| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Women with a diagnosis of non-metastatic high-risk invasive unilateral, HER2-positive breast cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Women with a diagnosis of non-metastatic high-risk invasive unilateral, HER2-positive breast cancer. |
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| 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 | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 |
| To determine if treatment with atezolizumab (arm B) is superior to a treatment without atezolizumab (arm A) in the improvement of 5-year Event-Free Survival (EFS). In case of superiority of arm B vs. arm A, a formal comparison of arm B1 vs arm A and arm B2 vs arm A will be tested for the 5-year EFS. |
|
| E.2.2 | Secondary objectives of the trial |
To determine if treatment with atezolizumab (arm B) is superior to a treatment without atezolizumab (arm A) for the following secondary endpoints:
- Rate of pathological complete response (pCR), defined as absence of invasive cells in breast and nodes (ypT0/is and ypN0) at surgery
- Clinical overall response (cOR) at the end of neo-adjuvant therapy
- Compare Disease-Free Survival (DFS) from the time of surgery in Arm B vs Arm A
- Distant EFS (DEFS) from the time of randomisation
- Overall survival from the time of randomisation
- Tolerability of the treatment regimens
- Composition and specificity of the immune infiltrate of the tumor and of draining lymph nodes
- Conduct molecular and clinical analyses to assess the presence of predictive markers of benefit or resistance to the study regimens |
|
| 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. NB: those sites who perform axillary ultrasound guided-fine needle aspiration or core biopsy are allowed to enroll patients with T2N0 tumors (assessed by paplation and/or imaging) after a pathological confirmation of axillary malignancy;
2. Histologically confirmed unilateral invasive breast cancer;
3. HER2 positive disease according to ASCO/CAP current guidelines;
4. Known estrogen (ER) and progesterone receptor (PgR) status;
5. Availability of a representative paraffin-embedded (FFPE) tumor block taken at diagnostic biopsy for central confirmation of HER2 status, for assessment of ER, PgR, Ki67 and PD-L1 expression and for biomarker evaluation is mandatory. Note: the diagnostic biopsy of the breast lesion may have been taken before screening procedures start. If diagnostic sentinel node or node core biopsy is performed, an FFPE block should be made available, along with the tumor block of the primary tumor. An FFPE tumor block is also mandatory after the first cycle of therapy. Surgery tissue (residual tumor or tumor bed in case of pCR and axillary node material) is also mandatory;
6. 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), 6 months after surgery and at the end of all treatments;
7. ECOG performance status 0 or 1;
8. For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): 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 7 months after the last dose of study drugs. 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, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices;
9. 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;
10. Willing and able to comply with the protocol. |
|
| E.4 | Principal exclusion criteria |
| 1. Evidence of bilateral breast cancer or metastatic disease (M1);2.Pts with HER2-NEG. 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 are considered not eligible for the study;3.Pregnant or lactating women. Documentation of a NEG. pregnancy test must be available for premenopausal women with intact reproductive organs and for women less than one year after the last menstrual cycle;4.Women with childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception as mentioned at point 8 of inclusion criteria;5.Previous treatment with chemotherapy, hormonal therapy or an investigational drug for any type of malignancy.Bleeding tumours;6.Previous investigational treatment for any condition other than malignancy within 4 weeks or 5 half-lives of randomisation,whichever is longer;7.Administration of a live,attenuated vaccine within 4weeks before D1 or anticipation that such a live attenuated vaccine will be required during the study;8.Previous or concomitant malignancy of any other type that could affect compliance with the protocol or interpretation of results.Pts with curatively treated basal cell carcinoma of the skin or in situ cervix cancer are eligible;9.Pre-existing motor or sensory neuropathy of grade>1 for any reason;10.History of severe allergic,anaphylactic,or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins or hyaluronidase. History of any protocol anticancer agent or any of the excipients;11.Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation;12.Pts with prior allogeneic stem cell or solid organ transplantation;13.History of autoimmune disease including,but not limited to,systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjörgren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis(see AppA for preexisting autoimmune diseases and immune deficiencies;14.History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest CT 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. (...);17.Active tuberculosis;18.Severe infections within 4 weeks prior to Day 1, including, but not limited to, hospitalisation for complications of infection, bacteriemia, or severe penumonia. Signs or symptoms of significant infection within 2weeks prior to Day 1;19.Received oral or IV antibiotics within 2weeks prior to Cycle 1 Day 1;20.Other serious illness or medical condition incl. but not limited to: 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 Day 1; evidence of transmural infarction on ECG; myocardial infarction stroke or TIA within 6 months prior to 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; severe dyspnea at rest requiring supplementary oxygen therapy;uncontrolled pleural effusion, pericardial effusion, or ascites (...), hypercalcemia (...)21.Pts with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant;22.Serious uncontrolled infections,poorly controlled diabetes mellitus;23.Any of the following abnormal baseline hematological values:WBC;ANC;lymphocyte;platelet count;Hb;24.Any of the following abnormal baseline laboratory tests:Serum total bilirubin (except for pts with clearly documented Gilbert’s syndrome);ALT or AST;AP;creatinine;INR and aPTT > 1.5 × ULN within 2 weeks prior to enrollment.Pts receiving therapeutic anticoagulation should be on a stable dose;25.LVEF<55% by echocardiography or MUGA;26.Major surgical procedure within 28 days prior to D1 or anticipation of need for a major surgical procedure during the course of the study;27.Influenza vaccination should be given during influenza season only.Pts must not receive live, attenuated influenza vaccine within 4weeks prior to D1 or at any time during the study.Concomitant admin. of yellow-fever vaccine is contraindicated.28.Prior Treatment with CD137 agonists (...)29.Treatment with systemic immunostimulatory agents (...) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| A 5-year EFS is foreseen to be 85% by the addition of atezolizumab (arm B) compared to a 75% 5-year EFS without atezolizumab (arm A). EFS is defined as the time from randomisation 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. Patients who terminate the study without evidence of any of the above events will be censored at the maximum of the following dates: date of last radiological examination, date of last treatment (considering both neo-adjuvant and adjuvant regimens), date of surgery. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At every cycle during neoadjuvant therapy, at every cycle during adjuvant therapy, on a yearly basis during follow-up. |
|
| E.5.2 | Secondary end point(s) |
1. Rate of pathological complete response (pCR), defined as absence of invasive cells in breast and nodes (ypT0/is and ypN0) at surgery;
2. Clinical overall reponse (cOR) at the end of neo-adjuvant therapy;
3. Disease-free survival (DFS) from the time of surgery
4. Distant Event Free Survival (DEFS) from the time of randomisation;
5. Overall Survival (OS) from the time of randomisation;
6. Evaluate tolerability of the treatment regimens;
7. Composition and specificity of the immune infiltrate of the tumor and of draining lymph nodes. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At surgery (about 6 months from randomisation);
2. At the end of neoadjuvant therapy (about 4 months from randomisation);
3. During adjuvant therapy and yearly during follow-up;
4. During adjuvant therapy and yearly during follow-up;
5. During entire study;
6. During neoadjuvant and adjuvant treatments;
7. Not applicable. |
|
| 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) | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Arm A: Trastuzumab, Pertuzumab, Carboplatin, Taxol. Trastuzumab emtansine. |
|
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Taiwan |
| Austria |
| Belgium |
| Germany |
| Italy |
| Romania |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| 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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