| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ER negative, PR negative and HER2 negative (triple negative) breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| ER negative, PR negative and HER2 negative (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 | 10075566 |
| E.1.2 | Term | Triple negative 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 |
| Compare efficacy in terms of pCR in TNBC with Atezolizumab 2-week monotherapy window followed by neoadjuvant CTX with Atezolizumab (Arm A) to neoadjuvant CTX with Atezolizumab (Arm B). |
|
| E.2.2 | Secondary objectives of the trial |
1. Asses and compare safety of Atezolizumab monotherapy window of 2 weeks followed by neoadjuvant treatment with Atezolizumab in combination with CTX (Arm A) to neoadjuvant CTX with Atezolizumab (Arm B):
- of patients with an ER/PR expression of <1% and an ER/PR expression of 1% to 10%.
- per alternative pCR definitions
2. Compare early biological response as measured by Complete Cell Cycle Arrest (CCCA), decrease of Ki-67 expression (≥30%), low cellularity and TILs (≥60%), or a combined early response
3. Compare early biological response as measured by CCCA, decrease of Ki-67 expression (≥30%), low cellularity and TILs (≥60%), or a combined early response
4. Assess and compare the prognostic and predictive values of the biomarkers
5.Compare the efficacy of Atezolizumab mono-therapy window of 2 weeks followed by treatment in (Arm A) to the treatment according (Arm B):
- by disease free survival (DFS)
- by overall survival (OS)
- by event free survival (EFS) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
● Female and male patients, age at diagnosis 18 years and above
● Written informed consent prior to admission to this study
● Histologically confirmed unilateral primary invasive carcinoma of the breast
● Clinical T1c – T4d *
● Stage N0 - N3 until 21 patients (5%) with stage N3 are randomized, thereafter N0 - N2
● TNBC defined by and confirmed by central pathology:
o ER negative (< 10% positive cells in IHC) and PR negative (< 10% positive cells on IHC)
o HER2 negative breast cancer:
▪ Either defined by IHC: ICH scores of 0 - 1 or an ICH score of 2 in combination with a negative ISH
▪ Or defined by ISH: negative ISH
● Identifiable PD-L1 IC-status by central pathology (positive or negative) by means of VENTANA PD-L1 (SP142) assay; positive status is defined by PD-L1 expression on IC on ≥ 1% of the tumor area, negative status is defined by PD-L1 expression on IC on < 1% of the tumor area
● No clinical evidence for distant metastasis (cM0)
● Tumor block available for translational research
● Performance Status ECOG ≤ 1 or KI ≥ 80%
● Negative pregnancy test (urine or serum) within 7 days prior to screening in premenopausal patients
● Women of childbearing potential and male patients with partners of childbearing potential must accept to implement a highly effective (less than 1% failure rate according to Pearl index) including at least one non-hormonal contraceptive measures during the study treatment and for 5 months following the last dose of study treatment such as:
o IUD
o bilateral tubal occlusion
o vasectomized partner
o sexual abstinence
● The patient must be accessible for treatment and follow-up
● Normal cardiac function:
o Normal ECG (within 6 weeks prior to screening)
o Normal LVEF on ECG
● Normal thyroid function
o Normal TSH and FT4
● Blood counts within 14 days prior screening:
o absolute neutrophile count (ANC) must be ≥ 1,500/mm3
o Platelet count must be ≥ 100,000/mm3
o Hemoglobin must be ≥ 10 g/dl
● Hepatic functions:
o Total bilirubin must be ≤ 1 upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > 1 x ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin
o ALK must be ≤ 2.5 x ULN for the lab
o AST and ALT must be ≤1.5 x ULN for the lab.
o Patients with AST and ALT or ALK > 1 x ULN are eligible for inclusion if liver imaging (CT, MRI, PET-CT, or PET scan) performed within 3 months prior to randomization (and part of SOC) does not demonstrate metastatic disease and the requirements in criterion (just above) are met
o Patients with ALK that is > 1 x ULN but less than or equal to 2.5 x ULN or with unexplained bone pain are eligible if bone imaging does not demonstrate metastatic disease.
o Creatinine clearance ≥ 40ml/min performed 28 days prior to screening
*TNM staging according to the Union for International Cancer Control (UICC) classification |
|
| E.4 | Principal exclusion criteria |
● Previous history of malign diseases, non-melanoma skin cancer and carcinoma of the cervix are allowed if treated with curative intent
● Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of Paclitaxel, Carboplatin, Epirubicin, Cyclophosphamide or Atezolizumab
● Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
● Concurrent treatment with other drugs that are contraindicating the use of the study drugs
● Existing pregnancy
● Breastfeeding
● Sequential breast cancer
● Concurrent treatment with other experimental drugs and participation in another clinical trial or clinical research project (except registry study) within 30 days prior to study entry
● Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including but not confined to:
o Uncompensated chronic heart failure or systolic dysfunction (LVEF < 55%, CHF NYHA classes II-IV),
o unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart rate ≥ 100 bpm at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block,
o Angina pectoris within the last 6 months requiring anti-anginal medication,
o Clinically significant valvular heart disease,
o Evidence of myocardial infarction on ECG,
o Poorly controlled hypertension (e.g., systolic > 180 mmHg or diastolic > 100 mmHg).
● Inadequate organ function including but not confined to:
o hepatic impairment as defined by bilirubin > 1.5 x ULN
o pulmonary disease (severe dyspnea at rest requiring oxygen therapy)
● Abnormal blood values:
o Platelet count below 100,000/mm3
o AST/ALT > 1.5 x ULN
o Hypokalaemia > CTCAE grade 1
o Neutropenia > CTCAE grade 1
o Anaemia > CTCAE grade 1
● Administration of a live, attenuated vaccine within 4 weeks before cycle 1 day 1 or anticipation that such a vaccine will be required during the study
● Treatment with systemic immunosuppressive medications (including but not limited to interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer, prior to randomization
● Treatment with systemic immunosuppressive medications (including but not limited to Prednisone, Cyclophosphamide, Azathioprine, Methotrexate, Thalidomide, and anti-TNF factor agents) within 14 days prior to screening or anticipation of need for systemic immunosuppressive medications during the study
● Patients with prior allogeneic stem cell or solid organ transplantation
● Active or history of autoimmune disease or immune deficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis with the following exceptions:
o Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study.
o Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
o Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are permitted provided all of following conditions are met: Rash must cover < 10% of body surface area; Disease is well controlled at baseline and requires only low-potency topical corticosteroids; No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, Methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
● History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
● History of HIV infection, hepatitis B or hepatitis C infection.
● Patients with significant cardiovascular disease
● Patients with inadequate hematological and end-organ function
● Patients receiving therapeutic anti-coagulants
● Stage N3, as soon as 21 patients with stage N3 are randomized |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
a) pCR defined as no residual invasive tumor cells in the breast and in the lymph nodes
(ypT0/is, ypN0)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 26 weeks in Arm A and after 24 weeks in Arm B.
|
|
| E.5.2 | Secondary end point(s) |
b) Safety (incidence, relationship, seriousness, and severity of all AEs, SAEs, AESIs coded by medical dictionary for regulatory activities (MedDRA), summarized by Preferred Term and System Organ Class and graded according to common terminology criteria of adverse events (CTCAE) V5.0)
c) pCR defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0) in patients with an ER/PR expression of < 1% and an ER/PR expression of 1% to 10%
d) pCR defined as no tumor cells (invasive or non-invasive) in the breast but also in the lymph nodes (ypN0, ypT0)
e) Near pCR defined as residual tumor < 5 mm in the breast irrespective of in situ and lymph nodes status
f) pCR defined as no invasive tumor in the breast, irrespective of lymph node status
g) Decrease of Ki-67 expression versus baseline after 14/28 days (+/- 2 days) of treatment as continuous predictor
h) TILs after 14/28 days (+/- 2 days) of treatment as continuous predictor
i) CCCA: Ki-67 expression ≤ 2.7% after 14/28 days (+/- 2 days) of treatment
j) Low cellularity: < 500 tumor cells after 14/28 days (+/- 2 days) of treatment
k) Decrease of Ki-67 expression versus baseline by 30% or more after 14/28 days (+/- 2 days) of treatment
l) TILs ≥ 60% after 14/28 days (+/- 2 days) of treatment
m) Combined early response defined by
o CCCA (Ki-67 expression < 2.7%) or
o low cellularity or
o decrease of Ki-67 expression (versus baseline) by 30% or more or
o TILs ≥ 60%
n) DFS1 defined as time from the first date of no disease [i.e. date of surgery] to the first occurrence of disease recurrence or death from any cause
o) OS defined as length of time from randomization to death from any cause
p) EFS defined as length of time after randomization till death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. constantly, on occurrence
2. - 5. 4 efficacy interim analyses in blocks of 40 patients after 100, 140, 180 and 220 patients
6. - 12. after 14/28 days (+/- 2 days) of treatment
13. defined as time from the first date of no disease or death
14. from randomization to death
15. after randomization till death |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 40 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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