Early-stage Breast Cancer, HER2-positive Breast Cancer
Conditions
Keywords
Neoadjuvant therapy, PD-L1 positive breast cancer
Brief summary
This is a phase 2 study evaluating medical treatment before surgery in HER2-amplified early breast cancer patients. Patients receive chemotherapy with HER2-targeted antibodies and are randomised to receive the checkpoint inhibitor atezolizumab or not.
Detailed description
The primary aim is to investigate whether the rate of pCR, after optimal neoadjuvant anti-HER2 based systemic therapy, can be increased by addition of atezolizumab. Secondary aims are to assess safety and tolerability of this treatment combination, and to identify therapy predictive factors for the anti-HER2 monoclonal antibodies trastuzumab and pertuzumab plus-minus atezolizumab with a backbone of chemotherapy, using modern molecular biological investigational procedures with analyses by repeated biopsies from an intra-patient longitudinal study design.
Interventions
DRUGDocetaxel
75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.
DRUGCarboplatin
AUC 6 iv, day 1 every third week, 4 courses preoperatively.
DRUGTrastuzumab
600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.
DRUGPertuzumab
840 mg iv starting dose, thereafter 420 mg, day 1 every third week. 14 courses postoperatively if complete response in patients with baseline high risk tumours.
DRUGEpirubicin
90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively
DRUGCyclophosphamide
600 mg/m2 iv, day 1 every third week, 3 courses preoperatively
DRUGAtezolizumab
840 mg iv, day 1 every third week, 3 courses preoperatively if randomised to arm A.
DRUGTrastuzumab emtansine
3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.
DRUGPaclitaxel
80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.
Sponsors
Renske Altena
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Both arms start with four cycles of docetaxel/paklitaxel+carboplatin+trastuzumab+pertuzumab. Thereafter arm A receives three cycles of epirubicin+cyclophosphamide+atezolizumab and arm B receives epirubicin+cyclophosphamide.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed PD-L1 expression ≥1% on tumour cells and/or TILs (prescreening phase) * Able to provide written informed consent * Female gender * Patients with breast cancer confirmed by histology, characterised by immunohistochemistry for ER, PR, HER2 and proliferation marker. * HER2 amplification, IHC 3+ and preferably confirmed by ISH * Tumor and blood samples available. * Age 18 years or older. Elderly patients in adequate condition for the planned therapy, which may be supported by a geriatric assessment (according to ASCO guideline; Mohile et al, JCO 2018) * Primary breast cancer \>20 mm in diameter or verified lymph node metastases * Adequate bone marrow, renal and hepatic functions (see Table 1) * LVEF ≥50% * ECOG performance status 0-1
Exclusion criteria
* Distant metastases without chance to cure, including node metastases in the contralateral thoracic region or in the mediastinum. An exception is presence of at most 2 morphologically characterized well-defined distant metastases accessible for stereotactic radiotherapy, provided that this treatment is available at the participating centre. * Other malignancy diagnosed within the last five years, except for radically treated basal or squamous cell carcinoma of the skin or CIS of the cervix * Patients in child-bearing age without adequate contraception * Pregnancy or lactation * Uncontrolled hypertension, heart-, liver-, or kidney-diseases or other medical/psychiatric disorders. * 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 are eligible for this study. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study. * Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., no psoriatic arthritis) are permitted provided that they meet the following conditions: * Rash must cover less than 10% of body surface area (BSA) * Disease is well controlled at baseline and only requiring low potency topical steroids * No acute exacerbations of underlying condition within the last 12 months (not requiring PUVA \[psoralen plus ultraviolet A radiation\], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high potency or oral steroids). * Vaccination with a live vaccine within 30 days of the first dose of study treatment * A known history of Human Immunodeficiency Virus (HIV) infection, hepatitis B (HBsAg reactive) or hepatitis C (HCV RNA detected) infection or active tuberculosis. * Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[TNF\] agents) within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial * Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study * Patients with a history of allergic reaction to IV contrast requiring steroid pre- treatment should have baseline and subsequent tumor assessments performed using MRI. * The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed. * Hypersensitivity to atezolizumab
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of pathological objective response to primary medical treatment | At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy. | Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate | After the 4th and 7th cycle (each cycle is 21 days) | Proportion of patients with reduction in tumour burden ≥30% according to RECIST |
| Distant disease-free survival | During the study period up to 10 years | Time from randomisation to distant metastases or death due to breast cancer |
| Event-free survival | During the study period up to 10 years | Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause |
| Overall survival | During the study period up to 10 years | Time from randomisation to death from any cause |
| Rate of breast conserving surgery | At surgery | Rate |
| Differences in PROMs according to EORTC C30 | At baseline, after cycle 4 (a cycle is 21 days), after cycle 7 (a cycle is 21 days), 2 months, 1 year and 5 years after surgery | Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire C30) |
| Incidence of treatment-emergent adverse events (Safety) | During the 18-week period of treatment and until 30 days after termination and during the follow-up period up to ten years | Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest |
| Differences in objective cognitive function | At baseline, 3 months after surgery, one and five year after treatment start | Assessed by an online neuropsychological test (Amsterdam Cognition Scan, validated for use in breast cancer patients \[Feenstra et al, J Clin Exp Neuropsychol. 2018 Apr;40(3):253-273. \]) |
| Treatment prediction, PD-L1 | At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years | % of Programmed Death Ligand 1 expressing cells \[tumour cells and tumour infiltrating lymphocytes\] |
| Treatment prediction, TMB | At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years | Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome) |
| Treatment prediction, TILs | At baseline, after the 4th cycle (each cycle is 21 days), at surgery and annually during the post-surgical follow-up period up to five years | Percentage of tumour infiltrating lymphocytes |
| Treatment prediction, composition of faeces microbiome | At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery | Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture) |
| Differences in PROMs | At baseline, after cycle 4 (each cycle is 21 days), after cycle 7 (each cycle is 21 days), 2 months, 1 year and 5 years after surgery | Symptoms using the Memorial Symptoms Assessment Scale (MSAS). The 32-item MSAS scale includes occurrence, frequency, severity, and distress associated with each symptom using four- and five-point rating scales. Symptom burden is calculated as the average of frequency, severity and distress of each symptom. Higher scores indicates higher symptom burden. |
| Differences in PROMs according to EORTC BR23 | At baseline, after cycle 4 (a cycle is 21 days), after cycle 7 (a cycle is 21 days), 2 months, 1 year and 5 years after surgery | Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire BR23) |
Countries
Sweden
Outcome results
None listed