Phase 1/2 Study of Anti-PD-L1 in Combination With Chemo(Radio)Therapy for Oesophageal Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 73
- 试验地点
- 1
- 主要终点
- Number of Subjects Reporting Treatment Emergent Adverse Events (TEAEs)
研究概览
简要总结
This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (MEDI4736) in combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC) and with neoadjuvant chemo(radio)therapy before surgery in operable OC. The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts. The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B, C, C-FLOT, D/D2).
详细描述
This is an open-label, Phase 1/2 study to evaluate the safety of immunotherapy in combination with chemo (radio) therapy with the following cohorts:
- Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC).
- Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in operable OC.
- Cohort C-FLOT: Neoadjuvant 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy before surgery in operable OC.
- Cohort D/D2: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before surgery in operable OC.
The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts for all cohorts except Cohort D.
The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B including the higher dose tremelimumab cohort from Cohort A2, C, C-FLOT, and D/D2).
Phase 1 will evaluate the safety of durvalumab alone (Cohort A1) administered before chemotherapy (oxaliplatin + capecitabine) in subjects with metastatic or locally advanced OC. After completion of Cohort A1, Phase 2 in Cohorts C, C-FLOT, and D/D2 will begin, and a safety review will determine whether to explore the tremelimumab + durvalumab combination (Cohort A2).
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
- •Histological diagnosis of oesophageal or gastrooesophageal cancer and have not received prior chemotherapy.
- •Cohorts A and B - metastatic/locally advanced cancer
- •Cohorts C/C-FLOT and D/D2 - deemed suitable for surgery with curative intent
- •Anticipated lifespan greater than 4 months.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •At the time of day 1 of the study, subjects with brain metastases must be asymptomatic for at least 4 weeks and:
- •at least 8 weeks without tumour progression after any whole brain radiotherapy
- •at least 4 weeks since craniotomy and resection or stereotactic radiosurgery
- •at least 3 weeks without new brain metastases as evidenced by MRI/CT
- •Adequate normal organ and marrow function. Laboratory parameters for vital functions should be in the normal range. Laboratory abnormalities that are not clinically significant are generally permitted.
- •Written informed consent obtained from the subject; subject been informed of other treatment options, and able to comply with study requirements.
- •Age 18 years or older.
- •Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Previous enrollment in the present study.
- •Participation in another clinical study with an investigational product during the last 4 weeks.
- •Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia's Correction.
- •Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
- •History of allogeneic organ transplant.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C, known immunodeficiency or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
- •Known history of previous clinical diagnosis of tuberculosis.
- •History of pneumonitis or interstitial lung disease.
排除标准
- 未提供
研究组 & 干预措施
Cohort A1: Metastatic/locally advanced OC, Durva + Chemotherapy (Chemo)
Durvalumab (750 mg IV every two weeks [Q2W]) was to be given for up to 11 doses. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Durvalumab (Drug)
Cohort A1: Metastatic/locally advanced OC, Durva + Chemotherapy (Chemo)
Durvalumab (750 mg IV every two weeks [Q2W]) was to be given for up to 11 doses. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Oxaliplatin (Drug)
Cohort A1: Metastatic/locally advanced OC, Durva + Chemotherapy (Chemo)
Durvalumab (750 mg IV every two weeks [Q2W]) was to be given for up to 11 doses. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Capecitabine (Drug)
Cohort A2: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Durvalumab (Drug)
Cohort A2: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Tremelimumab (Drug)
Cohort A2: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Oxaliplatin (Drug)
Cohort A2: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Capecitabine (Drug)
Cohort B: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Durvalumab (Drug)
Cohort B: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Tremelimumab (Drug)
Cohort B: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Oxaliplatin (Drug)
Cohort B: Metastatic/locally advanced OC, Durva, Treme + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses.
干预措施: Capecitabine (Drug)
Cohort C: Operable OC; Durva + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 5 doses. Two cycles of neoadjuvant oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy were to be administered before surgery. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Durvalumab (Drug)
Cohort C: Operable OC; Durva + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 5 doses. Two cycles of neoadjuvant oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy were to be administered before surgery. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Oxaliplatin (Drug)
Cohort C: Operable OC; Durva + Chemo
Durvalumab (750 mg IV Q2W) was to be given for up to 5 doses. Two cycles of neoadjuvant oxaliplatin (130 mg/m^2 IV)/capecitabine (1250 mg/m^2/day given orally) chemotherapy were to be administered before surgery. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Capecitabine (Drug)
Cohort C-FLOT: Operable OC, Durva + FLOT Chemotherapy
Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m^2 24-hr IV), leucovorin (200 mg/m^2 IV), oxaliplatin (85 mg/m^2 IV), and docetaxel (50 mg/m^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Durvalumab (Drug)
Cohort C-FLOT: Operable OC, Durva + FLOT Chemotherapy
Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m^2 24-hr IV), leucovorin (200 mg/m^2 IV), oxaliplatin (85 mg/m^2 IV), and docetaxel (50 mg/m^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Oxaliplatin (Drug)
Cohort C-FLOT: Operable OC, Durva + FLOT Chemotherapy
Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m^2 24-hr IV), leucovorin (200 mg/m^2 IV), oxaliplatin (85 mg/m^2 IV), and docetaxel (50 mg/m^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: 5-fluorouracil (5-FU) (Drug)
Cohort C-FLOT: Operable OC, Durva + FLOT Chemotherapy
Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m^2 24-hr IV), leucovorin (200 mg/m^2 IV), oxaliplatin (85 mg/m^2 IV), and docetaxel (50 mg/m^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Leucovorin (Drug)
Cohort C-FLOT: Operable OC, Durva + FLOT Chemotherapy
Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m^2 24-hr IV), leucovorin (200 mg/m^2 IV), oxaliplatin (85 mg/m^2 IV), and docetaxel (50 mg/m^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Docetaxel (Drug)
Cohort D/D2: Operable OC, Durva + Neoadjuvant Chemo(radio)therapy
Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation.
In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Durvalumab (Drug)
Cohort D/D2: Operable OC, Durva + Neoadjuvant Chemo(radio)therapy
Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation.
In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Radiotherapy (Radiation)
Cohort D/D2: Operable OC, Durva + Neoadjuvant Chemo(radio)therapy
Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation.
In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Paclitaxel (Drug)
Cohort D/D2: Operable OC, Durva + Neoadjuvant Chemo(radio)therapy
Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation.
In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.
干预措施: Carboplatin (Drug)
结局指标
主要结局
Number of Subjects Reporting Treatment Emergent Adverse Events (TEAEs)
时间窗: up to 1 year
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) were reported based on clinical laboratory tests, vital signs, physical examinations, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 110 days after the last dose of study treatment. Treatment-emergent AEs were those that occurred or worsened after administration of the first dose of study treatment. In Cohorts A1, A2 and B, 12, 5 and 7 subjects, respectively, were monitored for dose limiting toxicities (DLTs) during the first 10 weeks of treatment (DLT evaluation period).
Number of Subjects With Best Overall Tumor Response by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)
时间窗: up to 1 year
Tumor responses were evaluated using appropriate imaging and categorized according to irRECIST at Screening (up to 28 days before the first dose of study treatment), and in Cycles 1, 3, 5 and 6 in Cohorts A1, A2 and B. In the other cohorts, tumor response was assessed at baseline, post-surgery and 14 days after the last dose. In Cohorts C-FLOT and D, an additional assessment was done prior to surgery and in Cohorts C and D, an additional assessment was done in Cycle 3. Per irRECIST, measurable lesions are categorized as follows: Immune-related Complete Response (irCR): Complete disappearance of all target lesions; Immune-related Partial Response (irPR): ≥ 30% decrease from baseline in the Total Measurable Tumor Burden (TMTB); Immune-related Progressive Disease (irPD): ≥ 20% increase from nadir in TMTB; Immune-related Stable Disease (irSD): not meeting above criteria; irNon-CR/Non-PD: irNon-CR/Non-PD is preferred over SD when no lesions can be measured.
次要结局
- Number of Subjects With Metastatic/Locally Advanced Oesophageal Cancer (OC) Who Had a Response at Cycle 6 by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)(Up to 23 weeks)
- Median Progression-free Survival (PFS) by the Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) as Estimated Using the Kaplan-Meier Method(Up to 3 years)
- Median Overall Survival (OS) as Estimated Using the Kaplan-Meier Method(Up to 3 years)
- One Year Survival Rate in Subjects With Operable OC(up to 12 months)
- Overall Response Prior to Surgery in Operable OC (Cohorts C, C-FLOT and D/D2) Using Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST)(Up to 7months)