A Phase Ib/II Trial Evaluating the Efficacy of MK-3475 and Trastuzumab in Patients With Trastuzumab-resistant, HER2-positive Metastatic Breast Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 58
- 试验地点
- 11
- 主要终点
- Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab
研究概览
简要总结
Panacea is a phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab in patients with trastuzumab-resistant, HER2- positive metastatic breast cancers
详细描述
A significant amount of preclinical and correlative clinical data suggest that HER2-positive breast cancer could be amenable to immune¬therapeutic approaches. The presence of HER2-overexpression in breast cancers is associated with higher levels of proliferation, high histologic grade and higher levels of tumor infiltrating lymphocytes (TILs) compared with HER2-negative tumors. The investigators therefore hypothesize that for HER2-positive tumors, avoidance of destruction by the host immune system must be an important mechanism contributing to tumor growth and progression.
The term "immune evasion" refers to the ability of the tumor to suppress and change host anti-tumor immune reactions. The programmed cell death 1 (PD-1) pathway represents a major immune control switch which may be engaged by tumor cells to overcome active T-cell immune surveillance. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in various tumors. High expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in various other solid tumor types. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in patients with malignant melanoma. These observations suggest that the PD-1/PD-L1 pathway plays a critical role in the tumor immune evasion and could be considered an attractive target for therapeutic intervention in several solid organ types.
MK-3475 (previously known as SCH 900475) is a potent and highly-selective humanized mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human donors, cancer patients, and primatesMK-3475 also modulates the level of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines.
The investigators therefore propose to evaluate if the addition of an immunotherapy can reverse trastuzumab resistance and improve clinical outcomes in HER2-positive disease. In this study the investigators will determine if a monoclonal antibody targeted against PD-1, a T cell negative regulator, can reverse trastuzumab resistance in patients previously progressing on trastuzumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
MK-3475 with trastuzumab (single arm)
Phase Ib: MK-3475 at dose of 2 mg/kg or 10 mg/kg (i.v.), or a fall-back dose of 1 mg/kg, together with trastuzumab 6mg/kg by (i.v.) once every 3 weeks.
Phase II: MK-3475 at a flat dose of 200mg (i.v.) together with trastuzumab 6mg/kg (i.v.) once every 3 weeks until progression, lack of tolerability, or 24 months of treatment.
A dose of 8mg/kg trastuzumab will be used in cycle 1 if prior treatment with trastuzumab was stopped more than 3 months before.
干预措施: MK-3475 (Drug)
结局指标
主要结局
Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab
时间窗: Within the first 21 days
Determination of dose-limiting toxicity (DLT) which is defined as an adverse event or abnormal laboratory value assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to disease or disease progression. Toxicities and lab values will be graded according to the NCI CTCAE (v4.0). 1. Any grade-3 or greater non-hematological adverse event lasting at least one week; 2. Any grade-4 hematological toxicity; or, 3. Any adverse event resulting in a delay starting cycle 2 of more than 14 days.
Objective Response Rate (ORR)
时间窗: Clinical and radiological tumor assessment will be performed by CT scan or MRI at baseline, at weeks 12, 18 and 24, then every 12 weeks until progression, or 24 weeks after stop of treatment if before progression.
Confirmed CR or PR as best overall response. At the time of each restaging, patients will be classified as achieving complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) criteria.
次要结局
- Duration of Response (DoR)(From date of first documentation of objective response until first documentation of progressive disease, up to 24 weeks after stop of treatment (=30 months))
- Time to Progression (TTP)(From the first trial treatment until first documentation of progressive disease up to 24 weeks after stop of treatment (=30 months))
- Progression-Free Survival (PFS)(From the date of first treatment dose until documented disease progression or death from any cause. whichever occur first, assessed up to 30 months)
- Disease Control Rate (DCR)(From the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer)
- Overall Survival (OS) at 12 Months(Time from start of trial treatment to death from any cause, assessed up to 30 months)