| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Women with a diagnosis of invasive unilateral, early high-risk and locally advanced or inflammatory, triple negative (HER2-negative and ER-negative and PgRnegative) breast cancer of high proliferation or grade suitable for neoadjuvant Therapy.
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Women with triple negative, early invasive unilateral breast cancer and suitable for neoadjuvant therapy |
|
| 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 | LLT |
| E.1.2 | Classification code | 10006196 |
| E.1.2 | Term | Breast cancer NOS stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10006201 |
| E.1.2 | Term | Breast cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021975 |
| E.1.2 | Term | Inflammatory breast cancer stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10006200 |
| E.1.2 | Term | Breast cancer stage II |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006195 |
| E.1.2 | Term | Breast cancer NOS stage II |
| 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 Event Free Survival (EFS) in the 2 study arms from the time of randomization |
|
| E.2.2 | Secondary objectives of the trial |
- Compare the rate of pathological complete response (pCR) defined as
ypT0-ypTis ypN0 at surgery
- Compare clinical overall response (cOR) at the end of neo-adjuvant
therapy.
- Compare Distant EFS (DEFS) from the time of randomization
- Compare overall survival from the time of randomization
- Evaluate tolerability of the treatment regimens in the different study arms
- Conduct molecular and clinical analyses to assess the presence of
prognostic and/or predictive markers of benefit and/or resistance to the
study regimens and to improve our understanding of breast cancer
disease. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Female patients aged 18 years or older with early high-risk (T1cN1; T2N1; T3N0) or locally advanced and inflammatory breast cancers (stage III A-C according to AJCC) suitable for neoadjuvant Treatment
2.Histologically confirmed unilateral breast cancer with invasive ductal histology
3.HER2 negative disease (defined as 0-1+ by immunohistochemistry or 2+ by immunohistochemistry without HER2 amplification by either In Situ Hybridization (ISH) or other amplification tests done locally)
4.Negative estrogen receptor (ER) and progesterone receptor (PgR), both < 1% locally assessed
5.Representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for confirmation of HER2, ER and PgR eligibility, for assessment of PD-L1 expression and for further exploratory biomarker evaluation is mandatory. Note: FFPE tumor blocks are also mandatory after the first cycle of therapy; surgery tissue (residual tumor or tumor bed in case of pCR) is also mandatory
6.ECOG performance status 0 or 1
7.Written informed consent to participate in the trial (approved by the Institutional Review Board [IRB]/ Independent Ethics Committee [IEC]) obtained prior to any study specific screening procedures
8.Willing and able to comply with the protocol
9.Consent to the collection of blood samples mandatorily before starting neoadjuvant treatment, after the first cycle of therapy, at the end of neoadjuvant treatment (before surgery), at the end of adjuvant chemotherapy and once a year for 2 years during follow-up
10. For women who are not postmenopausal (≥ 12 months of nontherapy-induced amenorrhea) or surgically sterile: agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of study. drug. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. Note: patients with no uterus do not need to be on contraception.
|
|
| E.4 | Principal exclusion criteria |
1.Evidence of bilateral breast cancer or metastatic disease (M1);2.Cases with an histology different from invasive ductal NOS of high proliferation or grade;3.Patients with HER2-positive disease according to ASCO/CAP guidelines 2013 (defined as IHC 3+ or ISH positive according to the Guidelines) are considered not eligible for the study;4.Pregnant or lactating women;5.Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy;6.Previous investigational treatment for any condition within 4 weeks of randomization date;7.Administration of a live,attenuated vaccine within 4 weeks before C1D1 or anticipation that such a live attenuated vaccine will be required during the study or within 5 months after last atezolizumab dose;8.Previous or concomitant invasive malignancy of any other type or previous invasive breast cancer or curatively treated basal cell carcinoma of the skin or in situ cervix cancer are generally eligible;9.Pre-existing motor or sensory neuropathy of grade>1 for any reason;10.Reactions to chimeric or humanized antibodies or fusion proteins,to human albumin solution,hypersensitivity to platinum containing compounds;11.Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation;12.Patients with prior allogeneic stem cell or solid organ Transplantation;13.History of autoimmune disease incl. but not limited to,systemic lupus erythematosus,eumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Bell’s palsy,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis;14.History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest computed tomography scan;15.Known clinically significant liver disease, including active viral,alcoholic,or other hepatitis,cirrhosis,fatty liver,and inherited liver disease;16.History of HIV infection,active hepatitis B (chronic or acute),or hepatitis C infection. Patients with past or resolved hepatitis B infection (defined as having a negative HBsAg test and a positive hepatitis B core antigen [anti-HBc] test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction assay (PCR) is negative for HCV RNA;17.Active tuberculosis;18.Severe infections within 4 weeks prior to C1D1, incl. but not limited to,hospitalization for complications of infection, bacteremia, or severe pneumonia. Signs or symptoms of significant infection within 2 weeks prior to C1D1;19.Received oral or IV antibiotics within 2 weeks prior to C1D1;20.History of documented congestive cardiac failure; New York Heart Association (NYHA) Class II or greater CHF; angina pectoris requiring anti-anginal medication or unstable angina within 6 months prior to cycle 1 Day 1; evidence of transmural infarction on ECG; myocardial infarction stroke or transient ischemic attack (TIA) within 6 months prior to cycle 1 Day 1; poorly controlled hypertension (e.g. systolic >180 mm Hg or diastolic >100 mm Hg; however, patients with hypertension which is well controlled on medication are eligible); clinically significant valvular heart disease; high-risk uncontrolled arrhythmias;21.Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance with study drugs;22.Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus;23.Abnormal baseline hematological values: a. White blood count (WBC) < 2.5 x 10 9/L // b. Absolute Neutrophil Count (ANC) < 1.5 x 10 9/L// c. Lymphocyte count < 0.5 x 10 9/L //d. Platelet count < 100 x 10 9/L // e. Hemoglobin (Hb) < 10 g/dL;24.Abnormal baseline laboratory tests a. Serum total bilirubin > 1.5 x ULN (upper limit of normal) (except for patients with clearly documented Gilbert’s syndrome) b. Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.25x ULN c. Alkaline phosphatase > 2.5x ULN d. Serum creatinine > 1.5 x ULN e. INR and aPTT > 1.5 × ULN within 2 weeks prior to enrollment. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose;25.Baseline left ventricular ejection fraction (LVEF) < 50% by echocardiography or multi-gated scintigraphic scan (MUGA);26.Major surgical procedure within 28 days prior to cycle 1 Day 1 or anticipation of need for a major surgical procedure during the course of the study;27.Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to C1D1 or at any time during the study or within 5 months after the last atezolizumab dose
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Event Free Survival (EFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast) after surgery or death due to any cause. (before surgery and every 12 months after surgery (until EOS = 5 years after last patient in) |
|
| E.5.2 | Secondary end point(s) |
1 Pathological Complete Response (pCR)
2 Relationship between pCR and EFS
3 Clinical Overall Response (cOR) at the end of neo-adjuvant treatment
4 Distant Event Free Survival
5 Overall Survival
6 Safety |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 at time of surgery
2 at EOS
3 at the end of neo-adjuvant treatment
4 before surgery and every 12 months after surgery (until EOS = 5 years after last patient in)
5 time from randomisation to death
6 time form treatment start until end of treatment
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|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Singapore |
| Taiwan |
| Canada |
| Russian Federation |
| Austria |
| Germany |
| Italy |
| Poland |
| Spain |
|
| 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 end of the study is defined as the date when the last patient last visit (LPLV) occurs and it is expected approximately 5 years after the last patient
is randomized in the study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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