolumab as a Single Agent or in Combination With Ipilimumab
The median (min,max) of the half-life of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose. The reported half-life was calculated using a linear regression of the log (concentration) versus time data for days 4, 8 and 15.
Time frame: Up to 15 days
Maximum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab
Median (min,max) of the maximum serum concentration of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose.
Time frame: Up to 15 days
Minimum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab
Median (min,max) of the minimum serum concentration of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose.
Time frame: Up to 15 days
Clearance of Nivolumab as a Single Agent or in Combination With Ipilimumab
Median (min,max) of the clearance of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose.
Time frame: Up to 15 days
PD-L1 Expression of Nivolumab as a Single Agent or in Combination With Ipilimumab
Median (min, max) of PD-L1 expression levels by study part, dose level, and disease cohort.
Time frame: Cycle 1 (21 days)
Biomarker Expression Analysis of Nivolumab as a Single Agent or in Combination With Ipilimumab
Median (min, max) expression levels by biomarker, dose level, study part, and disease cohort.
Time frame: Cycle 1 (21 days)

Results

Posted Jan 10, 2023

Participant flow

Participant flow — Overall Study
Milestone	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
Started	7	6	72	6	6	6	29	8
Completed	0	0	1	0	0	0	0	0
Not completed	7	6	71	6	6	6	29	8
Withdrew: Adverse event	0	0	7	0	0	0	3	4
Withdrew: Death	0	0	2	0	0	0	1	0
Withdrew: Lack of efficacy	4	6	38	5	6	6	21	4
Withdrew: Physician decision	2	0	16	1	0	0	3	0
Withdrew: Protocol violation	0	0	1	0	0	0	0	0
Withdrew: Withdrawal by subject	1	0	7	0	0	0	1	0

Outcome measures

PrimaryFrequency of Dose Limiting Toxicities of Nivolumab as a Single Agent or in Combination With Ipilimumab

The frequency (%) of patients experiencing a dose limiting toxicity at least possibly attributable to nivolumab as a single agent or in combination with ipilimumab by study part and dose level.

Time frame:: 28 days
Reported as:: Count of participants · Participants

Frequency of Dose Limiting Toxicities of Nivolumab as a Single Agent or in Combination With Ipilimumab
Participants	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
Frequency of Dose Limiting Toxicities of Nivolumab as a Single Agent or in Combination With Ipilimumab	0	0	5	0	0	1	1	1

Statistical analysis

Part A: 3 mg/kg Nivolumab vs Part A PK: 3 mg/kg Nivolumab vs Part B: 3 mg/kg Nivolumab vs Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab vs Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab vs Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab vs Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab vs Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab · Maximum tolerate dose level: 3Maximum Tolerate Dose Level is 3 mg/kg Nivolumab

PrimaryAntitumor Effect of Nivolumab as a Single Agent or in Combination With Ipilimumab

Frequency of disease response (best overall response of partial or complete response) assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR by study part and dose level.

Time frame:: Up to 5 years
Reported as:: Count of participants · Participants

Antitumor Effect of Nivolumab as a Single Agent or in Combination With Ipilimumab
Participants	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B1: 3 mg/kg Nivolumab	Part B2: 3 mg/kg Nivolumab	Part B3: 3 mg/kg Nivolumab	Part B4: 3 mg/kg Nivolumab	Part B5: 3 mg/kg Nivolumab	Part B6: 3 mg/kg Nivolumab	Part B7: 3 mg/kg Nivolumab	Part B8: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D2: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D3: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D4: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E3: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Part E4: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
Antitumor Effect of Nivolumab as a Single Agent or in Combination With Ipilimumab	0	0	0	0	0	0	3	1	0	0	0	0	0	0	1	1	0	0

SecondaryPharmacodynamics of Nivolumab as a Single Agent or in Combination With Ipilimumab

Median (min,max) concentration by protein, study part, and dose level.

Time frame:: Up to 28 days

No measurements were reported for this outcome.

SecondaryArea Under the Drug Concentration Curve of Nivolumab as a Single Agent or in Combination With Ipilimumab

The median (min,max) of the area under the drug concentration curve for nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24,72,192, and 360 hours post-dose.

Time frame:: Up to 15 days
Reported as:: Median · hr*ug/mL

Area Under the Drug Concentration Curve of Nivolumab as a Single Agent or in Combination With Ipilimumab
hr*ug/mL	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab
Area Under the Drug Concentration Curve of Nivolumab as a Single Agent or in Combination With Ipilimumab	20744.5 (11840.0 to 31067.0)	18338 (9383.0 to 31188.0)	20816 (6442.0 to 133556.0)

SecondaryHalf-life of Nivolumab as a Single Agent or in Combination With Ipilimumab

The median (min,max) of the half-life of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose. The reported half-life was calculated using a linear regression of the log (concentration) versus time data for days 4, 8 and 15.

Time frame:: Up to 15 days
Reported as:: Median · hours

Half-life of Nivolumab as a Single Agent or in Combination With Ipilimumab
hours	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab
Half-life of Nivolumab as a Single Agent or in Combination With Ipilimumab	312.5 (154.0 to 444.0)	281.5 (263.0 to 426.0)	379 (92.0 to 2772.0)

SecondaryMaximum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab

Median (min,max) of the maximum serum concentration of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose.

Time frame:: Up to 15 days
Reported as:: Median · ug/mL

Maximum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab
ug/mL	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
Maximum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab	80.9 (56.9 to 119.4)	72 (39.0 to 93.7)	68.1 (37.6 to 224.9)	17.3 (14.4 to 23.1)	43.3 (35.4 to 48.6)	41.7 (23.2 to 74.4)	34.6 (15.9 to 61.7)	49.1 (10.0 to 62.5)

SecondaryMinimum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab

Median (min,max) of the minimum serum concentration of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose.

Time frame:: Up to 15 days
Reported as:: Median · ug/mL

Minimum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab
ug/mL	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
Minimum Serum Concentration of Nivolumab as a Single Agent or in Combination With Ipilimumab	29.6 (13.7 to 60.9)	30.4 (9.7 to 46.7)	26.4 (8.9 to 85.3)	3.8 (2.0 to 5.6)	10.5 (7.4 to 14.0)	9.2 (7.9 to 12.9)	10.8 (2.9 to 30.0)	8 (7.7 to 12.8)

SecondaryClearance of Nivolumab as a Single Agent or in Combination With Ipilimumab

Median (min,max) of the clearance of nivolumab as a single agent or in combination with ipilimumab by study part and dose level. Measured during cycle 1 at 0, 24, 72, 192, and 360 hours post-dose.

Time frame:: Up to 15 days
Reported as:: Median · mL/hr/kg

Clearance of Nivolumab as a Single Agent or in Combination With Ipilimumab
mL/hr/kg	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab
Clearance of Nivolumab as a Single Agent or in Combination With Ipilimumab	0.1 (0.1 to 0.3)	0.2 (0.1 to 0.3)	0.1 (0.0 to 0.5)

SecondaryPD-L1 Expression of Nivolumab as a Single Agent or in Combination With Ipilimumab

Median (min, max) of PD-L1 expression levels by study part, dose level, and disease cohort.

Time frame:: Cycle 1 (21 days)
Reported as:: Median · percent

PD-L1 Expression of Nivolumab as a Single Agent or in Combination With Ipilimumab
percent	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B1: 3 mg/kg Nivolumab	Part B2: 3 mg/kg Nivolumab	Part B3: 3 mg/kg Nivolumab	Part B4: 3 mg/kg Nivolumab	Part B5: 3 mg/kg Nivolumab	Part B6: 3 mg/kg Nivolumab	Part B7: 3 mg/kg Nivolumab	Part B8: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D2: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D3: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D4: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E3: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Part E4: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
PD-L1 Expression of Nivolumab as a Single Agent or in Combination With Ipilimumab	0 (0.0 to 0.0)	0 (0.0 to 0.0)	2.5 (0.0 to 70.0)	0 (0.0 to 1.0)	0 (0.0 to 3.0)	0 (0.0 to 1.0)	100 (30.0 to 100.0)	7.5 (0.0 to 100.0)	0 (0.0 to 0.0)	0 (0.0 to 0.0)	0 (0.0 to 97.0)	3 (0.0 to 100.0)	0 (0.0 to 0.0)	0 (0.0 to 0.0)	0 (0.0 to 3.0)	0 (0.0 to 25.0)	0 (0.0 to 0.0)	0 (0.0 to 0.0)

SecondaryBiomarker Expression Analysis of Nivolumab as a Single Agent or in Combination With Ipilimumab

Median (min, max) expression levels by biomarker, dose level, study part, and disease cohort.

Time frame:: Cycle 1 (21 days)

No measurements were reported for this outcome.

Adverse events

Collected over Up to 5 years. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Part A: 3 mg/kg Nivolumab	3/7 (42.9%)	6/7 (85.7%)	7/7 (100%)
Part A PK: 3 mg/kg Nivolumab	3/6 (50%)	6/6 (100%)	6/6 (100%)
Part B: 3 mg/kg Nivolumab	38/72 (52.8%)	70/72 (97.2%)	72/72 (100%)
Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	2/6 (33.3%)	4/6 (66.7%)	6/6 (100%)
Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	4/6 (66.7%)	6/6 (100%)	6/6 (100%)
Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	4/6 (66.7%)	5/6 (83.3%)	6/6 (100%)
Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	19/29 (65.5%)	26/29 (89.7%)	29/29 (100%)
Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	1/8 (12.5%)	7/8 (87.5%)	8/8 (100%)

Most frequent serious events

Showing 10 of 177

Most frequent serious events
Event	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, PROGRESSIVE DISEASENeoplasms benign, malignant and unspecified (incl cysts and polyps)	2/7	2/6	30/72	2/6	3/6	4/6	9/29	0/8
Lymphocyte count decreasedInvestigations	3/7	3/6	35/72	1/6	3/6	0/6	12/29	5/8
Neutrophil count decreasedInvestigations	3/7	1/6	26/72	0/6	1/6	1/6	2/29	2/8
Platelet count decreasedInvestigations	3/7	0/6	21/72	0/6	1/6	1/6	4/29	1/8
AnemiaBlood and lymphatic system disorders	0/7	2/6	25/72	1/6	1/6	2/6	8/29	2/8
Aspartate aminotransferase increasedInvestigations	0/7	0/6	4/72	0/6	2/6	0/6	3/29	1/8
HyponatremiaMetabolism and nutrition disorders	1/7	1/6	5/72	2/6	1/6	0/6	4/29	0/8
Pleural effusionRespiratory, thoracic and mediastinal disorders	1/7	2/6	4/72	0/6	0/6	0/6	5/29	1/8
White blood cell decreasedInvestigations	1/7	2/6	19/72	0/6	1/6	1/6	3/29	2/8
Alanine aminotransferase increasedInvestigations	0/7	0/6	5/72	1/6	0/6	0/6	2/29	2/8

Most frequent other events

Showing 10 of 581

Most frequent other events
Event	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab
AnemiaBlood and lymphatic system disorders	6/7	6/6	62/72	5/6	6/6	6/6	20/29	6/8
ConstipationGastrointestinal disorders	3/7	6/6	28/72	2/6	3/6	2/6	14/29	3/8
FatigueGeneral disorders	4/7	4/6	48/72	2/6	4/6	3/6	20/29	8/8
HyperglycemiaMetabolism and nutrition disorders	3/7	3/6	29/72	3/6	3/6	3/6	11/29	7/8
Lymphocyte count decreasedInvestigations	5/7	3/6	37/72	3/6	2/6	2/6	17/29	7/8
HypoalbuminemiaMetabolism and nutrition disorders	2/7	4/6	43/72	3/6	3/6	5/6	14/29	6/8
ProteinuriaRenal and urinary disorders	1/7	0/6	20/72	1/6	5/6	4/6	11/29	4/8
Abdominal painGastrointestinal disorders	1/7	2/6	22/72	1/6	2/6	1/6	8/29	6/8
Aspartate aminotransferase increasedInvestigations	5/7	3/6	36/72	3/6	3/6	4/6	10/29	6/8
HypocalcemiaMetabolism and nutrition disorders	4/7	3/6	36/72	3/6	3/6	2/6	9/29	6/8

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Total
<=18 years	7	6	59	6	6	6	18	4	112
Between 18 and 65 years	0	0	13	0	0	0	11	4	28
>=65 years	0	0	0	0	0	0	0	0	0

Age, Continuous
Age, Continuous(years)	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Total
Median	12 (5 to 13)	9.5 (7 to 15)	15 (1 to 27)	15 (12 to 15)	14.5 (11 to 17)	8.5 (4 to 27)	17 (5 to 27)	19 (11 to 28)	15 (1 to 28)

Sex: Female, Male
Sex: Female, Male(Participants)	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Total
Female	5	1	28	1	3	4	8	5	55
Male	2	5	44	5	3	2	21	3	85

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Total
Hispanic or Latino	2	1	9	1	1	1	5	1	21
Not Hispanic or Latino	5	5	62	5	5	5	23	7	117
Unknown or Not Reported	0	0	1	0	0	0	1	0	2

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Part A: 3 mg/kg Nivolumab	Part A PK: 3 mg/kg Nivolumab	Part B: 3 mg/kg Nivolumab	Part C: 1mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part C PK: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part D: 3mg/kg Nivolumab and 1mg/kg Ipilimumab	Part E: 1mg/kg Nivolumab and 3mg/kg Ipilimumab	Total
American Indian or Alaska Native	0	0	0	0	0	1	0	0	1
Asian	0	0	5	1	1	0	0	0	7
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0
Black or African American	0	0	8	1	1	0	2	0	12
White	7	6	51	3	4	4	23	8	106
More than one race	0	0	2	0	0	0	0	0	2
Unknown or Not Reported	0	0	6	1	0	1	4	0	12

Study locations

25 sites

Children's Hospital of Alabama
Birmingham, Alabama 35233, United States
Children's Hospital Los Angeles
Los Angeles, California 90027, United States
Children's Hospital of Orange County
Orange, California 92868, United States
Lucile Packard Children's Hospital Stanford University
Palo Alto, California 94304, United States
UCSF Medical Center-Mission Bay
San Francisco, California 94158, United States
Children's Hospital Colorado
Aurora, Colorado 80045, United States
Children's National Medical Center
Washington, District of Columbia 20010, United States
Children's Healthcare of Atlanta - Egleston
Atlanta, Georgia 30322, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois 60611, United States
Riley Hospital for Children
Indianapolis, Indiana 46202, United States
National Institutes of Health Clinical Center
Bethesda, Maryland 20892, United States
Dana-Farber Cancer Institute
Boston, Massachusetts 02215, United States
C S Mott Children's Hospital
Ann Arbor, Michigan 48109, United States
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota 55455, United States
Washington University School of Medicine
Saint Louis, Missouri 63110, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York 10032, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio 45229, United States
Oregon Health and Science University
Portland, Oregon 97239, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania 19104, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania 15224, United States
Saint Jude Children's Research Hospital
Memphis, Tennessee 38105, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas 77030, United States
Seattle Children's Hospital
Seattle, Washington 98105, United States
Children's Hospital of Wisconsin
Milwaukee, Wisconsin 53226, United States
Hospital for Sick Children
Toronto, Ontario M5G 1X8, Canada

References and documents

Publications

Davis KL, Fox E, Merchant MS, Reid JM, Kudgus RA, Liu X, Minard CG, Voss S, Berg SL, Weigel BJ, Mackall CL. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 2020 Apr;21(4):541-550. doi: 10.1016/S1470-2045(20)30023-1. Epub 2020 Mar 17. PubMed 32192573 ↗
Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14. PubMed 31401903 ↗

Study documents

Protocol and statistical analysis plan · Mar 30, 2020

Documents are hosted by the registry — open the source record to download them.

Registry details

Key details

Study ID: NCT02304458
Lead sponsor: National Cancer Institute (NCI)
Responsible party: Sponsor
First posted: Dec 2, 2014
Start date: Mar 30, 2015
Primary completion: Sep 30, 2021
Completion: Mar 31, 2023
Results posted: Jan 10, 2023
Last update: Oct 17, 2023

Study contacts

Crystal L Mackall

principal investigator · COG Phase I Consortium

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

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