| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 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 |
Validate the BRCA-like test*in predicting differential progression free survival (PFS) according to RECIST v1.1 definitions with first line alkylating and platinum agents when compared to paclitaxel in TNBC
* BRCA-like status determined by array comparative genomic hybridization (aCGH), multiplex ligase-dependent probe amplification (MLPA), or next generation sequencing (NGS); BRCA-like test positive when the genomic profile resembles that of BRCA-mutated breast cancers (BRCA-like genomic profile, derived from BRCA1 or BRCA2 mutation), or when the tumor is BRCA1-mutated, BRCA2-mutated, the patient is a BRCA1 and/or BRCA2 germline mutation carrier, or has a BRCA1 promoter hypermethylation |
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| E.2.2 | Secondary objectives of the trial |
1.Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1).
2.Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide for patients with PD-L1 positive tumors defined as combined positive score (CPS) 10 or higher (PFS1).
3. Whether the addition of atezolizumab to chemotherapy will result in more objective responses and a higher proportion of patients who are free of progression at 6 and 12 months
4. Whether PD-L1 status in tumor cells or TI immune cells predicts for PFS benefit of atezolizumab in first line
5. Whether intratumoral CD8 and/or TIL predict for PFS benefit of atezolizumab in first line
6. Whether alkylating-platinum regimen is more effective than paclitaxel as first line chemotherapy regarding PFS in BRCA-like TNBC
See protocol for objectives 7-19. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Metastasized or locally advanced incurable triple negative breast cancer; patients with stage IV at diagnosis are eligible as well. If the primary lesion is the only measurable lesion according to RECIST criteria, every locoregional treatment must be mentioned to the investigators.
- Histologically confirmed triple negative breast cancer (ER: < 10% nuclear staining of tumor cells on IHC; HER2: either score 0 or 1 at immunohistochemistry or negative at in situ hybridization [CISH or FISH] in case of score 2 or 3 on IHC) 47
- Histological confirmation of triple negative breast cancer of a metastatic lesion is
recommended
- Histological or cytological confirmation of metastatic breast cancer is required in case of
normal CA 15.3 levels, unless according to the principal investigators there is no doubt that the metastatic disease concerns triple negative breast cancer origin based on the course of the disease. In case patient has bone-only disease, a bone-biopsy of a metastatic lesion should be taken. A patient is only eligible if there is measurable or evaluable disease according to RECIST v1.1 (bone metastases with soft tissue masses measuring ≥ 10mm).
- Primary tumor or metastasis tissue (tumor blocks, or 10 x10 μm blank slides FFPE tumor material) sent to NKI-AVL for BRCA-like testing
- Pretreatment histological biopsy of a metastatic lesion for the translational research questions (tumor tissue from bone metastases cannot be used). In case patient has metastatic lesions that are too risky to take a biopsy from according to the principal investigators or radiologist (including but not limited to mediastinal lymph nodus with EBUS) or the biopsy failed, patient could be included without a pretreatment biopsy of a metastatic lesion.
- No previous cytotoxic therapy for metastatic disease
- Disease-free interval of at least 12 months after completion of (neo)adjuvant paclitaxel or (neo)adjuvant platinum compound
- Disease-free interval of at least 6 months after completion of (neo) adjuvant docetaxel
- Measurable or evaluable disease according to RECIST v1.1
- WHO performance status of 0 or 1
- For women of childbearing potential: agreement 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 5 months after the last dose of atezolizumab/ or 5 months after the last dose of chemotherapy, whichever is later.
A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state ( 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs.
- Women who are not postmenopausal ( 12 months of nontherapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
- Adequate bone marrow function*: neutrophils ≥ 1.5 x 10E9 cells/l, platelets ≥100 x 10E9
cells/l, Hb ≥ 6.2 mmol/l.
- Normal liver function: bilirubin < 1.5 x upper limit of the normal range (ULN) (except elevated bilirubin due to Gilbert’s disease or a similar syndrome involving slow conjugation of bilirubin); alkaline phosphatase < 5 x ULN (< 7 x ULN in case of liver metastases or bone metastases); transaminases (ASAT/ALAT) < 5 x ULN (and < 7 x ULN in case of liver metastases).
- Normal renal function: calculated (Cockcroft-Gault) or measured creatinine clearance > 50 mL/min*
- INR < 1.5 unless patient is on stable anti-coagulant treatment with a low molecular weight heparine or coumarine, then an INR within the target range (usually between 2 and 3) is allowed. It is highly recommended that patients who are receiving a Direct Oral Anticoagulant (DOAC) replace it with a low molecular weight heparine.
- Written informed consent
* In case one of these values deviates only minimally, the principal investigators may decide in consultation with the treating physician and after informing the Sponsor to include this patient after all in case this has no consequences for patient safety and for the quality of the data.
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| E.4 | Principal exclusion criteria |
-Receptor conversion to hormone receptor positive(≥ 10% ER positive tumor cells 44 or HER2 positive
-Diagnosis of any other active malignancy prior to randomization, except those that are not believed to influence the patient’s prognosis and do not require further treatment. This includes, but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix
-Other antitumor therapy within the previous 21 days, with the exception of endocrine therapy. The patient should have stopped any endocrine therapy before start study treatment.
-Radiotherapy with palliative intent within the previous 7 days before start of study treatment. After 7 days patients may be included under the condition that at least one measurable/evaluable lesion was not irradiated.If radiation is needed on bone with an extensive amount of bone marrow, the interval between treatment and randomization might be longer(at the physician’s discretion)
-Known CNS disease except for treated brain metastases.Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment, as ascertained by clinical examination and brain imaging during the screening period and no ongoing requirement for systemic corticosteroids.Anticonvulsants(stable dose)are allowed.Treatment for brain metastases may include whole brain radiotherapy, radiosurgery(gamma knife, LINAC or equivalent)or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 2 weeks prior to randomization will be excluded
-Use of denosumab;Patients who are receiving denosumab must discontinue denosumab use and replace it with a bisphosphonate instead while on study.There is no required minimum washout period for denosumab
-Uncontrolled serious medical or psychiatric illness
-Pre-existing peripheral neuropathy>grade 1(NCI-CTC AE(version 4.03))at inclusion
-Severe infection within 4 weeks prior to randomization
-Received antibiotics within 2 weeks prior to cycle 1,day 1,for a severe infection(in need of hospitalization or in need of i.v. antibiotics)
A non-severe infection includes,but is not limited to,an uncomplicated urinary tract infection
-Major surgical procedure,open biopsy,or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgical procedure during the course of the study
-New York Heart Association Class II or greater congestive heart failure.LVEF by MUGA or ultrasound or MRI must be≥50% and should be performed within 4 weeks prior to randomization if cardiac failure is suspected.
-History of myocardial infarction or unstable angina or unstable arrhythmias within 3 months prior to randomization
-History of autoimmune disease,including but not limited to myasthenia gravis,myositis,autoimmune hepatitis,systemic lupus erythematosus,rheumatoid arthritis,inflammatory bowel disease,vascular thrombosis associated with antiphospholipid syndrome,Wegener’s granulomatosis,Sjögren’s syndrome,Guillain-Barré syndrome,multiple sclerosis,vasculitis,or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study
-Prior allogeneic stem cell or solid organ transplantation
-History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan
-Positive HIV test
-Active hepatitis B or hepatitis C
Past or resolved HCB infection(having a negative HBsAg test and a positive antibody to hepatitis B core antigenare eligible.
Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA
-Active tbc
-Live,attenuated vaccine within 4 weeks prior to randomization or anticipation that such a vaccine will be required during the study
-Prior treatment with anti-cancer vaccines or immune checkpoint blockade therapies
-Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug prior to randomization
-Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization,or anticipated requirement for systemic immunosuppressive medications during trial. See protocol for exeptions.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| BRCA-like test* as predicator of differential progression free survival (PFS) with first line alkylating and platinum agents when compared to paclitaxel in TNBC |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1. Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide for patients with PD-L1 positive tumors defined as CPS 10 or higher (PFS1).
2. Evaluate whether the addition of atezolizumab to paclitaxel is more favorable than adding atezolizumab to carboplatin-cyclophosphamide (PFS1).
3. Number of responses and proportion of patients who are free of progression at 6 months and at 12 months
4. PD--L1 in tumor cells or TIL as predictors for PFS benefit of atezolizumab in first line
5. Intratumoral CD8 and TIL as predictors for benefit of atezolizumab in first lineC
6. Alkylating-platinum regimen is more effective than paclitaxel in first line regarding PFS
7. Paclitaxel is more effective than an alkylating regimen in first line regarding PFS
6. Different TNBC molecular subtypes as poredictor of PFS benefit of atezolizumab in first line
8. Pretreatment LDH level as predictor for PFS benefit of atezolizumab in first line
9. Biomarkers for a PFS advantage of carboplatin-cyclophosphamide as first line
10. Biomarkers for a PFS advantage of paclitaxel in first line
11. Biomarkers for a PFS advantage of addition of atezolizumab in first line
12. PFS after cross-over to the other chemotherapy regimen with atezolizumab (PFS2)
13. Proportion of patients that is free of progression at 6 and 12 months after cross-over to chemotherapy with atezolizumab
14. Addition of atezolizumab in first line is more beneficial than in second line (PFS1+PFS2)
15. OS
16. Toxicity
17. PFS and OS in subgroups treated before amendment 3 with carboplatin/cyclophosphamide or paclitaxel with or without bevacizumab
18. BRCA-like status as predictor in subgroups defined by treatment regimen received before amendment 3
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
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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 | 14 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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