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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
6
75 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 4 courses preoperatively.
AUC 6 iv, day 1 every third week, 4 courses preoperatively.
600 mg sc, day 1 every third week, 4 courses preoperatively. 14 courses postoperatively if complete response.
Sahlgrenska universitetssjukhuset
Gothenburg, Sweden
Skånes universitetssjukhus
Malmö, Sweden
Örebro universitetssjukhus
Örebro, Sweden
Karolinska universitetssjukhuset
Stockholm, Sweden
Rate of pathological objective response to primary medical treatment
Efficacy measure at surgery that is performed 2-3 weeks after 7 cycles (each cycle lasts 21 days) of preoperative treatment.
Time frame: At surgery 2-3 weeks after the last (of 7) cycles of neo-adjuvant systemic therapy.
Objective response rate
Proportion of patients with reduction in tumour burden ≥30% according to RECIST
Time frame: After the 4th and 7th cycle (each cycle is 21 days)
Distant disease-free survival
Time from randomisation to distant metastases or death due to breast cancer
Time frame: During the study period up to 10 years
Event-free survival
Time from randomisation to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death from any cause
Time frame: During the study period up to 10 years
Overall survival
Time from randomisation to death from any cause
Time frame: During the study period up to 10 years
Rate of breast conserving surgery
Rate
Time frame: At surgery
Incidence of treatment-emergent adverse events (Safety)
Rate of grade 3-4 toxicity, rate of % of discontinuation of study medication due to toxicity, rate of AE's of special interest
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
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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.
90 mg/m2 iv, escalated to 100 mg/m2 if tolerated, day 1 every third week, 3 courses preoperatively
600 mg/m2 iv, day 1 every third week, 3 courses preoperatively
840 mg iv, day 1 every third week, 3 courses preoperatively if randomised to arm A.
3.6 mg/kg iv, day 1 every third week, 14 courses postoperatively if not complete response.
80 mg/m2 iv, day 1 weekly, 12 weeks (4 cycles), in case of (anticipated) unmanageable toxicity related to docetaxel.
S:t Görans sjukhus
Stockholm, Sweden
Södersjukhuset
Stockholm, Sweden
Länssjukhuset Sundsvall
Sundsvall, Sweden
Norrlands universitetssjukhus
Umeå, Sweden
Differences in PROMs according to EORTC C30
Health related Quality of Life using the EORTC C30 scale (EORTC Quality of Life questionnaire 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
Differences in PROMs according to EORTC BR23
Health related Quality of Life using the EORTC BR23 scale (EORTC Quality of Life breast specific questionnaire 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
Differences in objective cognitive function
Assessed by an online neuropsychological test (Amsterdam Cognition Scan, validated for use in breast cancer patients \[Feenstra et al, J Clin Exp Neuropsychol. 2018 Apr;40(3):253-273. \])
Time frame: At baseline, 3 months after surgery, one and five year after treatment start
Treatment prediction, PD-L1
% of Programmed Death Ligand 1 expressing cells \[tumour cells and tumour infiltrating lymphocytes\]
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
Treatment prediction, TMB
Tumour-mutational burden (total number of nonsynonymous mutations per coding area of a tumor genome)
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
Treatment prediction, TILs
Percentage of tumour infiltrating lymphocytes
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
Treatment prediction, composition of faeces microbiome
Composition of bacterial strains in gastro-intestinal flora (% of different strains measured with DNA/RNA analysis and in microbiotic culture)
Time frame: At baseline, after 7th cycle (each cycle is 21 days) before surgery, and one year after surgery
Differences in PROMs
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.
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