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

NCT03740893 | Recruiting Phase 2 DMC

• 4 other identifiers: ICR-CTSU/2017/100652018-002077-21ISRCTN47127434CRUKE/16/026
• Study Type: interventional
• Target: 119
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Breast Neoplasm; Triple Negative Breast Cancer (TNBC); HRD

Keywords

AZD6738; Olaparib; Durvalumab; Window of opportunity; Triple negative breast cancer; Breast cancer; Homologous Repair Deficiency (HRD)

Outcome Measures

Primary Outcomes (7)

• 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.

  Post 2 weeks of trial treatment in the window of opportunity

• 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.

  Post 2 weeks of trial treatment in the window of opportunity

• 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.

  Post 2 weeks of trial treatment in the window of opportunity

• 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.

  Post 2 weeks of trial treatment in the window of opportunity

• 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.

  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

  Post 2 weeks of trial treatment in the window of opportunity

• 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.

  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

  Post 2 weeks of trial treatment in the window of opportunity

• Cohorts F and G co-primary endpoint #3: Changes in the plasma ctDNA (D0-D14) post WOP intervention compared to pre-treatment.

  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

  Post 2 weeks of trial treatment in the window of opportunity

Secondary Outcomes (3)

• 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

Study Arms (7)

Cohort A (standard care reference cohort)

NO INTERVENTION

Arm formally closed to recruitment since 06 August 2024

Cohort B (AZD6738 monotherapy)

EXPERIMENTAL

Arm formally closed to recruitment since 06 August 2024

Drug: AZD6738

Cohort C (olaparib monotherapy)

EXPERIMENTAL

Arm formally closed to recruitment since 06 August 2024

Drug: Olaparib

Cohort D (durvalumab monotherapy)

EXPERIMENTAL

Arm formally closed to recruitment since 06 August 2024

Drug: Durvalumab

Cohort E: non-HRD and gBRCA1gBRCA1/2 wildtype confirmed at HRD screening

EXPERIMENTAL

Drug: Olaparib

Cohort F: gBRCA1/2 mutation confirmed at HRD screening

EXPERIMENTAL

Drug: Olaparib; Drug: Durvalumab

Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening

EXPERIMENTAL

Drug: Olaparib; Drug: Durvalumab

Interventions

AZD6738 DRUG

PART 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)

Cohort B (AZD6738 monotherapy)

Olaparib DRUG

PART 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.

Cohort C (olaparib monotherapy); Cohort E: non-HRD and gBRCA1gBRCA1/2 wildtype confirmed at HRD screening; Cohort F: gBRCA1/2 mutation confirmed at HRD screening; Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening

Durvalumab DRUG

PART 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.

Cohort D (durvalumab monotherapy); Cohort F: gBRCA1/2 mutation confirmed at HRD screening; Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• Radiographically measurable tumour mass assessable for new distinct radio-opaque marker insertion and repeated biopsies on the NACT mid-assessment standard of care imaging modality;
• Eastern Oncology Cooperative Group (ECOG) performance status 0-1;
• Considered fit enough to have breast cancer surgery with curative intent;
• Considered fit to complete at least 2 weeks of pre-operative trial treatment in the WOP;
• Patients must be suitable for a mandatory pre-treatment baseline biopsy performed Day -1 or 1 of the window of opportunity (WOP) and a post-treatment biopsy performed on Day 14 of the WOP. Registered patients who are approached for Trial Entry will be required to consent to the pre- and post- WOP treatment biopsy. If it is deemed unsafe to proceed with biopsy upon Trial Entry the patient will not be eligible for participation in the trial.
• Patients with clinical stage II or III disease or clinical suspicion of metastatic disease must have staging studies to exclude metastatic disease if this is standard of care, and staging methods should be used as per standard of care (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease);
• Patients with previous invasive cancers (including breast cancer) are eligible if the treatment was completed \>5 years prior to Trial Registration, and there is no evidence of recurrent disease;
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before Trial Registration;
• Patients must be a) surgically sterile (i.e. if female have undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy; if male have undergone a bilateral orchidectomy); b) have a sterilised sole partner; or c) be post-menopausal; or d) must agree to practice total/true abstinence; or e) use a condom and one highly effective form of contraception in combination during the period of trial treatment and be willing to do so for a period of at least 6 months following the end of trial treatment. Please refer to Section 5.4 Lifestyle Guidance for the definition of total/true abstinence and a list of the permitted highly effective forms of contraception.
• Post-menopausal is defined by at least one of the following criteria:
• Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments

You may not qualify if:

• 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.
• History of another primary malignancy within the last 5 years prior to Trial Registration, except for:
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
• Adequately treated carcinoma in situ without evidence of disease;
• Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML;
• Severe concurrent disease, infection or co-morbidity that, in the judgment of the local Investigator, would make the patient inappropriate for Trial Registration;
• Resting ECG indicating uncontrolled, potentially irreversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>470 msec, electrolyte disturbances, etc.), or patients with congenital long QT syndrome;
• Patients unable to swallow orally administered medication;
• Patients receiving therapeutic anti-coagulation treatment (including warfarin and novel oral anti-coagulants).
• Patients with gastrointestinal disorder affecting absorption (e.g. gastrectomy, active peptic ulcer disease within last 3 months);
• History of seizure or any condition that may predispose to seizure.
• Other non-malignant systemic disease that would preclude trial treatment or would prevent required follow-up;
• Pregnant or breast-feeding;
• Prior exposure to PARP inhibitor, including olaparib, anti-PD-1 or anti-PDL1 immunotherapy (including durvalumab) except for pembrolizumab if received as standard of care in combination with neoadjuvant chemotherapy;

Sponsors & Collaborators

• Institute of Cancer Research, United Kingdom: lead
• AstraZeneca: collaborator

Study Sites (6)

Royal Bournemouth Hospital

Bournemouth, Dorset, BH7 7DW, United Kingdom

NOT YET RECRUITING

King's College Hospital

London, England, SE5 9RS, United Kingdom

RECRUITING

Christie Hospital NHS Trust

Manchester, England, M20 4BX, United Kingdom

NOT YET RECRUITING

Velindre Cancer Center at Velinde Hospital

Cardiff, Wales, CF14 2TL, United Kingdom

RECRUITING

Guy's and St Thomas' Hospital NHS Foundation Trust

London, SE1 9RT, United Kingdom

RECRUITING

Weston Park Hospital

Sheffield, United Kingdom

NOT YET RECRUITING

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

ceralasertib; olaparib; durvalumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Andrew Tutt

  Institute of Cancer Research, United Kingdom

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christophe Verstegen

CONTACT

0203 437 6886; phoenix-icrctsu@icr.ac.uk

Michelle Frost

CONTACT

phoenix-icrctsu@icr.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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).

Study Record Dates

• First Submitted: October 5, 2018
• First Posted: November 14, 2018
• Study Start: October 15, 2019
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): June 1, 2029
• Last Updated: August 11, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

GB (6)