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.
Signed Informed Consent Form (ICF) for Trial Registration;
Aged ≥18 years old;
Histologically confirmed invasive triple negative breast cancer (TNBC). TNBC defined as ER negative, PgR negative (ER and PgR negative as defined by Allred score 0/8, 1/8 or 2/8 or stain in <1% of cancer cells) or PgR unavailable, and HER2 negative (immunohistochemistry 0/1+ or negative in situ hybridization) as determined by local laboratory and recorded in the patients notes;
Planned definitive surgical treatment after at least 6 cycles of neoadjuvant chemotherapy (NACT) Patients currently receiving SOC pembrolizumab, or having previously received SOC pembrolizumab but subsequently discontinued treatment, in combination with NACT are eligible for Trial Registration;
Definitive evidence of metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease) ;
Patients with bilateral tumours.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
Adequately treated carcinoma in situ without evidence of disease;
Parallel
AZD6738
DrugPART 1: Pre-operative exposure of 160mg AZD6738 to be administered orally twice daily on Days 5 -14 of the WOP. PART 2: 12 months post-operative exposure to 160mg AZD6738 to be administered orally twice daily on Days 1 - 14 of a 28 day cycle. AZD6738 was removed as intervention under investigation as of 06 August 2024 (due to formal closure of cohort B)
Olaparib
DrugPART 1 (cohort C, and cohorts E-G): Pre-operative exposure to 300mg of olaparib to be administered orally twice daily on Days 1-14 of the WOP. PART 2 (cohort C, and cohorts F and G): 12 months post-operative exposure to 300mg olaparib (2 x 150mg tablets) to be administered orally twice daily on a continuous schedule Day 1-28 of a 28 day cycle. Cohort C was formally closed to recruitment since 06 August 2024.
Durvalumab
DrugPART 1 (cohort D): Pre-operative exposure to 1500mg durvalumab to be administered via intravenous (IV) infusion on Day 1 only of the WOP. PART 2 (cohorts A and D, and cohorts F and G): 12 months post-operative exposure to 1500mg durvalumab to be administered via intravenous (IV) infusion on Day 1 only of a 28 day cycle. Cohorts A and D were formally closed to recruitment since 06 August 2024.
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Treatment groupsSee each treatment group below.
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.
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.
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.
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.
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.
Incidence of adverse events during trial treatment
Incidence of adverse events (AEs) during trial treatment (including surgical complications) by treatment cohort at 1 month post-surgery.
Response in cohort E
Response in Cohort E, defined as per the co-primary endpoints for cohorts F-G.
Methylation status of BRCA1 and RAD51C
Methylation status (methylated vs. non-methylated and level of methylation) of BRCA1 and RAD51C on diagnostic and pre- and post-WOP tumour samples and changes in methylation levels between these timepoints.
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Institute of Cancer Research, United Kingdom
Lead sponsor
AstraZeneca
Collaborator
