| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic triple-negative breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic 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 | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 efficacy –in terms of progression-free survival (PFS)– of first line atezolizumab in combination with paclitaxel and bevacizumab (Avastin®) in patients with unresectable locally advanced or metastatic TNBC. |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy
To assess the efficacy –in terms of time to response (TTR), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), overall survival (OS), and best percentage of change in target tumor lesions– of first-line atezolizumab in combination with paclitaxel and bevacizumab (Avastin®) in these patients.
Safety
To evaluate the safety and tolerability of the addition of atezolizumab to the combination of paclitaxel and bevacizumab (Avastin®) in these patients.
Exploratory objectives:
• To assess the efficacy of first-line atezolizumab in combination with paclitaxel and bevacizumab (Avastin®) based on Immune-Related RECIST (irRECIST).
• To evaluate predictive or prognostic biomarkers associated with disease activity status or response to treatment.
• To identify possible mechanisms of resistance to study treatment through the comparative analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or blood samples. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent form (ICF) prior to participation in any study-related activities
2. Male or female patients ≥ 18 years at the time of signing ICF
3. Ability to comply with the study protocol, in the investigator's judgment
4. Histologically confirmed TNBC –regardless of PD-L1 status– per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria based on local testing on the most recent analyzed biopsy. Triple-negative is defined as <1% expression for estrogen receptor (ER) and progesterone receptor (PgR) as determined by immunohistochemistry (IHC),and negative for HER2 (0–1+ by immunohistochemistry [IHC] or 2+ and negative by in situ hybridization [ISH] test)
5. Unresectable locally advanced or metastatic disease documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent
6. No prior chemotherapy and/or targeted therapy and/or immunotherapy and/or antiangiogenic agent for MBC. Patients who have received (neo)adjuvant taxane-based chemotherapy and/or immunotherapy and/or an antiangiogenic agent are required to have a disease-free interval (DFI) of at least 12 months after completion of each of these treatments. For (neo)adjuvant non-taxane-based chemotherapy, a DFI of at least 6 months is required
7. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the NCI-CTCAE v.5.0 (except for alopecia, grade ≤ 2 peripheral neuropathy, or other toxicities not considered a safety risk for the patient at investigator's discretion)
8. Evidence of measurable disease or non-measurable disease as per RECIST v.1.1. Patients with only bone lesions are also eligible
9. Willingness and ability to provide the most recent tumor biopsy since last progression from either metastatic or primary tissues at the time of the inclusion to perform exploratory studies. If not feasible, patient eligibility should be evaluated by a Sponsor’s qualified designee. An additional tumor biopsy from either metastatic or primary (only if metastatic biopsies cannot be obtained for inaccessible lesion or subject safety concern) tissues would be collected at disease progression or study termination whenever it is feasible
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
11. Life expectancy of ≥12 weeks
12. Adequate hematologic and organ function within 14 days before the first study treatment on Cycle 1 Day 1 (C1D1), defined by the following parameters:
a. Hematological:i. White blood cell (WBC) count > 3.0 x 109/L; ii. Absolute neutrophil count (ANC) > 1.5 X 109/L; iii. Lymphocyte count 0.5 x 109/L (500L); iv. Platelet count 75.0 x 109/L; v. Hemoglobin > 9.0 g/dL
b. Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (≤ 3 x ULN in the case of Gilbert’s disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case of liver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2.5 × ULN (≤ 5 × ULN in the case of liver and/or bone metastases).
c. Serum albumin ≥ 2.5 g/dL
d. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min based on Cockcroft−Gault glomerular filtration rate estimation. No proteinuria by dipstick urinalysis (trace proteinuria is allowed). In cases of proteinuria at least 1+ by urinalysis, proteinuria should be less than 500 mg by 24-hour urine collection.
e. Coagulation:
- For patients not receiving therapeutic anticoagulation: Partial Thromboplastin Time (PTT) (or activated Partial Thromboplastin Time [aPTT]) and International Normalized Ratio (INR) ≤ 1.5 × ULN.
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.
13. Negative human immunodeficiency virus (HIV) test at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count larger 200/microL, and have an undetectable viral load.
14. Negative hepatitis B surface antigen (HBsAg) test and negative total hepatitis B core antibody (HBcAb) tests at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. Current treatment with anti-viral therapy for HBV is not allowed.
15. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening.
16. Women of childbearing potential must have a negative serum pregnancy test within 14 days before study treatment initiation and agree to remain abstinent (refrain from heterosexual intercourse) or use one highly effective contraceptive method, or two effective contraceptive methods, as defined in the protocol during the treatment period for at least 5 months after the last dose of atezolizumab, and for at least 6 months after the last dose of paclitaxel and bevacizumab (Avastin®). |
|
| E.4 | Principal exclusion criteria |
1. Known active uncontrolled or symptomatic central nervous system (CNS) metastases as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases are eligible if they meet the following criteria:
• Evidence of measurable disease or non-measurable disease as per RECIST v.1.1.
• The patient has no history of intracranial hemorrhage.
• The patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.
• The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anticonvulsant therapy at a stable dose is permitted.
2. History of leptomeningeal disease.
3. Uncontrolled tumor-related pain.
4. Active or history of autoimmune disease or immune deficiency
5. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures.
Note: Patients with indwelling catheters (e.g., PleurX®) are allowed.
6. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L; calcium > 12 mg/dL).
7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
8. Active tuberculosis.
9. Significant cardiovascular disease 6 months prior to initiation of study treatment. These include New York Heart Association Class II or greater cardiac disease, myocardial infarction, unstable arrhythmia, or unstable angina, symptomatic pericarditis, ventricular arrhythmias –except for benign premature ventricular contractions–, arrhythmias or conduction abnormalities requiring a pacemaker or not controlled with medication, and prior peripheral vascular disease including any cerebrovascular accident including transient ischemic attack, any pulmonary embolism, any prior deep vein thrombosis, and/or any grade ≥ 2 peripheral vascular disease.
10. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO).
11. Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg and diastolic blood pressure greater than 100 mmHg).
12. Major surgical procedure (defined as requiring general anesthesia) or significant traumatic injury within 28 days of start of study drug, or patients who have not recovered from the side effects of any major surgery.
13. Concurrent malignancy(ies) or malignancy(ies) within 5 years of study enrollment except for carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
14. Treatment with therapeutic oral or IV antibiotics or severe infection 2 weeks prior to initiation of study treatment.
Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
15. Prior allogeneic stem cell or solid organ transplantation
16. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
17. Extracranial radiotherapy or limited-field palliative radiotherapy within seven days prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to baseline or grade ≤ 1.
18. Treatment with investigational therapy within 28 days prior to initiation of study treatment.
19. Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) or anticipation of need for systemic immunosuppressive medication during study treatment
20. Chronic daily intake of antiplatelet drugs (e.g., aspirin doses of 325 mg/day or higher or non-steroidal anti-inflammatory medication known to inhibit platelet function).
21. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or
22. Breast-feeding women
23. Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgement, contraindicate patient participation in the clinical study.
24. Concurrent participation in other interventional clinical trials. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Median PFS, defined as the period of time from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Analysis will be performed on full analysis and per-protocol sets. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
• TTR, defined as the time from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a complete response (CR) or partial response (PR), as determined locally by the investigator using RECIST v.1.1.
• ORR, defined as the sum of CR and PR as determined locally by the investigator using RECIST v.1.1.
• CBR, defined as the sum of objective responses (CR or PR), or stable disease (SD) for at least 24 weeks, as determined locally by the investigator using RECIST v.1.1.
• DoR, defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1.
• OS, defined as the time from treatment initiation to death from any cause or last patient contact.
• Best percentage of change from baseline in the size of target tumor lesions, defined as the biggest decrease, or smallest increase in case of no observed increase, as determined locally by the investigator using RECIST v.1.1.
Safety
Incidence and severity of adverse events (AEs), serious adverse events (SAEs) according to the National Cancer Institute’s – Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0, including dose reductions, delays, and treatment discontinuations.
Exploratory endpoints
• Immune-related PFS (irPFS) and immune-related ORR (irORR) based on investigator assessment using irRECIST.
• Relationship between tumor- and/or immune-related biomarkers and treatment efficacy (PD-L1 expression and tumor-infiltrating lymphocytes [TILs]; mutational tumor load; cytokine profiling; etc.).
• Changes in mutation and copy number in oncogenes, tumor suppressors, and/or other genes associated with disease progression assessed in liquid biopsy and/or tumor samples. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Analysis will be performed on full analysis and per-protocol sets. |
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 40 |
| 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 |
| France |
| Spain |
| Germany |
| Italy |
| Portugal |
| United Kingdom |
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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
|
| The End of study will occur 12 months after the last patient has been enrolled in the study (coinciding with date of treatment initiation) or when at least 67 PFS events with 100 patients included have been reached, whichever occurs later. |
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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 | 2 |
| 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 | 2 |
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