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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

NCT03740893

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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 and/or Anti-PD-L1 Immunotherapy in Patients With Neoadjuvant Chemotherapy Resistant Residual Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: ICR-CTSU/2017/10065
  • SECONDARY ID: 2018-002077-21
  • NCT ID: NCT03740893

Conditions

  • Breast Neoplasm

Interventions

DrugSynonymsArms
AZD6738Cohort B (AZD6738 monotherapy)
OlaparibCohort C (olaparib monotherapy)
DurvalumabCohort D (durvalumab monotherapy)

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Cohort A (standard care reference cohort)No Intervention
    Cohort B (AZD6738 monotherapy)Experimental
    • AZD6738
    Cohort C (olaparib monotherapy)Experimental
    • Olaparib
    Cohort D (durvalumab monotherapy)Experimental
    • Durvalumab

    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. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                 treatment may be included only after consultation with the CI or Coordinating
                 Investigator;
    
             13. Other non-malignant systemic disease that would preclude trial treatment or would
                 prevent required follow-up;
    
             14. Pregnant or breast-feeding;
    
             15. Prior exposure to ATR inhibitor (including AZD6738), PARP inhibitor (including
                 olaparib), anti-PD-1 or anti-PDL1 immunotherapy (including durvalumab);
    
             16. 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;
    
             17. Patients with a known hypersensitivity to the trial treatments or any excipients of
                 the products;
    
             18. Previous allogenic bone marrow transplant or double umbilical cord blood
                 transplantation (dUCBT);
    
             19. 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;
    
             20. 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.
    
            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. 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
    
              4. Patients 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.
    
              5. 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.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Cohorts B and C co-primary endpoint #1: Change in mean proliferation index (as measured by tumour cell Ki67 immunohistochemistry) 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
    Safety Issue:
    Description:Change in mean proliferation index (as measured by tumour cell Ki67 immunohistochemistry) 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 surgical resection sample. AND/OR Cohorts B and C co-primary endpoint #2, as described below.

    Secondary Outcome Measures

    Measure:Incidence of adverse events during trial treatment
    Time Frame:1 month post-surgery
    Safety Issue:
    Description:Incidence of adverse events (AEs) during trial treatment (including surgical complications) by treatment cohort at 1 month post-surgery.
    Measure:Changes in phosphorylation of ATR and its downstream effectors
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Changes in phosphorylation of ATR and its downstream effectors (Chk1, γH2AX, TAO upon drug exposure: including but not limited to levels of phosphorylation of p53, p38, p21/p27, cyclin dependent kinases (CDC25))
    Measure:Changes in biomarkers of DNA Damage Response (DDR) and adaptive and innate response
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Changes in biomarkers of DDR and adaptive and innate response, including but not limited to 53BP1, RAD51, RPA, RPA32, pRPA, BRCA1/2, PARP expression and immune checkpoint ligands and receptors and adaptive and innate immune response markers (IFNg, cGAS-STING pathway, NKG2D receptors, ligands and cell markers) in the post treatment biopsy compared to pre-treatment baseline biopsy using gene expression profiling.
    Measure:Assessment of associated expression of co‐inhibitory immune checkpoint receptors
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Assessment of associated expression of co‐inhibitory immune checkpoint receptors using immune cell markers and high content image de-convolution.
    Measure:Assessment of associated expression of co‐inhibitory immune checkpoint ligands
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Assessment of associated expression of co‐inhibitory immune checkpoint ligands using immune cell markers and high content image de-convolution.
    Measure:Assessment of frequency and function of tumour‐infiltrating lymphocyte subsets
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Assessment of frequency and function of tumour‐infiltrating lymphocyte subsets using immune cell markers and high content image de-convolution.
    Measure:Assessment of frequency and function of tumour‐infiltrating myeloid cells subsets
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Assessment of frequency and function of tumour‐infiltrating myeloid cells subsets using immune cell markers and high content image de-convolution.
    Measure:Changes in the levels of Th1/IFNg response
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Change in the levels of Th1/IFNg response measured by transcriptional and proteomic profiling.
    Measure:Immune cell population sub-set characterisation
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:Immune cell population sub-set characterisation using appropriate and T and B cell receptor DNA sequencing methodologies.
    Measure:Assess change in Ki67+:CD8+ ratio within the post-treatment biopsy sample compared to pre-treatment baseline biopsy.
    Time Frame:Post 2 weeks of trial treatment in the window of opportunity
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:Institute of Cancer Research, United Kingdom

    Trial Keywords

    • AZD6738
    • Olaparib
    • Durvalumab
    • Window of opportunity
    • Triple negative breast cancer
    • Breast cancer

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