ABCSG 52 Details *
This is an open-label, two-arm, randomized, single-stage phase II study of atezolizumab with dual HER2 blockade (trastuzumab and pertuzumab) and epirubicin as neoadjuvant immunichemotherapy in patients with HER2-positive, HR positive/negative early breast cancer.
|Coordinating Investigator:||Greil, Richard (Salzburg), Gnant, Michael (Vienna)|
|Sample size:||58 (national)|
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58 patients will be randomized in a 1:1 ration to receive either
- 2 cycles of atezolizumab q3w + 2 cycles of pertuzumab q3w and trastuzumab q3w (arm A)
- or 2 cycles of pertuzumab q3w and trastuzumab q3w (arm B)
in treatment part 1.
Treatment part 2 (consisting of 4 cycles of atezolizumab q3w, pertuzumab q3w, trastuzumab q3w and epirubicin q3w) will apply to all patients regardless of previous treatment assignment.
To evaluate the efficacy of a neoadjuvant immunochemotherapy regimen consisting of atezolizumab, trastuzumab, pertuzumab and epirubicin in regards to pathologic complete response (pCR = ypT0/is, ypN0) which is assessed in the overall study population at the time of surgery.
To evaluate efficacy in regards to
- Residual Cancer Burden (RCB)
- Overall Response Rate (ORR)
which are assessed in the overall study population at the time of surgery.
To evaluate the safety and tolerability of a neoadjuvant immunochemotherapy regimen consisting of atezolizumab, trastuzumab, pertuzumab and epirubicin which is assessed in the overall study population.
Patient Reported Outcome (PRO) Objective:
To evaluate Quality of Life (QoL) of a neoadjuvant immunochemotherapy regimen consisting of atezolizumab, trastuzumab, pertuzumab and epirubicin which is assessed in the overall study population at baseline, V3, the surgery visit and the EOSV.
- To evaluate the endpoints radiographic complete response (rCR) and radiographic partial response (rPR) which are assessed in the overall study population at the time of surgery
- To evaluate the endpoints early rCR, rPR, mCR, and mPR at V3 which are assessed in the overall study population as well as between the two treatment arms
- To evaluate the rate of patients considered as not suitable for breast conserving surgery at baseline but finally performed breast conserving surgery assessed at the EOSV in the overall study population
- To evaluate surgery-associated and any other perioperative complications at the EOSV in the overall study population
To explore signals of magnitude of association in regards to changes from baseline to V3 in immunological and genetic biomarkers which are assessed in the overall study population as well as between the two treatment arms.
Patients must meet the following criteria for study entry:
Patient / Disease Specifics
- Signed informed consent obtained prior to any study specific assessments and procedures which are not performed as part of standard of care
- Female patients, age ≥ 18 years at the time of signing informed consent form (ICF)
- Histologically confirmed invasive, unilateral adenocarcinoma of the breast with the following characteristics:
- cT1c-4a-d, N0–3, M0 per AJCC (American Joint Committee on Cancer) Breast Cancer Staging version 8 (refer to section 3, Appendix III)
- In the case of a multifocal tumor (defined as the presence of two or more foci of cancer within the same breast quadrant), the largest lesion must be > 1 cm and designated as the “target” lesion for all subsequent tumor evaluations
- In the case of a multicentric tumor (defined as the presence of two or more foci of cancer within different quadrants), the largest lesion must be > 1 cm and designated as the “target” lesion for all subsequent tumor evaluations
- histologically confirmed HER2 positivity; HER2 measurement to be assessed locally as 3+ by immunohistochemistry or 2+ by immunohistochemistry with HER2 amplification by In Situ Hybridization (ISH) according to the ASCO/CAP guideline (refer to section 4, Appendix IV)
- If biopsies were taken from more than one focus, all histologically confirmed invasive breast cancer foci have to be HER2 positive. In case of a multicentric tumor, at least two foci in different breast quadrants have to be histologically confirmed HER2 positive breast cancer.
- Hormone receptor positive or negative tumors
- Tumor tissue from FFPE core-needly biopsy of breast tumor measuring at least 3×1 mm must be transmitted to a central sample repository and feedback on central TIL assessment must be available prior to randomization
- Neoadjuvant chemotherapy indicated (at the discretion of the investigator)
- ECOG performance status 0-1
- In women of childbearing potential, urine or serum pregnancy test must be negative within 28 days prior to randomization. In postmenopausal women or hysterectomized patients, pregnancy tests do not need to be performed.
Note: Women of childbearing potential must agree to remain abstinent or use adequate contraception that result in a failure rate < 1 % per year during the study treatment and for a period of 7 months following the last administration of study drug. Adequate contraception is defined as one highly effective form (abstinence, (fe)male sterilization) OR two effective forms (e.g. non-hormonal IUD and condom / occlusion cap with spermicidal foam / gel / film / cream / suppository). Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- Adequate left ventricular ejection fraction (LVEF) at baseline, defined as LVEF ≥ 55 % by either echocardiogram or MUGA.
Adequate hematologic and end-organ function, defined by the following laboratory results:
Baseline body function specifics
- ANC ≥ 1.5 x 10^9/L (1500/µL) without granulocyte colony-stimulating factor support
- Lymphocyte count ≥ 0.5 x 10^9/L (500/µL)
- Platelet count ≥ 100 x 10^9/L (100,000/µL) without transfusion
- Hemoglobin ≥ 90 g/L (9 g/dL). Patients may be transfused to meet this criterion
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.
- Aspartate amino transferase (AST), alanine amino transferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 x ULN
- Serum bilirubin ≤1.5 x ULN with the following exception: Patients with known Gilbert’s syndrome: serum bilirubin level ≤ 3 x ULN
- Serum creatinine ≤ 1.5 x ULN AND creatinine clearance ≥ 50 mL/min (calculated using the Cockcroft-Gault formula)
- Ability to understand and fill out PRO questionnaires
Patients who meet any of the following criteria must be excluded from study entry:
- Metastatic or locally advanced disease (without loco-regional treatment options with curative intention)
- Patient receiving any prior cancer therapy for invasive breast cancer and/or the same disease
- Bilateral invasive breast cancer
- Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
- History of other malignancy; patients who have been disease-free for 5 years or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible
- Pregnant or lactating women
- Serious medical or psychiatric disorders that would interfere with the patient’s safety or informed consent (at the discretion of the investigator)
- Clinically significant cardiovascular disease, requiring medication during the study and which might interfere with regularity of the study treatment, or not controlled by medication (at the discretion of the investigator)
- Clinically relevant, active bacterial, viral or fungal infection (at the discretion of the investigator)
- History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, uncontrolled inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis. Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible. Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible as well
- Prior allogeneic stem cell or solid organ transplantation
- Concurrent participation in another clinical trial with the same primary endpoint and/or concurrent participation in another clinical trial with an investigational product
- Known hypersensitivity to the study drugs
- Active tuberculosis
- Patients receiving live, attenuated vaccine within 4 weeks prior to Cycle 1 Day 1 (= V1) AND not fit for study participation as per investigator’s assessment.
Note: Patients may receive influenza vaccination if individual risk-benefit-assessment leads to investigator’s decision that harmful effects would be otherwise anticipated during study participation
- Treatment with therapeutic oral or iv antibiotics within 2 weeks prior to randomization
Note: Patients receiving prophylactic antibiotics (e.g. to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible
- Known uncontrolled HIV, HCV and HBV infection
* studyinformation based on protocol version 1.0