A Phase IB/II, 2-stage, Open-label, Multicenter Study to Determine the Efficacy and Safety of Durvalumab (MEDI4736) + Paclitaxel and Durvalumab (MEDI4736) in Combination With Novel Oncology Therapies With or Without Paclitaxel for First-line Metastatic Triple Negative Breast Cancer
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- AstraZeneca
- 入组人数
- 243
- 试验地点
- 34
- 主要终点
- Dose Limiting Toxicity (DLT) Events
研究概览
简要总结
This study is designed to determine the efficacy and safety of durvalumab in combination with novel oncology therapies with or without paclitaxel and durvalumab + paclitaxel for first-line metastatic triple negative breast cancer
详细描述
This is a Phase IB/II, 2-stage, open-label, multicenter study to determine the efficacy and safety of durvalumab in combination with novel oncology therapies (i.e. therapies designed for immune modulation) with or without paclitaxel and durvalumab + paclitaxel as first-line treatment in patients with metastatic triple negative breast cancer (TNBC). The study is designed to concurrently evaluate potential novel treatment combinations with clinical promise using a 2-stage approach. The study will use a Simon 2-Stage design to evaluate which cohorts may proceed to expansion.
Part 1 is a Phase IB study of safety and initial efficacy, and Part 2 may expand patient enrollment if adequate efficacy signal is observed in Part 1. The treatment regimens evaluated in Part 2 will depend on the evaluation of safety and efficacy outcomes in Part 1.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- Female
- 接受健康志愿者
- 否
入选标准
- •At least 18 years of age at the time of screening
- •Patient must have locally confirmed advanced/unresectable or metastatic TNBC.
- •No prior treatment for metastatic (Stage IV) TNBC
- •Patient must have at least 1 lesion, not previously irradiated, that can be accurately measured
- •WHO/ECOG status at 0 or 1 at enrollment
- •Patients enrolled to Arm 6 (durvalumab and DS-8201a) Must provide documentation of locally determined advanced/unresectable or metastatic TNBC with HER2 low tumor expression (IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested)
- •Patients enrolled in Arm 8 (durvalumab + Dato-DXd) Must have PD-L1 positive tumor as determined by an IHC based assay
排除标准
- •History of allogeneic organ transplantation
- •Active or prior documented autoimmune or inflammatory disorders
- •Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C virus (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies)
- •Untreated CNS metastases
- •Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- •Any concurrent chemotherapy, IP, or biologic therapy for cancer treatment
- •Female patients who are pregnant, breastfeeding
- •Cardiac Ejection Fraction less than 50%
- •Patients enrolled in Arm 2 only:
- •Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2C9 or CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort)
- •Diagnosis of diabetes mellitus Type I or diabetes mellitus Type II requiring insulin treatment.
- •Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QT interval
- •Prior treatment with PI3K inhibitors, AKT inhibitors, or mammalian target of rapamycin (mTOR) inhibitors.
- •Patients enrolled in Arm 5 only: History of venous thromboembolism in the past 3 months
- •Patients enrolled in Arm 7 and 8 only: Clinically significant corneal disease in the opinion of the Investigator.
- •Patients enrolled in Arm 6, 7 and 8 only:
- •History of or active interstitial lung disease/pneumonitis
- •Use of chloroquine or hydroxychloroquine in <14 days prior to Day 1 of DS-8201a (Arm 6) or Dato-DXd (DS-1062a; Arm 7 and 8) treatment
- •Patients enrolled in Arm 6 only: Previously been diagnosed as HER2+ or received HER2-targeted therapy.
研究组 & 干预措施
Arm 1
durvalumab + paclitaxel
干预措施: Durvalumab (Drug)
Arm 1
durvalumab + paclitaxel
干预措施: Paclitaxel (Drug)
Arm 2
durvalumab + paclitaxel + capivasertib
干预措施: Durvalumab (Drug)
Arm 2
durvalumab + paclitaxel + capivasertib
干预措施: Capivasertib (Drug)
Arm 5
durvalumab + paclitaxel + oleclumab
干预措施: Oleclumab (Drug)
Arm 5
durvalumab + paclitaxel + oleclumab
干预措施: Paclitaxel (Drug)
Arm 6
durvalumab + trastuzumab deruxtecan
干预措施: Durvalumab (Drug)
Arm 2
durvalumab + paclitaxel + capivasertib
干预措施: Paclitaxel (Drug)
Arm 5
durvalumab + paclitaxel + oleclumab
干预措施: Durvalumab (Drug)
Arm 6
durvalumab + trastuzumab deruxtecan
干预措施: Trastuzumab deruxtecan (Drug)
Arm 7
durvalumab + datopotamab deruxtecan
干预措施: Durvalumab (Drug)
Arm 7
durvalumab + datopotamab deruxtecan
干预措施: Datopotamab deruxtecan (Drug)
Arm 8
durvalumab + datopotomab deruxtecan (patients with PD-L1 positive status)
干预措施: Durvalumab (Drug)
Arm 8
durvalumab + datopotomab deruxtecan (patients with PD-L1 positive status)
干预措施: Datopotamab deruxtecan (Drug)
结局指标
主要结局
Dose Limiting Toxicity (DLT) Events
时间窗: From the time of first dose until completion of the first cycle (28 days for Arms 2-5, 21 days for Arms 6-7 (no safety run-in for Arms 1 and 8))
The occurrence of a severe adverse event (meeting pre-specified criteria) that is at least possibly related to durvalumab and/or the novel oncology therapy in 6 DLT-evaluable patients
次要结局
- Objective Response Rate (ORR)(Tumor assessments: every 8 wks (Arms 1-5) or every 6 wks (Arms 6-8) until wk 48, then every 12 wks from first IP dose until radiologic progression, death, withdrawal of consent, or study completion; up to max 54 mos (observed longest duration in Arm 1))
- Progression-free Survival (PFS)(Tumor assessments: every 8 wks (Arms 1-5) or every 6 wks (Arms 6-8) until wk 48, then every 12 wks from first IP dose until radiologic progression, death, withdrawal of consent, or study completion; up to max 54 mos (observed longest duration in Arm 1))
- Duration of Response (DoR)(Tumor assessments: every 8 wks (Arms 1-5) or every 6 wks (Arms 6-8) until wk 48, then every 12 wks from first IP dose until radiologic progression, death, withdrawal of consent, or study completion; up to max 54 mos (observed longest duration in Arm 1))
- Overall Survival (Count)(From date of first dose until date of death due to any cause; up to the maximum of 54 months (observed longest duration in Arm 1))
- Overall Survival (Duration)(From date of first dose of IP until date of death due to any cause; up to the maximum of 54 months (observed longest duration in Arm 1))
- Progression-free Survival at 6 Months (PFS6)(6 months following date of first dose)