| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with early breast cancer |
| Patienten mit primärem Brustkrebs |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with early breast cancer |
| Patienten mit primärem Brustkrebs |
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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 | LLT |
| E.1.2 | Classification code | 10007050 |
| E.1.2 | Term | Cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Event-free survival (EFS)
Aim: To determine whether the addition of atezolizumab to chemotherapy followed by adjuvant atezolizumab improves EFS.
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| E.2.2 | Secondary objectives of the trial |
- Overall survival (OS)
- Pathologic complete response in the breast and lymph
nodes (ypT0/Tis ypN0)
- Disease-free survival (DFS)
- Distant disease-free survival (DDFS)
- Toxicity
- Cardiac safety lead-in study |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Ovarian subfunction study - part of the given protocol
Young women treated with chemotherapy for early breast cancer have a high risk for chemotherapy-induced ovarian failure , impacting their quality of life and family plans. Analysis of hormones such as follicle-stimulating hormone, estradiol and anti-Müllerian hormone can be used for defining the ovarian damage and the loss of fertility with modern therapeutic regimen, including new targeted therapy and immune therapy. Furlanetto et al had previously shown that 85% of women ≤45 years treated with anthracycline/taxane-based chemoterapy for early breast cancer from 4 German neo-/adjuvant trials experienced chemotherapy-induced ovarian failure after chemotherapy for early breast cancer. After 2 years, over 70% regained premenopausal hormone levels, but only one-third maintained the fertility potential defined by anti‐Müllerian hormone (Furlanetto 2017). Chemotherapy-induced ovarian failure was associated with better DFS, especially in patients with HR-positive early breast cancer or <30 years (Furlanetto 2019). In order to investigate these findings also in patients treated with chemotherapy in combination with an immunotherapy serum samples will be collected (optional collection, GBG sites Europe).
Microbiome testing
The intestinal microbiota plays a crucial role in the life-long programming of innate and acquired immune responses. Only recently the cardinal role of the intestinal microbiota in regulating cancer incidence or progression has been fully acknowledged (Arthur 2012, Garrett 2015, Louis 2014) and there are solid arguments in favor of the critical impact of the gut microbiome in oncogenesis and tumor progression. Stool samples will be collected in order to analyse the microbiome in patients with breast cancer (optional collection, only selectes GBG sites Europe).
Stool samples from patients who have agreed to an optional collection have to be collected in selected GBG sites Europe for microbiome testing with standard material provided before start of treatment. With Amendment 3 an addidional stool sample 30 days after the last dose of study therapy was included.
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| E.3 | Principal inclusion criteria |
- Patient must have consented to participate and, prior to beginning specific study procedures, must have signed and dated an appropriate IEC-approved consent form.
- Diagnosis of invasive adenocarcinoma of the breast must have been made by core needle biopsy.
- Pretreatment research core biopsy of the primary tumor must be performed with submission of 2 cores for required correlative studies.
- Local testing on the diagnostic core must have determined the tumor to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAP guidelines.
- Central testing for ER, PgR, HER2 and Ki-67 will be performed, and the tumor must be determined to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAP Guidelines Recommendations. Stromal TILs wil be evaluated in three groups: low immune infiltrate (0-10% stromal TILs), intermediate immune infiltrate(11-59% stromal TILs), LPBC (060-100% stromal TILs. Material from either the diagnostic core biopsy or the research biopsy can be used for central testing depending on local preferences and standards.
- Tumor specimen must also be used for central testing of PD-L1 Status.
- Patients must be >= 18 years old.
- ECOG performance status must be 0-1
- Primary tumor can be clinical stage T2 or T3, if clinically node negative according to AJCC 7th Edition. If the regional lymph nodes are cN1 and cytologically or histologically positive or cN2–N3 with or without a biopsy, the primary breast tumor can be clinically T1c, T2, or T3.
- Ipsilateral axillary lymph nodes must be evaluated by imaging (mammogram, ultrasound, and/or MRI) within 84 days prior to study entry. If suspicious or abnormal, FNA or core biopsy is recommended. Findings of these evaluations will be used to define the nodal status prior to study entry according to the following criteria:
• Nodal status – negative
Imaging of the axilla is negative;
Imaging is suspicious or abnormal but the FNA or core biopsy of the questionable node(s) on imaging is negative;
• Nodal status – positive
FNA or core biopsy of the node(s) is cytologically or histologically suspicious or positive.
Imaging is suspicious or abnormal but FNA or core biopsy was not performed.
- Patients with synchronous bilateral or multicentric HER2-negative breast cancer are eligible as long as the highest risk tumor is ER-negative and PgR-negative and meets stage eligibility criteria. All of the other invasive tumors must also be HER2-negative by ASCO/CAP Guidelines based on local testing. Central testing to confirm TNBC status is only required for the highest risk tumor.
- Blood counts performed within 28 days prior to randomization must meet the following criteria:
• ANC must be 2000/mm3
• platelet count must be 100,000/mm3
• hemoglobin must be 10 g/dL
- The following criteria for evidence of adequate hepatic function performed within
28 days prior to randomization must be met:
• total bilirubin must be ULN for the lab unless the patient has a bilirubin elevation
ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin; and
• alkaline phosphatase must be 2.5 x ULN for the lab
• AST and ALT must be 1.5 x ULN for the lab
- Patients with AST or ALT or alkaline phosphatase ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET-CT, or PET scan) performed within 28 days prior to randomization does not demonstrate metastatic disease and the requirements in criterion above are met.
- Patients with alkaline phosphatase that is ULN but 2.5 x ULN or with unexplained bone pain are eligible for inclusion in the study if bone imaging (bone scan, PET-CT scan, or PET scan) performed within 42 days prior to randomization does not demonstrate metastatic disease.
- Patients with N2 or N3 nodal disease or T3 primary disease must undergo liver imaging within 28 days prior to randomization and bone imaging (as described in the two sections above) within 42 days prior to randomization, irrespective of baseline lab results, and studies must not demonstrate metastatic disease. Chest imaging with chest x-ray PA and Lateral, CT of the chest, or PET-CT must also be performed.
- Creatinine clearance 40 mL/min performed within 28 days prior to randomization.
- Serum TSH and AM (morning) cortisol performed within 28 days prior to randomization to obtain a baseline value. Patients with abnormal TSH or AM cortisol baseline levels should be further evaluated and managed per institutional standards.
- The LVEF must be 55% regardless of the cardiac imaging facility's lower limit of normal.
- For women of childbearing potential: abstinence or use contraceptive methods during the treatment period and for at least 5 months after the last dose of atezolizumab / placebo or 12 months after the last dose of chemotherapy.
- Patient must be willing and able to comply with scheduled visits, treatment plans, lab tests, and other study procedures. |
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| E.4 | Principal exclusion criteria |
- Excisional biopsy or lumpectomy performed prior to study entry.
- FNA alone to diagnose the breast cancer.
- Surgical axillary staging procedure prior to randomization. Exception: FNA or core biopsy of an axillary node is permitted for any patient. A pre-neoadjuvant therapy sentinel lymph node biopsy for patients with clinically negative axillary nodes is prohibited.
- Definitive clinical or radiologic evidence of metastatic disease.
- Previous history of contralateral invasive breast cancer. (Patients with synchronous and/or previous contralateral DCIS or LCIS are eligible.)
- Previous history of ipsilateral invasive breast cancer or ipsilateral DCIS. (Patients with synchronous or previous ipsilateral LCIS are eligible.)
- History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.
- Treatment including radiation therapy, chemotherapy, or targeted therapy, for the currently diagnosed breast cancer prior to randomization.
- Previous therapy with anthracyclines or taxanes for any malignancy.
- Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens.
- Uncontrolled hypertension defined as sustained systolic BP 150 mmHg or diastolic BP 90 mmHg. Patients requiring 3 BP medications are not eligible.
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
- Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells.
- Known allergy or hypersensitivity to the components of the atezolizumab formulation.
- Known allergy or hypersensitivity to the components of the doxorubicin, cyclophosphamide, carboplatin, or paclitaxel formulations.
- Known allergy or hypersensitivity to liposomal or pegylated G-CSF formulations.
- Active or history of autoimmune disease or immune deficiency.
- 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.
- Patients known to be HIV positive.
- Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B surface antigen (HBsAg) test at screening.
Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study if active HBV infection is ruled out on the basis of HBV DNA viral load per local guidelines.
- Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test at screening confirmed by a polymerase chain reaction (PCR) positive for HCV RNA.
- Patients with clinically active tuberculosis.
- Severe infection within 28 days prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
- Prior allogeneic stem cell or solid organ transplantation.
- Patients receiving therapeutic anti-coagulants are not eligible.
- Administration of a live, attenuated vaccine within 28 days prior to randomization or anticipation that such vaccine will be required during the study. Patients must agree not to receive live, attenuated influenza vaccine within 28 days prior to randomization, during treatment or within 5 months following the last dose of atezolizumab/placebo.
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
- Prior treatment with CD137 agonists or immune checkpoint-blockade therapies, including anti-CD40, anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
- Treatment with systemic immunosuppressive medications 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−tumor necrosis [anti-TNF] factor agents) within 14 days prior to randomization or anticipation of need for systemic immunosuppressive medications during the study.
- Nervous system disorder (paresthesias, peripheral motor neuropathy, or peripheral sensory neuropathy) Grade 2, per the CTCAE v4.0.
- Symptomatic peripheral ischemia.
- Pregnancy or lactation at the time of randomization or intention to become pregnant during the study. (Note: Negative serum pregnancy test must be obtained within
14 days prior to randomization).
- Use of any investigational agent within 28 days prior to randomization.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Event-free survival (EFS)
Aim: To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves event-free survival (EFS) in patients with triple-negative breast cancer. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoint: EFS is defined as time from randomization until event: EFS events are progression on protocol therapy resulting in administration of non-protocol cancer therapy or inoperability, local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause prior to recurrence or second primary cancer. |
|
| E.5.2 | Secondary end point(s) |
Overall survival (OS)
Aim: To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves overall survival (OS) in patients with triple-negative breast cancer.
• Pathologic complete response in the breast and lymph nodes (ypT0/Tis ypN0)
Aim: To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) improves pathologic complete response in the breast and post-therapy lymph nodes evaluated histologically (pCR breast and nodes) in patients with triple-negative breast cancer.
• Disease-free survival (DFS)
Aim: To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves disease-free survival (DFS) in patients with triple-negative breast cancer.
• Distant disease-free survival (DDFS)
Aim: To determine whether the addition of atezolizumab to chemotherapy (weekly paclitaxel plus carboplatin followed by AC or EC) followed by adjuvant atezolizumab improves distant disease-free survival (DDFS) in patients with triple-negative breast cancer.
• Toxicity
Aim: To evaluate toxicity associated with study therapy added to chemotherapy and radiation therapy.
Aim: To evaluate immune-adverse events of special interest
• Cardiac safety lead-in study
Aim: To assess for potential augmentation of anthracycline-related cardiac toxicity with co-administration of study therapy. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS - Time from randomization until death from any cause.
pCR- in the breast (ypT0/Tis) defined as the absence of any invasive component in the resected breast specimen.
DFS - Time from the first breast operation to the first occurrence of disease recurrence or death from any cause.
DDFS - Time from randomization until distant recurrence, death from breast cancer, death from other causes, and second primary invasive cancer (non-breast).
Toxicity - Frequency and severity of AEs graded according to the NCI Common Terminology Criteria 4.0 (CTCAE v4.0).
• Cardiac safety lead-in study - Troponin-T levels 1) prior to initial dose of AC/EC; LVEF levels at 1) baseline prior to initiation of carboplatin/paclitaxel and atezolizumab/placebo, 2) before 3rd cycle of AC/EC, and 3) after surgery. |
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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 | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 112 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 86 |
| 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 |
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| 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
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Time point until 252 events will have occured.
With the final enrollment period and accrual information, follow-up of an additional 22 months after completion of accrual should be sufficient to obtain 252 EFS events (total time from first patient in to EFS analysis of 64 months). |
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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
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