PHOENIX DDR/Anti-PD-L1 Trial: A Pre-surgical Window of Opportunity and Post-surgical Adjuvant Biomarker Study of DNA Damage Response Inhibition With or Without Anti-PD-L1 Immunotherapy in Patients With Neoadjuvant Treatment Resistant Residual Triple Negative Breast Cancer
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 119
- 试验地点
- 6
- 主要终点
- Cohorts B and C co-primary endpoint #1: Change in mean proliferation index (as measured by tumour cell Ki67 staining) post WOP intervention within post-treatment biopsy compared to pre-treatment baseline biopsy.
研究概览
简要总结
PHOENIX is a window of opportunity (WOP), open-label, multi-centre, phase IIa trial comprising multiple non-comparative treatment cohorts with patient allocation via minimisation (cohorts A-D) or allocation according to HRD and germline BRCA1/2 mutation status (cohorts E-G). The trial consists of two parts: a post-neoadjuvant treatment preoperative WOP component (PART 1); and a post-operative component (PART 2).
Cohorts A-D: To assess whether short exposure to a DDR inhibitor or anti-PD-L1 immunotherapy in a preoperative WOP in patients with post-NACT high risk residual disease, generates a signal of anti-tumour biological activity within residual disease tissue.
Cohort E: To assess whether short exposure to a DDR inhibitor with or without anti-PD-1 immunotherapy in a preoperative WOP in patients with non-HRD associated TNBC and post-neoadjuvant treatment high risk residual disease, generates a signal of anti-tumour biological activity within residual disease tissue.
Cohorts F & G: To assess whether short exposure to the DDR inhibitor olaparib with or without anti-PD-1 immunotherapy in a preoperative WOP in patients with HRD associated TNBC and post-neoadjuvant treatment high risk residual disease, generates a signal of anti-tumour biological activity within residual disease tissue.
详细描述
Cohorts A-D have been formally closed for recruitment since 06 August 2024.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cohort B (AZD6738 monotherapy)
Arm formally closed to recruitment since 06 August 2024
干预措施: AZD6738 (Drug)
Cohort C (olaparib monotherapy)
Arm formally closed to recruitment since 06 August 2024
干预措施: Olaparib (Drug)
Cohort D (durvalumab monotherapy)
Arm formally closed to recruitment since 06 August 2024
干预措施: Durvalumab (Drug)
Cohort E: non-HRD and gBRCA1gBRCA1/2 wildtype confirmed at HRD screening
干预措施: Olaparib (Drug)
Cohort F: gBRCA1/2 mutation confirmed at HRD screening
干预措施: Olaparib (Drug)
Cohort F: gBRCA1/2 mutation confirmed at HRD screening
干预措施: Durvalumab (Drug)
Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening
干预措施: Olaparib (Drug)
Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening
干预措施: Durvalumab (Drug)
结局指标
主要结局
Cohorts B and C co-primary endpoint #1: Change in mean proliferation index (as measured by tumour cell Ki67 staining) post WOP intervention within post-treatment biopsy compared to pre-treatment baseline biopsy.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Change in mean proliferation index (as measured by tumour cell Ki67 staining) post WOP intervention within post-treatment biopsy compared to pre-treatment baseline biopsy. A patient will be defined as being a Ki67 responder if they experience a relative decrease in Ki67 positive cells of ≥33% in the post-treatment biopsy sample. This represents a characterised threshold that we do not believe would be exceeded by chance in this patient population. AND/OR Cohorts B and C co-primary endpoint #2, as described below.
Cohorts B and C co-primary endpoint #2: Changes in the proliferation gene expression signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Changes in the proliferation gene expression signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy. A patient will be defined as being a responder if there is a ≥1.5-fold drop in the proliferation gene expression in the surgical resection sample. The proliferation gene signature will be based on this list of 11 highly correlated proliferation genes shown in multiple studies including those published by The Cancer Genome Atlas and they also contribute to the calculation of the proliferation score in the publicly available PAM50 classifier. The list consists of :"CCNB1","UBE2C","BIRC5","NDC80","CDC20","PTTG1","RRM2","MKI67","TYMS","CEP55","NUF2" For each sample, a proliferation gene module score will be calculated according to the expression of the relevant genes. AND/OR Cohorts B and C co-primary endpoint #1, as described above.
Cohort D co-primary endpoint #1: Change in frequency of CD8+ sTILs post anti-PD-L1 immunotherapy within the post-treatment biopsy compared to pre-treatment baseline biopsy.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Change in frequency of CD8+ sTILs post anti-PD-L1 immunotherapy within the post-treatment biopsy compared to pre-treatment baseline biopsy. A patient will be defined as being a responder if they experience an absolute increase of ≥ 10% in the percentage CD8+ sTILs within the post-treatment biopsy sample. The % CD8+ sTILs value denotes the area occupied by CD8+ sTILs over total intratumoural stromal area. AND/OR Cohort D co-primary endpoint #2, as described below.
Cohort D co-primary endpoint #2: Changes in the interferon gamma-positive (IFNγ+) signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Changes in the interferon gamma-positive (IFNγ+) signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy. A patient will be defined as being a responder if there is a ≥2-fold increase in the IFNγ+ gene expression in the post-treatment biopsy sample.The four-gene IFNγ+ score will be calculated, comprising of IFNγ, CD274, LAG3, and CXCL9. AND/OR Cohort D co-primary endpoint #1, as described above.
Cohorts F and G co-primary endpoint #1: Change in mean proliferation index (as measured by tumour cell Ki67 staining) post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Change in mean proliferation index (as measured by tumour cell Ki67 staining) post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy. A patient will be defined as being a Ki67 responder if they experience a relative decrease in Ki67 positive cells of ≥33% in the post-treatment biopsy sample. This represents a characterised threshold that we do not believe would be exceeded by chance in this patient population. AND/OR Cohorts F and G co-primary endpoints #2 and #3, as described below
Cohorts F and G co-primary endpoint #2: Changes in the proliferation gene expression signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Changes in the proliferation gene expression signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy. A patient will be defined as being a responder if there is a ≥1.5-fold drop in the proliferation gene expression in the post-treatment biopsy sample. The proliferation gene signature will be based on this list of 11 highly correlated proliferation genes shown in multiple studies including those published by The Cancer Genome Atlas and they also contribute to the calculation of the proliferation score in the publicly available PAM50 classifier. The list consists of : "CCNB1","UBE2C","BIRC5","NDC80","CDC20","PTTG1","RRM2","MKI67","TYMS","CEP55","NUF2" For each sample, a proliferation gene module score will be calculated according to the expression of the relevant genes. AND/OR Cohorts F and G co-primary endpoints #1 and #3, as described above, and below respectively
Cohorts F and G co-primary endpoint #3: Changes in the plasma ctDNA (D0-D14) post WOP intervention compared to pre-treatment.
时间窗: Post 2 weeks of trial treatment in the window of opportunity
Changes in the plasma ctDNA (D0-D14) post WOP intervention compared to pre-treatment. A patient will be defined as being a responder if the ratio of ctDNA post-WOP compared to pre-WOP is \<0.25. This cut-off has been selected in line with other studies of PARP inhibitors in TNBC. AND/OR Cohorts F and G co-primary endpoints #1 and #2, as described above
次要结局
- Incidence of adverse events during trial treatment(1 month post-surgery)
- Response in cohort E(Post 2 weeks of trial treatment in the window of opportunity)
- Methylation status of BRCA1 and RAD51C(Post 2 weeks of trial treatment in the window of opportunity)