A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 23
- 试验地点
- 1
- 主要终点
- Number of Participants With Dose-Limiting Toxicities (DLT)
研究概览
简要总结
A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations (with chemotherapy or AZD5069) in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
详细描述
This is a Phase Ib and II open-label, multi-center study to evaluate the safety, tolerability, pharmacodynamics, and antitumor activity of MEDI4736 in combination with chemotherapy or AZD5069 in patients with pancreatic ductal adenocarcinoma (PDAC). This study will consist of 2 independent cohorts.
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 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior chemotherapy regimen or treatment-naïve patients
- •Eastern Cooperative Oncology Group 0 or 1
- •At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) scan and that is suitable for accurate repeated measurements
- •MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy cohort: treatment-naïve patients with metastatic PDAC who have received no previous systemic chemotherapy 5 MEDI4736 + Cohort: Patient should receive no more than 1 prior systemic chemotherapy regimen.
- •Life expectancy ≥ 12 weeks.
- •ECOG PS of 0 or 1
- •Adequate organ and bone marrow function
- •Ability to undergo during screening a tumor biopsy that is adequate for biomarker analysis.
排除标准
- •Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.
- •Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
- •Major surgical procedure within 21 days prior to the first dose of IP.
- •Patients weighing less than 30 kg
- •History of leptomeningeal carcinomatosis
- •Ascites requiring intervention
- •Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy
- •Current or prior use of immunosuppressive medication within 14 days of first dose
- •Brain metastases or spinal cord compression.
- •Medi4736+AZD5069 Cohort only: received any potent and moderate cytochrome CYP3A4 inhibitors, potent and moderate CYP3A4 inducers, P-gp substrates, BCRP substrates, sensitive CYP2B6 substrates, warfarin and coumarin derivatives, or herbal supplements within 14 days of the first dose of study treatment
- •Uncontrolled intercurrent illness
- •Other malignancy within 5 years except for noninvasive malignancies
- •Mean QT interval ≥470 ms
- •Active infection
- •Receipt of live attenuated vaccine within 30 days prior to the first dose of IP
- •Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of birth control
- •Prior exposure to immune-mediated therapy
- •Known allergy or hypersensitivity to IP formulations or to other human monoclonal antibodies
研究组 & 干预措施
MEDI4736 +nab-paclitaxel + gemcitabine
MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion
干预措施: MEDI4736 in combination with nab-paclitaxel and gemcitabine (Drug)
MEDI4736+AZD5069
MEDI4736 via IV infusion and oral AZD5069
干预措施: MEDI4736 in combination with AZD5069 (Drug)
结局指标
主要结局
Number of Participants With Dose-Limiting Toxicities (DLT)
时间窗: Cohort 1: From time of first dose of MEDI4736 on Day 1 up to Day 28 of Cycle 1 and Cohort 2: From time of first dose of AZD5069 and MEDI4736 on Day 1 up to Day 28 of Cycle 1 or until a participant experiences a DLT, whichever occurs first.
DLT period was defined as first treatment cycle for Cohort 1, and first dose of AZD5069 and MEDI4736 to end of Cycle 1 or until a participant experienced a DLT, whichever occurs first for Cohort 2. A DLT was defined as any of below listed laboratory abnormalities or adverse events (AE) related to MEDI4736 collected during DLT period. * Liver transaminase elevation \>= 5× but \<= 8× upper limit of normal (ULN) that doesn't resolve to Grade 2 within 5 days * Transaminase elevation \> 8× ULN or total bilirubin \> 5× ULN * Any Grade 4 immune-related AE (irAE) not attributed to local tumor response, Grade \>=3 colitis, Grade \>=2 pneumonitis that doesn't resolve to \<= Grade 1 within 7 days, Grade 3 irAE, that doesn't resolve to Grade \<=1 or baseline status within 14 days * Any Grade \>=3 non-irAE toxicity that doesn't resolve to Grade \<=1 or baseline status within 14 days A DLT was defined as any Grade 3 or worse AE related to AZD5069 that occurs from first dose of AZD5069 up to end of DLT period.
Objective Response Rate (ORR) in Cohort 2
时间窗: RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
ORR is defined as the percentage of participants with a confirmed overall response of complete response (CR) or partial response (PR). A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit and not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. CR is defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for PD were not met. ORR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
Number of Participants With AEs
时间窗: From first dose of study treatment administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.
An AE is the development of an undesirable medical condition or deterioration of a pre-existing medical condition following or during exposure to study treatment, whether or not considered causally related to study treatment. An undesirable medical condition can be symptoms, signs or abnormal results of an investigation. A serious AE (SAE) is an AE that fulfills one or more following criteria: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital abnormality or birth defect, and an important medical event that may jeopardize participant or may require medical intervention to prevent one of outcomes listed above. AEs leading to discontinuation of study treatment were those with action taken was 'Drug Permanently Discontinued' for any study treatment. Only treatment emergent AEs were presented.
次要结局
- Mean Plasma Concentrations of AZD5069 in Cohort 2(Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and postdose (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1, 2, and 7)
- Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2(RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 3 months)
- Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2(RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 6 months)
- Overall Survival at 6 Months (OS6) in Cohort 2(From first dose of study treatment (Day 1) up to 6 months)
- Overall Survival at 12 Months (OS12) in Cohort 2(From first dose of study treatment (Day 1) up to 12 months)
- Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2(On Day 1 of Cycles 1, 2, 3, 4, and 7; At months 3 and 6 after last dose)
- Disease Control Rate (DCR) in Cohort 2(RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days for first 48 weeks up to 6 months and 12 months)
- Median Progression-Free Survival (PFS) in Cohort 2(RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.)
- Mean Plasma Concentrations of MEDI4736 in Cohort 2(Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and post infusion (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1 and 7)
- Duration of Response (DoR) in Cohort 2(RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.)
- Median Overall Survival (OS) in Cohort 2(RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.)