An Exploratory Study of the Biologic Effects of Nivolumab and Ipilimumab Monotherapy and Nivolumab in Combination With Ipilimumab Treatment in Subjects With Advanced Melanoma (Unresectable or Metastatic)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 170
- 试验地点
- 14
- 主要终点
- Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors
研究概览
简要总结
The purpose of this study is to evaluate pharmacodynamic changes of Nivolumab and Nivolumab in combination with Ipilimumab treatment on the biomarkers measured in the peripheral blood and tumor tissues of subjects with advanced melanoma (unresectable or advanced)
详细描述
Allocation:
Part 1 and 2: Single Arm study
Part 3 and 4: Randomized Controlled Trial
Intervention Model:
Part 1 and 2: Single group: Single arm study
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women >18 years
- •Eastern Cooperative Oncology Group (ECOG) status = 0 to 1
- •Subjects with unresectable Stage III or IV melanoma who are either refractory or intolerant to, or have refused standard therapy for treatment of metastatic melanoma
- •Subject must have histologic or cytologic confirmation of advanced melanoma
- •Subjects must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
- •Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and post-treatment biopsies
排除标准
- •Active or progressing brain metastases
- •Other concomitant malignancies (with some exceptions per protocol)
- •Active or history of autoimmune disease
- •Positive test for human immunodeficiency virus (HIV) 1&2 or known acquired immunodeficiency syndrome (AIDS)
- •History of any hepatitis
- •Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies. However, half the patients must have progressed on anti Cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA4) monoclonal antibody therapy
- •Part 2, 3 and 4:
- •Inclusion Criteria
- •Men and women >16 years
- •Eastern Cooperative Oncology Group (ECOG) status = 0 to 1
- •Subjects with unresectable Stage III or IV melanoma who are either refractory or intolerant to, or have refused standard therapy for treatment of metastatic melanoma
- •Subjects must never received anti-CTLA4 therapy
- •Subjects must have histologic or cytologic confirmation of advanced melanoma
- •Subjects must have at least two measurable lesions at baseline by CT or MRI as per RECIST 1.1 criteria
- •Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and post-treatment biopsies
- •Subjects in Part 4 must have brain metastases
- •Exclusion Criteria
- •Active or progressing brain metastases (except for Part 4 subjects)
- •Other concomitant malignancies (with some exceptions per protocol)
- •Active or history of autoimmune disease
- •Positive test for HIV 1&2 or known AIDS
- •History of any hepatitis
- •Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies
研究组 & 干预措施
Part 1-Cohort 1 and 2: Nivolumab
Nivolumab 3 mg/kg solution intravenously Every 2 weeks, Up to 2 years depending on response
干预措施: Nivolumab (Biological)
Part 2-Arm A: Nivolumab + Ipilimumab
Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Nivolumab (Biological)
Part 2-Arm A: Nivolumab + Ipilimumab
Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Ipilimumab (Drug)
Part 3-Arm A: Nivolumab + Ipilimumab
Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Nivolumab (Biological)
Part 3-Arm A: Nivolumab + Ipilimumab
Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Ipilimumab (Drug)
Part 3-Arm B: Nivolumab
Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Nivolumab (Biological)
Part 4-Arm D: Nivolumab + Ipilimumab
Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Nivolumab (Biological)
Part 4-Arm D: Nivolumab + Ipilimumab
Nivolumab 1 mg/kg combined with Ipilimumab 3 mg/kg solution intravenously and then Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Ipilimumab (Drug)
Part 4-Arm E: Nivolumab
Nivolumab 3 mg/kg solution intravenously as specified
干预措施: Nivolumab (Biological)
结局指标
主要结局
Median Change From Baseline to Week 7, of Interferon (IFN) and Interferon Gamma (IFN-gamma) Inducible Factors
时间窗: From last non-missing value prior to first dose to week 7 day 1
Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine \[C-X-C motif\] ligand 9 (CXCL9) and CXCL10
Tumor Infiltrating Lymphocytes (TILs) as Measured by Medians in Percent Positive CD8 and Positive CD4 at Baseline and On-treatment Biopsy, Both Using the Mosaic Singleplex IHC Assay
时间窗: From last non-missing value prior to first dose to week 4 day 1
Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment.
次要结局
- Frequency of Adverse Events or Death(Includes events reported between first dose and up to 100 days after last dose of study medication (up to approximately 73 months).)
- Frequency of AEs Leading to Discontinuation of Study Drug and SAEs(From enrollment to 100 days after the last dose date (up to approximately 73 months))
- Number of Laboratory Abnormalities in Specific Liver Tests(101-120 days after last dose.)
- Number of Laboratory Abnormalities in Specific Thyroid Tests(101-120 days after last dose.)
- Objective Response Rate (ORR)(Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months))
- Median Duration of Response (mDOR)(From date of first documented objective response to date of disease progression or death, up to approximately 27 months)
- Median Time to Response (mTTR)(From the first dosing date to the date of the first documented objective response, up to approximately 15 months)
- Progression Free Survival (PFS)(From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months)
- Immunogenicity of Nivolumab and Nivolumab in Combination With Ipilimumab as Measured by the Number of Serum Anti-drug Antibody (ADA) Positive Participants and the Number of Neutralizing ADA Positive Participants(Up to follow-up visit 2 (101-120 days since last treatment))
- Objective Response Rate (ORR) by PD-L1 Expression(Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 73 months))
- Duration of Response (DOR) by PD-L1 Expression(From the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, up to approximately 73 months)
- Progression Free Survival (PFS) by PD-L1 Expression(From first dose of study medication to the date of progression or death, whichever occurs first, up to approximately 29 months)
- Overall Survival Rate (OSR)(From first dose of study medication to the date of death for any cause, up to approximately 73 months)
- Percent Probability for Progression Free Survival Rate (PFSR)(From first dose up to the specified timepoints of 3, 6, 9, 12, and 24 months)