| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple-negative breast cancer patients With matasteses |
|
| E.1.1.1 | Medical condition in easily understood language |
| 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 |
- Assessment of toxicity of combined treatment with atezolizumab, pegylated liposomal doxorubicin and cyclophosphamide
- Assessment of clinical response: Progression-free survival; descriptive comparison of the PFS rates in the total per protocol (PP) population, and the PD-L1+ PP population |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objective:
- Assessment of clinical response: Overall tumor response rate (ORR), duration of response (DR), durable tumor response rate (DRR; >6 months), overall survival (OS)
- Assessment of changes in imminological milieu in tumor and peripheral blood
- Assessment of PD-L1 expression
- Assessment of patient reported outcomes, as measured by the Chalder Fatigue Questionnaire (FQ), an 11 point Numerical Rating Scale (NRS) for pain intensity and EORTC QLQ-C15-PAL
Exploratory objectives:
- Assessment of immunological response
- ldentification of biomarkers for clinical response, toxicity and immune response
- Characterization of tumor evolution induced by the study therapy concidering each study arm separately, and by comparing arm A to B
- Characterization of changes in microbiota induced by the study therapy, considering each study arm separately, and by comparing arm A to arm B
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Metastatic or incurable locally advanced, histologically documented TNBC
2. Adequate newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. No anti-tumor treatment is allowed between the time point for biopsy and study entry. If a patient has undergone chemotherapy in the metastatic setting, a new biopsy must be obtained after this therapy
3. Measurable disease according to iRECIST
4. Signed Informed Consent Form
5. Women or men aged ≥ 18 years
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. A minimum of 12 months from (neo)adjuvant treatment with anthracyclines or cyclophosphamide until relapse of disease
8. A maximum of one previous line with chemotherapy in the metastatic setting
9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication.
10. Female subjects of childbearing potential should agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, during the treatment period and for at least 90 days after the last dose of study therapy.
11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy
12. Able to swallow orally administrated medication.
13. Adequate organ function as defined in Table 1 in the protocol
For details regarding the critierias, see section 4.0 in the protocol |
|
| E.4 | Principal exclusion criteria |
1. Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome
2. Patients with known PD-L1 positive TNBC, and no previous chemotherapy in the metastatic setting, should be offered standard therapy with nab-paclitaxel/atezolizumab outside of the trial. Please see detailed considerations section 5.0 in the protocol.
3. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomization
4. Known CNS disease, except for asymptomatic CNS metastases, provided the criterias, section 5.0 in the protocol.
5. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed
6. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry.
7. Ionized calcium > 1.2 x UNL. The use of bisphosphonates is allowed
8. Pregnant or breastfeeding
9. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results
10.Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to randomization, unstable arrhythmias, or unstable angina.
11. Severe infection within 14 days prior to randomization, requiring hospitalization
12. Received oral or IV antibiotics within 1 week prior to Cycle 1, Day 1. Patients receiving routine antibiotic prophylaxis are eligible
13. Major surgical procedure within 14 days prior to randomization or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis.
14. A history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
15. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
16. Known hypersensitivity to doxorubicin or cyclophosphamide or any of their excipients
17. A history of autoimmune disease that has required systemic treatment in the past 2 years. For further details/exceptions, see section 5.0 in the protocol
18. Undergone allogeneic stem cell or solid organ transplantation
19. A history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan.
20. A positive test for HIV
21. Active hepatitis B or hepatitis C.
22. Active tuberculosis
23. Currently receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
24. Received treatment with immune checkpoint modulators, including anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibodies
25. Received treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
26. Received treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
27. Received anti-cancer therapy (medical agents or radiation) within 2 1 weeks prior to study Cycle 1, Day 1.
28. A history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator
29. Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
30. Any reason why, in the opinion of the investigator, the patient should not participate. This includes a careful evulation of whether standard therapy is preferable to the study therapy, for the individual patient.
For further details re these bullet Points, see section 5.0 in the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from randomization to the time of disease (as assessed by irRECIST) or death from any cause during the study |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| We expect to reach the data-driven time point for PFS-analysis (95% PFS events in all patients and in PD-L1 positive PP) 2.5-3 years after the study opens. lf this is not met within 18 months after inclusion of the last patient, the PFS analysis will beperformed at this time point. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy outcome measures will beassessed in the ITT population and in the PD-L1-positive subpopulation as follows:
- Overall survival (OS), defined as the time from the date of randomization to the date of death from any cause
- Objective tumor response rate (ORR), defined as the proportion of patients with an objective tumor response (either partial response [PR] or complete response [CR] per investigator using irRECIST)
- Durable response rate (DRR), defined as the proportion of patients with an objective tumor response lasting at least 6 months
- Duration of objective response (DOR) among patients with an objective response
- PFS in the PD-L1-negative subpopulation assessed by irRECIST
- PFS, ORR, DRR and DOR assessed by RECIST v1.1
- lnvestigator-assessed PFS using irRECIST, with no censoring at missing scans
- lnvestigator-assessed PFS using RECIST v1.1, with no censoring at missing scans
Safety Outcome Measures
- lncidence, nature, and severity of adverse events graded according to NCI CTCAE v4.0 and AESls for atezolizumab.
- Changes in vital signs, physical findings, and clinical laboratory results
Exploratory Outcome Measures Assessment of immunological response:
- ldentification of biomarkers for clinical response, toxicity and immune response
- Characterization of tumor evolution and changes in immunological milieu induced by the combination therapy (atezolizumab+chemo), as compared to chemo only
- Development in FQ score(11). The analyses will include time to deterioration (TTD) in the FQ score, defined bya minimally clinically important difference (MCID) of ≥ 3 points. The maximum total FQ score is 33 points. For mean score, a separate analysis will beperfomed for subjects with a baseline FQ score ≥ 21 points
- Development in NRS pain intensity score for average pain the last 24 hours (corresponding to one item in BPI). The analyses will include TTD in the pain intensity score, defined by a minimally clinically important difference (MCID) of ≥ 2 points (scale 0-10). For mean score, a separate analysis will beperformed for subjects with a baseline score ≥ 4 points
- Mean changes and TTD in item 15of the EORTC QLQ-C15-PAL, defined bya MCID ≥ 20 points at patient individual level. A change of ≥ 10 points is considered to be of clinical importance at group level. The development of other scales and items of QLQ-C15 will also be recorded |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These endpoints will be evaluated at the time of final analysis. |
|
| 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) | 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 | 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 overall trial ends when the last patient included has completed 2 years FU With study medication. This is expected to be late 2023. It is thereafter expected one year until the final study report is available. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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