A Phase Ib/II Multicenter Study of Front Line Pembrolizumab and Valemetostat in PD-L1 Positive, HPV-Negative Recurrent/Metastatic Squamous Cell Carcinoma (SCC) of the Head and Neck: The PANTHERAS
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 入组人数
- 47
- 试验地点
- 1
- 主要终点
- Phase Ib: Safety of valemetostat in combination with pembrolizumab
研究概览
简要总结
Background:
Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. These cancers have different causes, with smoking/tobacco exposure and human papilloma virus infection being the most common. . When HNSCC occurs in people who are not infected with HPV, the cancers are more likely to return after treatment; when this happens, overall survival is only about 10 months, thus better treatments are needed.
Objective:
To test a combination treatment using 2 drugs (valemetostat and pembrolizumab) in people with HNSCC. Phase 1b of the study will determine a recommended dose of the 2 drugs and evaluate how safe the combination is.; this will include patients with HPV-positive and HPV-negative HNSCC, as well as squamous cell NSCLC that have progressed on anti-PD-1/anti-PD-L1 therapies.Phase II will determine how effective the combination is and will focus on patients with HPV-negative HNSCC.
Eligibility:
People aged 18 years and older with HPV-negative HNSCC, sinonasal carcinoma of the head and neck, or squamous non-small cell lung cancer (NSCLC).
Design:
Participants will be screened. They will have a physical exam. They will have blood and urine tests and tests of their heart function. They will have imaging scans. They may have a biopsy: A small sample of tissue will be removed from the tumor.
Treatment will be given in 21-day cycles.
Pembrolizumab is administered through a tube attached to a needle inserted into a vein in the arm. Participants will receive pembrolizumab on the first day of each cycle.
Valemetostat is a tablet taken by mouth. Participants will take the tablet once a day at home. They will record the date and time of each dose in a diary. They will also write down any adverse effects they experience.
Participants may remain in the study up to 2 years.
详细描述
Background:
- Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, with approximately 60,000 patients diagnosed annually in the United States.
- Only 14% of HNSCC patients have structural defects in the genes encoding for the human leukocyte antigens (HLA) class I components, while a higher percentage of these tumors show downregulation of HLA class I components by immunohistochemistry supports those epigenetic mechanisms may be involved in the deregulation of these genes.
- Valemetostat (DS-3201) is an enhancer of zeste homolog 1 and 2 (EZH1/2) dual inhibitor that is actively being investigated in phase I and II trials for hematologic malignancies and is approved for adult T-cell leukemia/lymphoma (ATL) indication in Japan.
- Patients with recurrent or metastatic (R/M) pembrolizumab-na(SqrRoot) ve human papillomavirus (HPV)-negative HNSCC have a low 6-month progression-free survival (PFS) (28%) with pembrolizumab monotherapy, thus novel interventions are needed to increase the efficacy of pembrolizumab.
Objectives:
Phase Ib:
- To determine the recommended phase II dose (RP2D) of valemetostat in combination with pembrolizumab.
- To evaluate the safety of valemetostat in combination with pembrolizumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 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
Arm 1
Pembrolizumab + de-escalating doses of valemetostat
干预措施: pembrolizumab (Drug)
Arm 1
Pembrolizumab + de-escalating doses of valemetostat
干预措施: valemetostat (Drug)
Arm 2
RP2D of valemetostat in combination with pembrolizumab
干预措施: pembrolizumab (Drug)
Arm 2
RP2D of valemetostat in combination with pembrolizumab
干预措施: valemetostat (Drug)
结局指标
主要结局
Phase Ib: Safety of valemetostat in combination with pembrolizumab
时间窗: Study start-30 days after last dose of study agents
Any toxicities that occur during timeframe.
Phase II: Disease control rate (DCR)
时间窗: Study start until progression or 2 years after treatment initiation
Best confirmed response in participants with PD-L1 positive (CPS \>=1), HPV-negative relapsing/metatstic HNSCC treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone, by CT scan and brain MRI (PR+CR+SD)
Phase Ib: Recommended phase II dose (RP2D) of valemetostat in combination with pembrolizumab
时间窗: 42 days
Number of dose limiting toxicities (DLTs) that occur within the DLT period will determine RP2D.
次要结局
- Pharmacokinetics of valemetostat in combination with pembrolizumab(Phase Ib: C1D1, C1D8, C1D15, and C2D1Phase II: C0D1, C1D1, C1D8, C1D15, and C2D1)
- Safety of the valemetostat and pembrolizumab combination (Phase II)(Treatment start until 30 days after last dose of study agents.)
- Progression free survival (PFS) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone(Phase Ib: Study start until progression or 2 years after treatment initiationPhase II: Study start until progression or 2 years after treatment initiation)
- Clinical benefit rate (CBR) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone(Phase 1b: Study start until progression or 2 years after treatment initiation.Phase II: Study start until progression or 2 years after treatment initiation.)
- Objective response rate (ORR) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone(Phase 1b: Treatment start until progression or 2 years after treatment initiation.Phase II: Treatment start until progression or 2 years after treatment initiation.)
- Overall survival (OS) in participants treated with valemetostat and pembrolizumab compared to historical controls with pembrolizumab alone(Study start until progression or 2 years after treatment initiation.)
- 6-month progression free survival (PFS) rate in participants treated with valemetostat and pembrolizumab compared to historical controls treated with pembrolizumab alone(Phase Ib: Study start until progression or 6 months after treatment initiationPhase II: Study start until progression or 6 months after tx initiation)