Breast NeoplasmPhase 2PHOENIXNCT03740893
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
A Phase 2 study testing AZD6738, Olaparib and Durvalumab in people with Breast Neoplasm and Triple Negative Breast Cancer (TNBC), run by Institute of Cancer Research, United Kingdom at 6 sites in United Kingdom.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Neoplasm, Triple Negative Breast Cancer (TNBC), HRD
- What is being tested?
- AZD6738, Olaparib and Durvalumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 119 participants
- Where
- 6 sitesUnited Kingdom
- Study dates
- 15 Oct 2019to Jun 2029
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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;
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- 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
- Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution for women < 50 years of age not using hormonal contraception or hormonal replacement therapy. Please note: in absence of amenorrhea for 1 year, a single LH and/or FSH measurement is insufficient.
- Radiation-induced oophorectomy with last menses >1 year ago
- Chemotherapy-induced menopause with >1 year interval since last menses
- Surgical sterilisation (hysterectomy, bilateral salpingectomy or bilateral oophorectomy)
- Signed Informed Consent Form (ICF) for Trial Entry;
- Residual disease is confirmed as at least one viable disease focus ≥1cm on trial-specific imaging performed at least 1 week following day 1 of the final cycle of NACT.
- Provision of acceptable archival diagnostic tumour tissue sample prior to Trial Entry as defined in the Investigator Laboratory Manual.
- Recovery from all acute adverse events of prior NACT or pembrolizumab to baseline or NCI CTCAE Grade ≤1, except for alopecia. Patients with irreversible toxicity not reasonably expected to be exacerbated by trial treatment may be included only after consultation with the CI or Coordinating Investigator.
- Patients must have adequate haematological, renal and hepatic function as defined by:
- Haemoglobin (Hb) ≥ 10 g/dL (≥ 100 g/L) with no blood transfusion in the past 28 days
- Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 x 109/L)
- Platelet count ≥100,000/mm3 (≥ 100 x 109/L)
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional ULN
- Calculated creatinine clearance ≥51 mL/min using the Cockcroft-Gault equation (please refer to Appendix 4) or based on a 24 hour urine test or another validated test as per local practice
- Women of childbearing potential must have a confirmed menstrual period and a negative urinary or serum pregnancy test prior to Trial Entry. This should be repeated as applicable to ensure a negative pregnancy test is performed on the day of planned trial treatment.
- Confirmation that all Trial Registration inclusion criteria listed in Section 5.3.1 remain satisfied.
Who cannot join
- 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;
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- 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;
- Any other disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that in the investigators opinion would cause reasonable suspicion of a disease or condition, that contraindicates the use of trial treatment, that may increase the risk associated with trial participation, that may affect the interpretation of the results, or that would make this trial inappropriate for the patient;
- Patients with a known hypersensitivity to pembrolizumab, durvalumab or olaparib or any excipients of the products;
- Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT);
- Active infection including tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (HBV; known positive HBV surface antigen (HBsAg) result), hepatitis C (HCV), or human immunodeficiency virus (HIV; positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA;
- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
- Major surgery (excluding minor procedures, e.g. placement of vascular access) within 2 weeks prior to Trial Entry. Patients must have recovered from any effects of any major surgery prior to commencing trial treatment.
- Use of any investigational agent within 30 days prior to commencing trial treatment.
- Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to commencing trial treatment is 5 weeks;
- Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (e.g. bosentan, efavirenz, modafinil) CYP3A inducers. The required washout period prior to commencing trial treatment is 5 weeks;
- Whole blood infusion within 28 days prior to trial entry (packed red blood cells and platelet transfusions are acceptable).
- Receipt of live attenuated vaccine within 30 days prior to commencing trial treatment.
- Confirmation that none of the Trial Registration exclusion criteria listed in Section 5.3.2 are met.
Trial locations and contacts
6 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Michelle Frost contact
6 sites in 1 country
United Kingdom6 sites, 6 recruiting
- Not yet recruiting
Royal Bournemouth Hospital
Bournemouth, Dorset, BH7 7DW
- Recruiting
Velindre Cancer Center at Velinde Hospital
Cardiff, Wales, CF14 2TL
Dr Borley
- Recruiting
King's College Hospital
London, England, SE5 9RS
Dr Castell
- Recruiting
Guy's and St Thomas' Hospital NHS Foundation Trust
London, SE1 9RT
Dr Irshad
- Not yet recruiting
Christie Hospital NHS Trust
Manchester, England, M20 4BX
- Not yet recruiting
Weston Park Hospital
Sheffield
About this study
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.
Read more
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.
Read the detailed description
Cohorts A-D have been formally closed for recruitment since 06 August 2024.
- Conditions
- Breast Neoplasm, Triple Negative Breast Cancer (TNBC), HRD
- Being tested
- AZD6738, Olaparib, Durvalumab
- Keywords
- AZD6738, Olaparib, Durvalumab, Window of opportunity, Triple negative breast cancer, Breast cancer, Homologous Repair Deficiency (HRD)
- Medical subject headings
- Breast Neoplasms, Triple Negative Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD6738Drug
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)
OlaparibDrug
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.
DurvalumabDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: AZD6738 |
| Cohort C (olaparib monotherapy) | Experimental | Arm formally closed to recruitment since 06 August 2024 Receives: Drug: Olaparib |
| Cohort D (durvalumab monotherapy) | Experimental | Arm formally closed to recruitment since 06 August 2024 Receives: Drug: Durvalumab |
| Cohort E: non-HRD and gBRCA1gBRCA1/2 wildtype confirmed at HRD screening | Experimental | Not described Receives: Drug: Olaparib |
| Cohort F: gBRCA1/2 mutation confirmed at HRD screening | Experimental | Not described Receives: Drug: Olaparib; Drug: Durvalumab |
| Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening | Experimental | Not described Receives: Drug: Olaparib; Drug: Durvalumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: Post 2 weeks of trial treatment in the window of opportunity
Secondary outcomes (3)
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.
Measured: 1 month post-surgery
Response in cohort E
Response in Cohort E, defined as per the co-primary endpoints for cohorts F-G.
Measured: Post 2 weeks of trial treatment in the window of opportunity
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.
Measured: Post 2 weeks of trial treatment in the window of opportunity
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Nov 2018
- Study start15 Oct 2019
- Primary completionDec 2026 (estimated)
- Study completionJun 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast NeoplasmStudies of the same condition, open and under way.
- More trials run by Institute of Cancer Research, United KingdomThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Model description
- 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).
- Masking
- None (open label)
- Enrolment
- 119 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institute of Cancer Research, United Kingdom
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
- Investigators
- Andrew Tutt, Principal investigator, Institute of Cancer Research, United Kingdom
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03740893
- Sponsor's protocol ID
- ICR-CTSU/2017/10065
- Other IDs
- 2018-002077-21, ISRCTN47127434, CRUKE/16/026, 2018
- Acronym
- PHOENIX
- Status last verified
- Aug 2025
- First submitted
- 5 Oct 2018
- Last updated
- 11 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 11 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03740893
- Acronym / sponsor ID
- PHOENIX / ICR-CTSU/2017/10065
- 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)
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 119 participants (estimated)
- Lead sponsor
- Institute of Cancer Research, United KingdomUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 15 Oct 2019 (actual)
- Primary completion
- Dec 2026 (estimated)
- Study completion
- Jun 2029 (estimated)
- First posted
- 14 Nov 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Cohorts A-D have been formally closed for recruitment since 06 August 2024.
Study design
- Primary purpose
- Other
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
- Model description
- 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).
| Arm | Type | Receives |
|---|---|---|
| Cohort A (standard care reference cohort) | No intervention | –Arm formally closed to recruitment since 06 August 2024 |
| Cohort B (AZD6738 monotherapy) | Experimental | Drug: AZD6738Arm formally closed to recruitment since 06 August 2024 |
| Cohort C (olaparib monotherapy) | Experimental | Drug: OlaparibArm formally closed to recruitment since 06 August 2024 |
| Cohort D (durvalumab monotherapy) | Experimental | Drug: DurvalumabArm formally closed to recruitment since 06 August 2024 |
| 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (32 listed)
- 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;
Key exclusion criteria (27 listed)
- 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:
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD6738PART 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) | Drug | Cohort B (AZD6738 monotherapy) |
| OlaparibPART 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. | Drug | 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 |
| DurvalumabPART 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. | Drug | Cohort D (durvalumab monotherapy), Cohort F: gBRCA1/2 mutation confirmed at HRD screening, Cohort G: HRD & gBRCA1/2 wildtype confirmed at HRD screening |
Primary outcome
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
3 secondary outcomes
Incidence of adverse events during trial treatment
Time frame: 1 month post-surgery
Response in cohort E
Time frame: Post 2 weeks of trial treatment in the window of opportunity
Methylation status of BRCA1 and RAD51C
Time frame: Post 2 weeks of trial treatment in the window of opportunity
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Aug 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Michelle Frost contact
Andrew Tutt principal investigator
Institute of Cancer Research, United Kingdom
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AZD6738, Olaparib and Durvalumab in people with Breast Neoplasm and Triple Negative Breast Cancer (TNBC), run by Institute of Cancer Research, United Kingdom at 6 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 32 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 11 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Christophe Verstegen (0203 437 6886, phoenix-icrctsu@icr.ac.uk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: Post 2 weeks of trial treatment in the window of opportunity). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Aug 2025.