Phase I/II Trial of Avelumab in Combination With Chemoradiation in the Treatment of Stage II/III Resectable Esophageal and Gastroesophageal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 22
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose Limiting Toxicity
研究概览
简要总结
This is a 2 part Phase I/II clinical trial evaluating the safety, tolerability and efficacy of avelumab in combination with chemoradiation in patients with resectable esophageal and gastroesophageal cancer.
Part 1: This is the run-in phase of the trial. This portion will determine the safety and tolerability of avelumab in combination with chemoradiotherapy in 6 patients. The proposed combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.
Part 2: This is a Phase 2 portion of the trial, which will evaluate the efficacy of the proposed treatment regimen in patients with stage II/III resectable esophageal and gastroesophageal cancer
详细描述
Background:
Neoadjuvant chemoradiation is part of the standard of care for patients with stage II and III resectable esophageal and gastroesophageal cancer. This approach is based on the results of a large randomized clinical trial (CROSS) that demonstrated superior survival in patients receiving neoadjuvant chemoradiotherapy followed by surgical resection compared to patients treated with surgery alone. Pathological complete response at the time of resection is strongly linked to better survival. However, with current strategies pathological complete response is achieved only in a minority (29%) of patients. Remaining patients, especially those with positive lymph nodes at the time of the resection, are at significant risk for recurrences. Five-year survival rate for these patients is only 37%, and overall survival is as low as 9 months for those with persistent lymph node disease. Among patients who develop recurrent disease, most present with distant metastases outside of the radiation field. This is not surprising since the accepted treatment paradigm for this disease does not target possible disseminated microscopic systemic disease. Hence, novel strategies are needed to improve outcomes of these patients. We propose conducting a phase I/II clinical trial evaluating a role of immune checkpoint inhibitor in combination with chemoradiotherapy and post-operatively in the management of resectable esophageal cancer.
Study Rationale:
- A number of preclinical and clinical studies demonstrated synergism between radiation and immunotherapy, suggesting that combining these approaches can enhance anti-tumor activity and increase treatment efficacy.
- Immune checkpoint inhibitors have demonstrated promising activity in a subset of patients with metastatic esophageal and gastric cancers. Moving these agents into neoadjuvant setting may increase the cure rate of this disease compared to the standard approach.
- Current neoadjuvant therapy does not target any potential microscopic disease outside of the radiation field since chemotherapy serves primarily as a radiation sensitizer. Immunotherapy treatment will target both local and systemic disease.
Hypothesis:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Patients with histologically confirmed, potentially curable squamous-cell carcinoma, adenocarcinoma, or large-cell undifferentiated carcinoma of the esophagus and gastroesophagus (Siewert type 1-3)
- •Locoregional disease with clinical stage of T1N1 or T2-3N0-2
- •No clinical evidence of metastatic spread. Staging should include endoscopic ultrasound and positron emission tomography/computed tomography (PET/CT) as recommended by National Comprehensive Cancer Network (NCCN) guidelines. PET/CT should be performed within 3 weeks of signing informed consent
- •Age 18 years or older
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Subjects must be deemed to be potential surgical candidates by an evaluating surgeon
- •Adequate organ function:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- •Hemoglobin ≥ 9 g/dL (transfusions allowed)
- •Platelets ≥ 100 x 109/L
- •Aspartate transaminase/Alanine transaminase (AST/ALT) ≤ 2.5 x ULN
- •Total serum bilirubin of ≤1.5 x institutional upper limit of normal (ULN)
- •Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula
- •Female patients of childbearing potential must have a negative pregnancy test (urine or serum) within 21 days prior to the start of the study drug treatment and must agree to use adequate birth control if conception is possible during the study and up to 30 days after the completion of adjuvant therapy
- •Male patients must agree to use adequate birth control during the study and up to 30 days after the last avelumab dose
- •Women who are nursing must discontinue breast-feeding prior to the enrollment in the trial
- •Patient must be able and willing to comply with study procedures as per protocol
- •Patient able to understand and willing to sign and date the written voluntary informed consent form (ICF) at screening visit prior to any protocol-specific procedures
排除标准
- •Prior history of radiation to the mediastinum
- •Diagnosis of cervical esophageal carcinoma
- •Other active malignancy within the last 3 years (except for non-melanoma skin cancer, a non-invasive/in situ cancer, or indolent non metastatic Gleason 6 prostate cancer)
- •Subjects with an active or known autoimmune disease. Subjects with type I diabetes mellitus, hypo- or hyperthyroidism only requiring hormone replacement/suppression, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic immunosuppressive treatment are eligible
- •Current use of immunosuppressive medication, except for the following:
- •intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection)
- •systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent
- •Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
- •Active infection requiring systemic therapy at the time of study treatment initiation
- •Prior organ transplantation including allogenic stem-cell transplantation
- •Known history of testing positive for HIV or known immunodeficiency syndrome
- •Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)
- •Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
- •Major surgery within prior 4 weeks of treatment initiation (the surgical incision should be fully healed prior to all neoadjuvant treatment initiation)
- •Any prior anticancer therapy for esophageal cancer
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to carboplatin, paclitaxel or avelumab, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade ≥ 3)
- •Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication. Patients with stable rate-controlled atrial fibrillation will be allowed to participate
- •Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
- •Psychological, familial, or sociological condition potentially hampering compliance with the study protocol and follow-up schedule
研究组 & 干预措施
Run-In Phase
6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) [intravenous infusion on days 1, 8, 15, 22, & 29] while undergoing radiation therapy [23 fractions, M-F, estimated completion day 35].
Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively.
Trial enrollment will resume after at least 5 patients do not have a dose-limiting toxicity (DLT) during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment.
干预措施: Avelumab combined with Chemoradiation (Combination Product)
Run-In Phase
6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) [intravenous infusion on days 1, 8, 15, 22, & 29] while undergoing radiation therapy [23 fractions, M-F, estimated completion day 35].
Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively.
Trial enrollment will resume after at least 5 patients do not have a dose-limiting toxicity (DLT) during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment.
干预措施: Carboplatin (Drug)
Run-In Phase
6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) [intravenous infusion on days 1, 8, 15, 22, & 29] while undergoing radiation therapy [23 fractions, M-F, estimated completion day 35].
Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively.
Trial enrollment will resume after at least 5 patients do not have a dose-limiting toxicity (DLT) during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment.
干预措施: Paclitaxel (Drug)
Run-In Phase
6 patients enrolled will receive weekly carboplatin (AUC2) and paclitaxel (50 mg/m2) [intravenous infusion on days 1, 8, 15, 22, & 29] while undergoing radiation therapy [23 fractions, M-F, estimated completion day 35].
Avelumab combined with Chemoradiation - Avelumab (10 mg/kg IV) every 2 weeks starting on the day of the last chemotherapy infusion (day 29). A total of 3 doses administered during the pre-operative period and an additional 6 doses of avelumab post-operatively.
Trial enrollment will resume after at least 5 patients do not have a dose-limiting toxicity (DLT) during the DLT evaluation period or until all 6 patients are seen for post-operative evaluation. If 2 or more patients experience dose limiting toxicities associated with the proposed treatments, further accrual of the subjects will be halted and trial will be suspended. Trial may be reopened in the future with appropriate schedule and dose modifications of the proposed treatment.
干预措施: Radiation (Radiation)
Expansion Cohort
Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation & Avelumab combined with Chemoradiation).
干预措施: Avelumab combined with Chemoradiation (Combination Product)
Expansion Cohort
Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation & Avelumab combined with Chemoradiation).
干预措施: Carboplatin (Drug)
Expansion Cohort
Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation & Avelumab combined with Chemoradiation).
干预措施: Paclitaxel (Drug)
Expansion Cohort
Following a determination of safe and tolerable treatment outcome of the Run-In Phase, Part 2 of the trial will enroll 18 additional patients to evaluate activity of the proposed treatment and to obtain further safety information (carboplatin, paclitaxel, radiation & Avelumab combined with Chemoradiation).
干预措施: Radiation (Radiation)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicity
时间窗: Up to 4 weeks post-resection (up to approximately 4 months on study) of all Run-In Phase participants
A total number of 6 subjects will be enrolled during the run-in phase of the trial. A sample size of 6 is sufficient to estimate the true dose limiting toxicity rate of the proposed avelumab/chemoradiation therapy with adequate accuracy.The proposed treatment combination will be considered as safe if dose limiting toxicities are observed in at most 1 patient.
Number of Participants With Pathological Complete Response
时间窗: Post-resection (80-100 days) pathology review for all participants (up to approximately 4 months on study)
Pathologic compete response (pCR) is defined as an absence of any viable tumor at microscopic examination of the primary tumor and any lymph nodes sampled after surgery following neoadjuvant therapy. Participants with invalid/missing pCR assessments will be defined as non-responders. The number and frequency of patients with a pCR will be summarized in tabular format.
次要结局
- Disease Free Survival(Up to 4 years post-resection for all participants)
- Number of Participants With Treatment Related Adverse Events Greater Than or Equal to Grade 3(Up to 30 days post-avelumab of all (up to 4 months on study))
- Number of Participants With Unexpected Surgical Complications(Following resection (80 -100 days) for all participants (up to approximately 5 months on study))
- Rate of R0 Resection(Following pathology review post-resection (80 -100 days) for all participants (up to approximately 4 months on study))
- Estimated 1-year Recurrence Free Survival(up to 1 year)
- Number of Participants Who Did or Did Not Complete Planned Treatment(Up to 30 days post-avelumab of all participants (up to 4 months on study))