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

Metastatic Melanoma Clinical Trial

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 Details — Status: Completed

Administrative data

• NCT number: NCT02304458
• Other study ID #: NCI-2014-01222
• Secondary ID: NCI-2014-01222AD
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 30, 2015
• Est. completion date: March 31, 2023

Study information

• Verified date: September 2023
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: March 31, 2023
• Est. primary completion date: September 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Months to 30 Years

Eligibility

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:

• 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

Related Conditions & MeSH terms

• Hodgkin Disease
• Lymphoma
• Lymphoma, Non-Hodgkin
• Melanoma
• Metastatic Melanoma
• Neoplasms
• Neuroblastoma
• Neuroectodermal Tumors
• Neuroectodermal Tumors, Primitive
• Neuroectodermal Tumors, Primitive, Peripheral
• Osteosarcoma
• Recurrence
• 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
• Rhabdomyosarcoma
• Sarcoma
• Sarcoma, Ewing
• Skin Neoplasms
• 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

Intervention

Biological:
• Ipilimumab
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Biological:
• Nivolumab
Given IV

Other:
• Pharmacological Study
Correlative studies

Locations

Country	Name	City	State
Canada	Hospital for Sick Children	Toronto	Ontario
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	National Institutes of Health Clinical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Saint Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	28 days
Primary	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.	Up to 5 years
Secondary	Pharmacodynamics of Nivolumab as a Single Agent or in Combination With Ipilimumab	Median (min,max) concentration by protein, study part, and dose level.	Up to 28 days
Secondary	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.	Up to 15 days
Secondary	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.	Up to 15 days
Secondary	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.	Up to 15 days
Secondary	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.	Up to 15 days
Secondary	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.	Up to 15 days
Secondary	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.	Cycle 1 (21 days)
Secondary	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.	Cycle 1 (21 days)