| 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 |
| Breast cancer is cancer that develops from breast tissue |
|
| 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 | 10039850 |
| E.1.2 | Term | Secondary malignant neoplasm of breast |
| 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 | 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 |
| •To evaluate the pathologic complete response rates (pCR) with atezolizumab + nab-pac-AC compared with placebo + nab-pac-AC in the neoadjuvant setting |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate survival rates (EFS, DFS, OS) with atezolizumab+nab-pac-AC compared with placebo + nab-pac-AC in the neoadjuvant setting
•To evaluate the pathologic complete response rates (pCR) with atezolizumab + nab-pac-AC compared with placebo + nab-pac-AC in the neoadjuvant setting in patients whose tumors are biomarker-positive
•To evaluate PROs of function and HRQoL associated with atezolizumab + nab-pac AC compared with placebo + nab-pac-AC, measured by the functional and HRQoL scales of the EORTC QLQ-C30
•To evaluate the safety and tolerability of atezolizumab + nab-pac-AC compared with placebo + nab-pac-AC
•To characterize the pharmacokinetics of atezolizumab when administered in combination with nab-pac-AC chemotherapy
•To evaluate the immune response to atezolizumab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Women or men aged >= 18 years
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Histologically documented triple-negative breast cancer (TNBC) (negative human epidermal growth factor receptor 2 [HER2], estrogen receptor [ER], and progesterone receptor [PgR]). HER2 negativity will be defined by central laboratory assessment using in situ hybridization or immunohistochemistry (IHC) assays per American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) criteria and ER/PgR negativity will be defined by central laboratory assessment using IHC per ASCO/CAP criteria. Central laboratory assessment will occur prior to randomization.
- Patients with multifocal tumors (more than one tumor confined to the same quadrant as the primary tumor) are eligible provided all discrete lesions are sampled and centrally confirmed as TNBC.
- Confirmed tumor programmed death−ligand 1 (PD-L1) evaluation as documented through central testing of a representative tumor tissue specimen
- Primary breast tumor size of > 2 cm by at least one radiographic or clinical measurement
- Stage at presentation: cT2 cT4, cN0 cN3, cM0
- Patient agreement to undergo appropriate surgical management including axillary lymph node surgery and partial or total mastectomy after completion of neoadjuvant treatment
- Baseline left ventricular ejection fraction >= 53% measured by echocardiogram or multiple-gated acquisition scans
- Adequate hematologic and end-organ function
- Representative formalin-fixed, paraffin-embedded tumor specimen in paraffin blocks (preferred) or at least 20 unstained slides, with an associated pathology report documenting ER, PgR, and HER2 negativity
- Women who are not postmenopausal (>=12 months of non-therapy-induced amenorrhea) or have undergone a sterilization procedure must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods and agreement to refrain from donating eggs.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
|
|
| E.4 | Principal exclusion criteria |
- Prior history of invasive breast cancer
- Stage IV (metastatic) breast cancer
- Prior systemic therapy for treatment and prevention of breast cancer
- Previous therapy with anthracyclines or taxanes for any malignancy
- History of ductal carcinoma in situ (DCIS), except for patients treated exclusively with mastectomy >5 years prior to diagnosis of current breast cancer
- History of pleomorphic lobular carcinoma in situ (LCIS), except for patients surgically managed >5 years prior to diagnosis of current breast cancer (note that patients with nonpleomorphic LCIS [either untreated or treated with surgery] are allowed)
- Bilateral breast cancer
- Undergone incisional and/or excisional biopsy of primary tumor and/or axillary lymph nodes
- Axillary lymph node dissection prior to initiation of neoadjuvant therapy
- History of other malignancy within 5 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year OS of >90%), such as adequately treated carcinoma in situ of the cervix, non melanoma skin carcinoma, localized prostate cancer, DCIS, or Stage I uterine cancer
- Cardiopulmonary dysfunction
- 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 formulations of atezolizumab, nab-paclitaxel, cyclophosphamide, or doxorubicin, filgrastim or pegfilgrastim
- Active or history of autoimmune disease or immune deficiency diseases except history of autoimmune-related hypothyroidism, controlled Type I diabetes mellitus, and only dermatologic manifestations of eczema, psoriasis, lichen simplex chronicus, or vitiligo (e.g., patients with psoriatic arthritis are excluded)
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Positive HIV test at screening
- Active hepatitis B and hepatitis C virus infection
- Active tuberculosis
- Severe infections within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment, except prophylactic antibiotics
- Major surgical procedure within 4 weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure during the course of the study
- Prior allogeneic stem cell or solid organ transplantation
- Administration of a live attenuated vaccine within 4 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the study
- 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 immunostimulatory agents within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment
- Treatment with systemic immunosuppressive medications within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medications during the study
- Pregnant or lactating, or intending to become pregnant during the study
- History of cerebrovascular accident within 12 months prior to randomization |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Pathologic complete response (pCR) (eradication of invasive cancer from both breast and lymph nodes [ypT0/is; ypN0]) in all patients and subpopulation with PD-L1-selected tumor status (IC1/2/3) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 1. Approximately 44 months |
|
| E.5.2 | Secondary end point(s) |
1) Event-free survival
2) Disease-free survival
3) Overall survival
4) Mean and mean changes from baseline score in functional and health-related quality of life scales of the European Organisation or Research and Treatment of Cancer Quality of Life Questionnaire Core 30
5) Incidence of adverse events
6) Serum concentration of atezolizumab
7) Incidence of anti-drug antibodies (ADAs) during the study and the prevalence of ADAs at baseline
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-7. Approximately 74 months
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Germany |
| Japan |
| Korea, Republic of |
| Taiwan |
| United Kingdom |
| United States |
|
| 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 for evaluation of secondary endpoints. Thirty-six months after randomization of the last patient, all patients will be contacted for final evaluation of the secondary endpoints of EFS, DFS, OS, and PROs. LPLV for Stage 1 is expected to occur approx. 51 months after the first patient is randomized. If the study expands to Stage 2, LPLV may occur at approx. 74 months after the first patient is randomized. |
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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