A Phase 2 Trial of Neoadjuvant Chemoradiation With Pembrolizumab Followed by Pembrolizumab With Lenvatinib in Esophageal/Gastroesophageal Junction Squamous Cell and Adenocarcinomas
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Pathological Complete Response (CR)
研究概览
简要总结
This phase II trial studies the effect of chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery in treating patients with esophageal or esophageal/gastroesophageal junction cancer that has not spread to other places in the body (non-metastatic). Pembrolizumab is an immunotherapy drug that works by harnessing the immune system to attack cancer. Lenvatinib is an anti-cancer drug that works by stopping or slowing down the growth of cancer cells. Chemotherapy drugs, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving chemoradiation and pembrolizumab followed by pembrolizumab and lenvatinib before surgery may kill more tumor cells.
详细描述
PRIMARY OBJECTIVE:
I. To evaluate pathologic complete response rate (path CR) and complete clinical response rate (clinical CR) at 14 weeks after starting chemoradiotherapy.
SECONDARY OBJECTIVES:
I. To assess safety and tolerability of pembrolizumab and lenvatinib in this patient population.
II. To establish that pembrolizumab + lenvatinib will increase immune response via increased expression of the 18 gene pro-immune response signature measured using the Nanostring platform on tumor tissue biopsies.
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
- All
- 接受健康志愿者
- 否
入选标准
- •Documented informed consent of the participant and/or legally authorized representative
- •Agreement to allow the use of archival tissue from diagnostic tumor biopsies
- •If unavailable, exceptions may be granted only with study principal investigator (PI) approval
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) =< 1
- •Non-metastatic cancer of the esophagus OR esophagus and gastroesophageal junction (GEJ; tumor extending =< 2 cm into the stomach)
- •Confirmed stage I (T1N1 only)-IVA diagnosis of one of the following:
- •Squamous cell; OR
- •Adenocarcinoma; OR
- •Mixed adenosquamous carcinoma
- •Deemed appropriate for neoadjuvant chemoradiation by the multidisciplinary team (surgeon, medical oncologist, and radiation oncologist)
- •Chemotherapy defined as weekly carboplatin/paclitaxel; AND
- •Radiation defined as external beam radiotherapy defined as: 50.4 Gy as per institutional and national treatment guidelines
- •Deemed appropriate for esophagectomy or repeat endoscopic biopsies if non-operative management is pursued
- •Absolute neutrophil count (ANC) >= 1500/mm^3 (performed within 14 days prior to day 1 of study participation/ 1st endoscopic biopsy unless otherwise stated)
- •Platelets >= 100,000/mm^3 (performed within 14 days prior to day 1 of study participation/ 1st endoscopic biopsy unless otherwise stated)
- •Serum total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN if total bilirubin levels > 1.5 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •Aspartate aminotransferase (AST) =< 2 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •Alanine aminotransferase (ALT) =< 2 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •Creatinine =< 1.5 x ULN OR for patients with creatinine > 1.5 x ULN creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •Female of childbearing potential only: Negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (performed within 14 days prior to day 1 of study participation/1st endoscopic biopsy unless otherwise stated)
- •Agreement by women of childbearing potential (WOCBP) and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 120 days after the last dose of protocol therapy
- •Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)
排除标准
- •Immune checkpoint inhibitor(s) (e.g. anti-PD-1, anti-CTLA4)
- •Multi-tyrosine kinase inhibitor(s) (e.g. lenvatinib)
- •Radiotherapy within 21 days prior to day 1 of study participation
- •Investigational agent within 21 days prior to day 1 of study participation
- •Live-virus vaccination within 30 days prior to day 1 of study participation
- •Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 21 days of study participation
- •Chronic systemic steroid therapy or on any other form of immunosuppressive medication
- •Coumarin-based anticoagulants
- •Unstable or untreated brain/leptomeningeal metastasis
- •Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
- •Severe hypersensitivity reaction to treatment with another antibody and/or hypersensitivity to lenvatinib and/or any of its excipients
- •Active autoimmune disease that has required systemic treatment in the past 2 years
- •Known history of human immunodeficiency virus (HIV), hepatitis B or hepatitis C (with confirmation of negative hepatitis B surface antigen [HBSAg], hepatitis B virus [HBV] polymerase chain reaction [PCR], and hepatitis C virus [HCV] PCR)
- •History of pneumonitis (non-infectious) that required steroids or current pneumonitis
- •Known history of active tuberculosis
- •Diagnosed with or treated for cancer within the previous two years, other than histologies listed in inclusion criteria or non-melanoma carcinoma of the skin
- •Female only: Pregnant or breastfeeding
- •Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
- •Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
研究组 & 干预措施
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: Endoscopic Biopsy (Procedure)
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: External Beam Radiation Therapy (Radiation)
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: Resection (Procedure)
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: Pembrolizumab (Biological)
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: Lenvatinib Mesylate (Drug)
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: Carboplatin (Drug)
Treatment (chemoradiation, pembrolizumab, lenvatinib)
CHEMORADIATION PHASE: Patients receive carboplatin IV and paclitaxel IV QW for up to 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also undergo EBRT over 6 weeks and receive pembrolizumab IV over 30 minutes on day 1 of radiation therapy in the absence of disease progression or unacceptable toxicity.
WINDOW PERIOD: Patients receive pembrolizumab IV over 30 minutes on day 1 of week 3 and lenvatinib mesylate PO QD at weeks 3-6 in the absence of disease progression or unacceptable toxicity.
SURGERY/SURVEILLANCE: Patients without complete response undergo standard of care surgical resection. Patients with complete response/pursue non-operative management undergo surveillance via periodic endoscopic biopsy.
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Pathological Complete Response (CR)
时间窗: At 14 weeks after starting protocol chemoradiotherapy
Defined as no residual cancer cells, including lymph nodes under pathologic examination of the surgically resected specimen and/or a Tumor Regression Score of 0 by the College of American Pathologist (CAP) Cancer Protocol for Esophageal Carcinoma. Pathological CR rate will be estimated by the proportion of patients achieving pathological CR, along with the 95% exact binomial confidence interval.
Clinical Complete Response (CR)
时间窗: At 14 weeks after starting protocol chemoradiotherapy
Defined as no radiographic evidence of disease on positron emission tomography /computed tomography or CT imaging. Clinical CR rate will be estimated by the proportion of patients achieving clinical CR, along with the 95% exact binomial confidence interval.
次要结局
- Number of Participants With Immune-mediated Tumor Cytotoxicity(Up to 3 years)
- Number of Participants With Adverse Events(Adverse events were assessed from the time of initial treatment until 90 days post-last dose of protocol therapy, an average of 49 days.)
- Disease-free Survival (DFS)(Up to 3 years. From initiation of treatment to the first occurrence of cancer relapse or death from any cause.)
- Overall Survival (OS)(Up to 3 years. From start of treatment to time of death.)