PHOENIX DDR/Anti-PD-L1 Trial: A Pre-surgical Window of Opportunity and Post-surgical Adjuvant Biomarker Study of DNA Damage Response Inhibition and/or Anti-PD-L1 Immunotherapy in Patients With Neoadjuvant Chemotherapy Resistant Residual Triple Negative Breast Cancer

PHOENIX is a window of opportunity (WOP), open-label, multi-centre, phase IIa trial comprising multiple non-comparative treatment cohorts with patient allocation via randomisation. The trial consists of two parts: a post-neoadjuvant chemotherapy, preoperative WOP component (PART 1); and a post-operative component (PART 2).

PHOENX aims to assess whether short exposure to a DNA damage response (DDR) inhibitor and/or anti-PD-L1 immunotherapy in a preoperative WOP in patients with post-NACT high residual disease, generates a signal of anti-tumour biological activity within residual disease tissue.


Eligibility Criteria:
Inclusion Criteria for Trial Registration:

1. Signed Informed Consent Form (ICF) for Trial Registration;
2. Aged ≥18 years old;
3. 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;
4. Planned definitive surgical treatment after at least 6 cycles of neoadjuvant chemotherapy (NACT);
5. 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 (MRI or USS); or clinically thought to be \>5cm in diameter (T3);
6. Eastern Oncology Cooperative Group (ECOG) performance status 0-1;
7. Considered fit enough to have breast cancer surgery with curative intent;
8. Considered fit to complete at least 2 weeks of pre-operative trial treatment in the WOP;
9. 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 Trial Registration.
10. Patients with clinical stage II disease or clinical suspicion of metastatic disease must have staging studies as per standard of care to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease);
11. Patients with stage III disease must have staging studies as per standard of care at any point after diagnosis but before Trial Registration, to exclude metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease), even if asymptomatic.
12. 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;
13. 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;
14. 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 two highly effective forms of contraception in combination during the period of trial treatment and be willing to do so for a period of 3 months following the end of trial treatment. Please refer to Section 6.4 Lifestyle Guidance for the definition of total/true abstinence and acceptable non-hormonal and hormonal birth control methods for the trial.

Post-menopausal is defined by at least one of the following criteria:

1. Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
2. 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.
3. Radiation-induced oophorectomy with last menses \>1 year ago
4. Chemotherapy-induced menopause with \>1 year interval since last menses
5. Surgical sterilisation (hysterectomy, bilateral salpingectomy or bilateral oophorectomy)

Exclusion Criteria for Trial Registration:

1. Definitive evidence of metastatic disease (axillary lymph nodes or internal mammary node involvement will not be regarded as evidence of metastatic disease);
2. Patients with bilateral tumour;
3. History of another primary malignancy within the last 5 years prior to Trial Registration, except for:

   1. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease;
   2. Adequately treated carcinoma in situ without evidence of disease;
4. Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML;
5. Severe concurrent disease, infection or co-morbidity that, in the judgment of the local Investigator, would make the patient inappropriate for Trial Registration;
6. Resting ECG with QTc\>470msec for females and \> 450 msec for men on 2 or more time points within a 24 hour period, factors which increase the risk of QTc prolongation or family history of long QT syndrome;
7. A diagnosis of ataxia telangiectasia;
8. Patients unable to swallow orally administered medication;
9. Patients receiving formal anti-coagulation treatment (including warfarin, novel oral anti-coagulants and LMWH).
10. Patients with gastrointestinal disorder affecting absorption (e.g. gastrectomy, active peptic ulcer disease within last 3 months);
11. History of seizure or any condition that may predispose to seizure.
12. Other non-malignant systemic disease that would preclude trial treatment or would prevent required follow-up;
13. Pregnant or breast-feeding;
14. Prior exposure to ATR inhibitor (including AZD6738), PARP inhibitor (including olaparib), anti-PD-1 or anti-PDL1 immunotherapy (including durvalumab);
15. 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;
16. Patients with a known hypersensitivity to the trial treatments or any excipients of the products;
17. Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT);
18. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease (e.g., colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia;
    2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on hormone replacement;
    3. Any chronic skin condition that does not require systemic therapy;
    4. Patients without active disease in the last 5 years prior to Trial Registration may be included but only after consultation with the CI or Coordinating Investigator;
    5. Patients with coeliac disease controlled by diet alone;
19. 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.
20. Patients with a history of non-infectious pneumonitis.

Inclusion Criteria for Trial Entry:

1. Signed Informed Consent Form (ICF) for Trial Entry;
2. Residual disease is confirmed as at least one viable disease focus ≥ 2cm on trial-specific dynamic contrast enhanced MRI scan performed 1 week following day 1 of the final cycle of NACT.
3. Recovery from all acute adverse events of prior NACT 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
4. Patients must have adequate haematological, renal and hepatic function as defined by:

   * Haemoglobin (Hb) ≥ 10 g/dL (≥ 100 g/L) with no blood transfusion or erythropoietin 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
5. 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 within 3 days prior to commencing trial treatment (or on the day of planned treatment for cohort C).
6. Confirmation that all Trial Registration inclusion criteria remain satisfied.

Exclusion Criteria for Trial Entry:

1. History of clinically significant or uncontrolled cardiovascular disease including:

   * Myocardial infarction within 6 months prior to Trial Entry;
   * Uncontrolled angina within 3 months prior to Trial Entry;
   * Congestive heart failure New York Heart Association (NYHA) class III or IV, or patients with history of congestive heart failure NYHA class III or IV in the past, unless an echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan performed within 3 months prior to Trial Entry results in a left ventricular ejection fraction that is 45%;
   * History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes);
   * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
   * Consistent evidence of hypotension as indicated by systolic blood pressure \< 90 millimeters of mercury (mm Hg) prior to Trial Entry;
   * Consistent evidence of bradycardia as indicated by a heart rate of \< 50 beats per minute on the ECG prior to Trial Entry;
   * Consistent evidence of uncontrolled hypertension as indicated by systolic blood pressure \> 170 mm Hg or diastolic blood pressure \> 105 mm Hg prior to Trial Entry.

   Patients with a history of any of the above listed cardiac conditions judged not to be clinically significant by the local Investigator must be notified to the trial team at the ICR-CTSU;
2. History of loss of consciousness or transient ischemic attack within 12 months prior to Trial Entry;
3. Patients with Grade ≥2 neuropathy, as defined by the National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) will be evaluated on a case-by-case basis after consultation with the CI or Coordinating Investigator;
4. 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.
5. Use of any investigational agent within 30 days prior to commencing trial treatment.
6. 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 (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to commencing trial treatment is 5 weeks;
7. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg. bosentan, efavirenz, modafinil) CYP3A inducers. The required washout period prior to commencing trial treatment is 5 weeks;
8. Whole blood transfusions in the last 4 months prior to commencing trial treatment (packed red blood cells and platelet transfusions are acceptable, with no blood transfusion or erythropoietin in the past 28 days prior to trial entry);
9. Current or prior use of immunosuppressive medication within 14 days prior to commencing trial treatment, with the exception of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisolone, or an equivalent corticosteroid.
10. Receipt of live attenuated vaccine within 30 days prior to commencing trial treatment.
11. Confirmation that none of the Trial Registration exclusion criteria listed in Section 5.3.2 are met.