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.
Suspended
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Docetaxel | A: Experimental | |
| Carboplatin | A: Experimental | |
| Trastuzumab | Herceptin | A: Experimental |
| Pertuzumab | Perjeta | A: Experimental |
| Epirubicin | A: Experimental | |
| Cyclophosphamide | A: Experimental | |
| Atezolizumab | Tecentriq | A: Experimental |
| Trastuzumab emtansine | Kadcyla | A: Experimental |
| Paclitaxel | A: Experimental |
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| A: Experimental | Experimental | Four courses of docetaxel or paclitaxel + carboplatin + trastuzumab sc + pertuzumab given every third week followed by three courses of epirubicin + cyclophosphamide + atezolizumab. In total seven courses of preoperative treatment. Response evaluations after course four. Postoperatively, if pathologic complete response, patients receive 14 courses of adjuvant trastuzumab every third week. If no pCR patients receive 14 courses of T-DM1 every third week. |
|
| B: Standard | Active Comparator | Four courses of docetaxel or paclitaxel + carboplatin + trastuzumab sc + pertuzumab given every third week followed by three courses of epirubicin + cyclophosphamide. In total seven courses of preoperative treatment. Response evaluations after course four. Postoperatively, if pathologic complete response patients receive 14 courses of adjuvant trastuzumab (combined with pertuzumab in case of high-risk disease features) every third week. If no pCR patients receive 14 courses of T-DM1 every third week. |
|
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
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | Female |
| Healthy Volunteers: | No |
| Measure: | Rate of pathological objective response to primary medical treatment |
| Time Frame: | At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy. |
| Safety Issue: | |
| Description: | Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment. |
| Measure: | Objective response rate |
| Time Frame: | After the 4th and 7th cycle (each cycle is 21 days) |
| Safety Issue: | |
| Description: | Proportion of patients with reduction in tumour burden ≥30% according to RECIST |
| Measure: | Distant disease-free survival |
| Time Frame: | During the study period up to 10 years |
| Safety Issue: | |
| Description: | Time from randomisation to distant metastases or death due to breast cancer |
| Measure: | Event-free survival |
| Time Frame: | During the study period up to 10 years |
| Safety Issue: | |
| Description: | Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause |
| Measure: | Overall survival |
| Time Frame: | During the study period up to 10 years |
| Safety Issue: | |
| Description: | Time from randomisation to death from any cause |
| Measure: | Rate of breast conserving surgery |
| Time Frame: | At surgery |
| Safety Issue: | |
| Description: | Rate |
| Measure: | Incidence of treatment-emergent adverse events (Safety) |
| Time Frame: | During the 18-week period of treatment and until 30 days after termination and during the follow-up period up to ten years |
| Safety Issue: | |
| Description: | Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest |
| Measure: | Differences in PROMs according to EORTC C30 |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire C30) |
| Measure: | Differences in PROMs according to EORTC BR23 |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire BR23) |
| Measure: | Differences in objective cognitive function |
| Time Frame: | At baseline, 3 months after surgery, one and five year after treatment start |
| Safety Issue: | |
| Description: | 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. ]) |
| Measure: | Treatment prediction, PD-L1 |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | % of Programmed Death Ligand 1 expressing cells [tumour cells and tumour infiltrating lymphocytes] |
| Measure: | Treatment prediction, TMB |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome) |
| Measure: | Treatment prediction, TILs |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | Percentage of tumour infiltrating lymphocytes |
| Measure: | Treatment prediction, composition of faeces microbiome |
| Time Frame: | At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery |
| Safety Issue: | |
| Description: | Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture) |
| Measure: | Differences in PROMs |
| Time Frame: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Suspended |
| Lead Sponsor: | Renske Altena |
March 3, 2021
