A Phase II Study of Anti-PD1 Monoclonal Antibody (Nivolumab, BMS-936558) Administered in Combination With Anti-LAG3 Monoclonal Antibody (Relatlimab, BMS-986016) in Patients With Metastatic Melanoma Naïve to Prior Immunotherapy in the Metastatic Setting
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 2
- 主要终点
- Change in LAG3 Expression
研究概览
简要总结
The main goal of this study is to evaluate the antitumor activity of relatlimab and nivolumab in combination in subjects with unresectable or metastatic melanoma who have not received prior treatment with immunotherapy.
详细描述
This study will evaluate the antitumor activity of anti-LAG3 monoclonal antibody relatlimab and the anti-PD1 monoclonal antibody nivolumab in combination in subjects with unresectable or metastatic melanoma who have not received prior treatment with immunotherapy. The trial is designed with a lead-in phase of 2 cycles (4 week) treatment of either nivolumab, relatlimab, or the combination of nivolumab/relatlimab, followed by a combination phase of nivolumab/relatlimab treatment in all subjects. This lead-in design with accompanying tumor biopsies and peripheral blood analyses will enable mechanistic analyses of the effect of LAG3 and PD1 blockade alone and in combination to enhance understanding of mechanisms of response and resistance. Duration of response, progression free survival, and safety will be assessed as secondary objectives.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 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 or women 18 years of age or older meeting AJCC 8th edition criteria for unresectable stage IIIB, stage IIIC, stage IIID, or stage IV melanoma who have not received treatment with immunotherapy in the metastatic setting
排除标准
- •Known or suspected CNS metastases, with the following exceptions:
- •Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following radiation and/or surgical treatment at the time of consent. Subjects must be off steroids for at least 2 weeks prior to randomization.
- •Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging.
- •Active autoimmune disease requiring treatment, with the exception of type 1 diabetes mellitus, vitiligo, resolved childhood asthma/atopy, controlled hyper/hypothyroidism, hypoadrenalism or hypopituitarism.
- •Prior systemic treatment in the metastatic setting, including anti-PD1, anti-PDL1, anti-PDL2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways; or chemotherapy.
- •Prior adjuvant treatment with anti-PD1, anti-PDL1, and/or anti-LAG3 antibody. Note that prior adjuvant treatment with targeted therapy (e.g. BRAF/MEK inhibition), anti-CTLA4, or treatment not otherwise specified above would be permitted.
- •Ocular melanoma
研究组 & 干预措施
Nivolumab
Cycle 1: Nivolumab (BMS-936558) is supplied as a sterile 10-mg/mL formulation to be administered as an IV infusion at 480 mg IV for the first 4 weeks.
Cycle 2+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV once every 4 weeks.
干预措施: Nivolumab (Drug)
Relatlimab + Nivolumab
Cycle 1+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV for the first 4 weeks (Cycle 1), then once every 4 weeks afterwards.
干预措施: Relatlimab + Nivolumab (Drug)
Relatlimab
Cycle 1: Relatlimab (BMS-986016) is supplied as a sterile 10mg/mL formulation to be administered as an intravenous (IV) infusion at 160 mg IV for the first 4 weeks (cycle 1).
Cycle 2+: Combination therapy will be administered by sequential infusion. Nivolumab administered at 480 mg IV followed by infusion of relatlimab at 160 mg IV once every 4 weeks.
干预措施: Relatlimab (Drug)
结局指标
主要结局
Change in LAG3 Expression
时间窗: At baseline and at 4 weeks
LAG3 (cell surface molecule expressed on activated T cells) expression is either positive (present) or not detectable if absent after completion of lead-in phase.
Change in PD1 expression
时间窗: At baseline and at 4 weeks
PD1 (programmed cell death protein 1) expression is either positive (present) or not detectable if absent after completion of lead-in phase
Change in Tumor Size
时间窗: At baseline and at 4 weeks
Percentage change in tumor size assessed per Response Evaluation Criteria in Solid Tumors. Per RECIST 1.1, Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of: * 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix II on imaging guidance). * 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable). * 20 mm by chest X-ray.
Overall Response Rate (ORR)
时间窗: Beginning at 12 weeks post initial treatment, up to 4 years
Percent of participants experiencing Complete Response (CR) + Number of participants experiencing Partial Response (PR)/total patients assessed. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
LAG3 Gene Expression From scRNAseq
时间窗: At Baseline
Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq
LAG3 Gene Expression From scRNAseq
时间窗: At Week 4
Percent Lymphocyte-activation gene 3 (LAG3) level (cell surface molecule expressed on activated T cells) expression from scRNAseq
PD1 Expression
时间窗: At baseline (Week 0)
Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase.
PD1 Expression
时间窗: At Week 4
Percent PD1 (programmed cell death protein 1) expression after completion of lead-in phase.
Overall Response Rate (ORR) - ITT (Intent-to-treat) Population
时间窗: Beginning at 12 weeks post initial treatment, up to 4 years
Percent of participants experiencing Complete Response (CR) + Number of participants experiencing Partial Response (PR)/total patients assessed. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
次要结局
- Duration of Response(12 weeks post initial treatment, up to 4 years)
- Clinical Benefit Rate(12 weeks post initial treatment, up to 4 years)
- Progression-free Survival (PFS)(Up to 4 years)
- Overall Survival (OS)(Up to 4 years)
- LAG3 Expression(At week 16 (2 weeks post combination treatment (3 cycles)))
- PD-1 Expression(At week 16 (12 weeks post combination treatment (3 cycles)))
- Change in CD4+ tumor infiltrating lymphocytes(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Change in CD8+ tumor infiltrating lymphocytes(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Change in granzyme B serum levels(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Change in cell effector/memory status(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Change in activation and maturation of dendritic cells(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Change in T cell count(At the time of disease progression - up to 4 years)
- Change in soluble LAG3 levels(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Soluble LAG3 levels(At the time of disease progression - up to 4 years)
- Change in Regulatory T cell (Treg) marker level(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- Regulatory T cell (Treg) marker levels(At the time of disease progression - up to 4 years)
- Secondary Outcome: Clinical Benefit Rate(12 weeks post initial treatment, up to 4 years)
- Clinical Benefit Rate - ITT (Intent-to-treat) Population(12 weeks post initial treatment, up to 4 years)
- Progression-free Survival (PFS) by Lead-in Arm(Up to 4 years)
- CD8+ Tumor Infiltrating Lymphocytes(At Baseline)
- CD8+ Tumor Infiltrating Lymphocytes(At Week 4)
- CD4+ Tumor Infiltrating Lymphocytes(At Week 4)
- CD4+ Tumor Infiltrating Lymphocytes(At Baseline)
- LAG3 Levels - PBMC(At Baseline)
- LAG3 Levels - PBMC(At Week 4)
- LAG3 Levels - TIL(At Baseline)
- LAG3 Levels - PBMC(At Week 16)
- LAG3 Levels - TIL(At Week 4)
- PD-1 Expression in PBMC(At Baseline)
- PD-1 Expression in PBMC(At Week 4)
- PD-1 Expression in PBMC(At Week 16)
- PD-1 Expression in TIL(At Baseline)
- PD-1 Expression in TIL(At Week 4)
- Cell Effector/Memory Status - TIL(At Baseline)
- Cell Effector/Memory Status - TIL(At Week 4)
- Cell Effector/Memory Status - PBMCs(At Baseline)
- Cell Effector/Memory Status - PBMC(At Week 4)
- Cell Effector/Memory Status - PBMC(At Week 16)
- Regulatory T Cell (Treg) Marker Levels - PMBCs(At Baseline)
- Regulatory T Cell (Treg) Marker Levels - PMBCs(At Week 4)
- Regulatory T Cell (Treg) Marker Levels - PMBCs(At Week 16)
- Regulatory T Cell (Treg) Marker Levels - TIL(At Baseline)
- Regulatory T Cell (Treg) Marker Levels - TIL(At Week 4)
- Activation and Maturation of Dendritic Cells - PBMC(At Baseline)
- Activation and Maturation of Dendritic Cells - PBMC(At Week 4)
- Activation and Maturation of Dendritic Cells - PBMC(At Week 16)
- Activation and Maturation of Dendritic Cells - TIL(At Baseline)
- Activation and Maturation of Dendritic Cells - TIL(At Week 4)
- Soluble LAG3 Levels - PBMC(At the time of disease progression - up to 4 years)
- Soluble LAG3 Levels - TIL(At the time of disease progression - up to 4 years)
- Granzyme B Serum Levels(At 2 weeks prior first study treatment, at 4 weeks, at 12 weeks)
- T Cell Count(At 4 weeks)
- T Cell Count(At 12 weeks)
- T Cell Count(At the time of disease progression - up to 4 years)
研究者
John Kirkwood
Usher Professor of Medicine
University of Pittsburgh