| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple Negative Breast Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| PHOENIX aims to assess whether, in patients who have moderate to significant residual disease remaining following neo-adjuvant chemotherapy (NACT), short exposure to trial treatment with a DNA damage response (DDR) inhibitor and/or anti-PD-L1 immunotherapy prior to surgery will demonstrate a signal of anti-tumour biological activity within the residual disease tissue. |
|
| E.2.2 | Secondary objectives of the trial |
1. To characterise the safety of trial treatment in a window of opportunity (WOP) context trial.
2. To examine biomarkers of cancer or stroma pathway reprogramming/signalling following trial treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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 US); 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 participation in the trial.
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 at least 6 months following the end of trial treatment.
Post-menopausal is defined in Protocol Section 6.3.1.
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 in Protocol Section 9.1.1.
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 trial treatment for Cohort C)
6. Confirmation that all Trial Registration inclusion criteria listed in Section 6.3.1 remain satisfied. |
|
| E.4 | Principal exclusion criteria |
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 tumours;
3. History of another primary malignancy within the last 5 years prior to Trial Registration, except for:
a. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease;
b. 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;
10. Patients with gastrointestinal disorder affecting absorption;
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 (examples & exceptions are listed in Protocol Section 6.3.1).
19. Active infection including tuberculosis (TB), hepatitis B, hepatitis C (HCV), or human immunodeficiency virus (HIV) as described in Protocol Section 6.3.1.
20. Patients with a history of non-infectious pneumonitis.
EXCLUSION CRITERIA FOR TRIAL ENTRY:
1. History of clinically significant or uncontrolled cardiovascular disease as described in Protocol Section 9.1.2;
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 NCI 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.
7. Concomitant use of known strong 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 6.3.2 are met. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is treatment cohort specific based on the nature of the target and the biological effect of targeting.
Cohorts B (AZD6738) and C (olaparib):
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.
AND/OR
2. Changes in the proliferation gene expression signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy.
Cohort D (durvalumab):
1. Change in frequency of CD8+ stromal tumour infiltrating lymphocyte (sTIL) post anti-PD-L1 immunotherapy within the post-treatment biopsy compared to pre-treatment baseline biopsy.
AND/OR
2. Changes in the Interferon Gamma-positive (IFNγ+) signature post WOP intervention within the post-treatment biopsy compared to pre-treatment baseline biopsy.
Cohort A (standard care reference cohort) will allow assessment of any biopsy effect on all co-primary endpoints assessed in treatment cohorts B, C and D. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| All co-primary endpoints will be assessed following collection of the post-treatment biopsy within the window of opportunity before surgery. |
|
| E.5.2 | Secondary end point(s) |
1. Incidence of adverse events (AEs) during trial treatment (including surgical complications) by treatment cohort at 1 month post-surgery.
2. 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)
3. 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.
4. Assessment of associated expression of co‐inhibitory immune checkpoint receptors and ligands and frequency and function of tumour‐infiltrating lymphocyte and myeloid cells subsets using immune cell markers and high content image de-convolution.
5. Changes in the levels of Th1/IFNγ response as measured by transcriptional and proteomic profiling.
6. Immune cell population sub-set characterisation using appropriate and T and B cell receptor DNA sequencing methodologies.
7. Assess change in Ki67+:CD8+ ratio within the post-treatment biopsy sample compared to pre-treatment baseline biopsy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Incidence of adverse events (AEs) during trial treatment (including surgical complications) by treatment cohort at 1 month post-surgery.
- All other secondary endpoints will be assessed following collection of the post-treatment biopsy within the window of opportunity before surgery. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.3.1 | Comparator description |
| Standard of care (no trial treatment) |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The trial end date is deemed to be the date of last data capture expected to be once all patients have completed 24 months of follow up from the 3 month post-surgery visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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