Sacituzumab govitecan for HER2-negative breast cancer | Breast cancer

Stratification factors

• HR status (HR-negative vs HR-positive)
• ypN status (ypN+ vs ypN0)

Inclusion criteria

• {"criterion_text":"- Women or men with age at diagnosis at least 18 years.\n- For women of childbearing potential and males with partners 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 a specified period after the last dose as specified in the protocol.\n- Complete staging work-up prior to the initiation of neoadjuvant chemotherapy. Missing staging investigations must be performed prior to randomization.\n- Formalin fixed paraffin embedded tissue (FFPE) block from surgery after neoadjuvant chemotherapy and from biopsy (excluding excisional biopsy or lumpectomy) preferably of the breast, before start of neoadjuvant chemotherapy. For patients with bilateral carcinoma, FFPE blocks from both sides have to be provided for central testing.\n- Histologically confirmed unilateral or bilateral primary invasive carcinoma of the breast, confirmed histologically by core biopsy. The lead tumor has to be defined by the investigator based on the inclusion criteria for the respective subtype and on the risk status.\n- Centrally confirmed HER2-negative (IHC score 0-1 or FISH negative according to ASCO/CAP guideline) and either: HR-positive (≥1% positive stained cells) disease or HR-negative (<1% positive stained cells), assessed preferably on tissue from postneoadjuvant residual invasive disease of the breast, or if not possible, of residual nodal invasion. If not evaluable, core of diagnostic biopsy will be used. In case of bilateral breast cancer, HER2-negative status has to be confirmed for both sides.\n- Patients with residual invasive disease after neoadjuvant chemotherapy at high risk of recurrence defined as follows: any residual invasive disease > ypT1mi and/or ypN1>1mm (for HR-negative disease) or a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ (for HR-positive disease) using local ER and grade assessed on core biopsies taken before start of neoadjuvant treatment.\n- Adequate surgical treatment including resection of clinically evident disease and ipsilateral axillary lymph node dissection. SNB before NACT is discouraged. Axillary dissection before NACT is not permitted. Axillary dissection, including Targeted Axillary Dissection (TAD) should be performed according to guidelines. Histologic complete resection (R0) of all invasive and in situ tumors is required.\n- Patients must have received neoadjuvant taxane-based chemotherapy for 16 weeks (anthracyclines are permitted). This period must include 6 weeks of a taxane containing neoadjuvant chemotherapy (exception: for patients with progressive disease that occurred after at least 6 weeks of taxane-containing neoadjuvant chemotherapy, a total treatment period of less than 16 weeks is also eligible).\n- No clinical evidence for locoregional or distant relapse during or after preoperative chemotherapy. Local progression during chemotherapy is not an exclusion criterion if adequate local control could be obtained. In case of local progression during neoadjuvant therapy, distant metastases must be excluded by adequate imaging (CT/MRI recommend) prior to entering the trial.\n- Immune checkpoint inhibitor / immunotherapy during (neo)adjuvant therapy is allowed until the completion of radiotherapy.\n- Patients with known gBRCA1/2 mutation without indication to adjuvant olaparib therapy are allowed to participate in the trial.\n- Inclusion criterium specific for France due to a request of the French ethics committee\n- Inclusion criterium specific for France due to a request of the French ethics committee\n- An interval of less than 16 weeks since the date of final surgery or less than 10 weeks from completing radiotherapy (whichever occurs last) and the date of randomization is required.\n- Radiotherapy should be delivered before the start of study treatment. Radiotherapy to the breast is indicated in all patients with breast conserving surgery and to the chest wall and lymph nodes according to local guidelines as well as in all patients with cT3/4 or ypN+ disease treated by mastectomy.\n- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.\n- Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedure or radiotherapy to NCI CTCAE v 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patients at the investigator´s discretion).\n- Normal cardiac function after neoadjuvant chemotherapy must be confirmed according to local guidelines. Results for LVEF must be above the normal limit of the institution.\n- Laboratory requirements within range as specified in the protocol: hematology (ANC ≥1.5 x 10^9 / L; platelets ≥100 x 10^9 / L; hemoglobin ≥10 g/dL (≥6.2 mmol/L)), hepatic function (total bilirubin <1.25x UNL; AST and ALT ≤1.5x UNL; alkaline phosphatase ≤2.5x UNL), renal function (<1.25x ULN creatinine or creatinine clearance ≥30 ml/min (according to Cockroft-Gault, if creatinine is above UNL)).\n- Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential."}

Exclusion criteria

• {"criterion_text":"- Known hypersensitivity reaction to one of the compounds or substances used in this protocol.\n- Female patients: pregnancy or lactation at the time of randomization or intention to become pregnant during the study and up to 6 months after sacituzumab govitecan and up to 6 months after treatment with capecitabine or carboplatin/cisplatin.\n- Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study, including Gilbert´s disease, Crigler-Najjar-Syndrome, known hepatitis B, hepatitis C, known HIV positivity, infection requiring intravenous antibiotic use within 1 week of enrolment or known autoimmune disease other than diabetes, stable thyroid disease, vitiligo, or other autoimmune skin disease with dermatologic manifestations only are permitted provided particular exception specified in the protocol.\n- Any condition that interferes with the safe administration of the treatment of physician’s choice in case the patient is randomized into the TPC arm.\n- Known or suspected congestive heart failure (>NYHA I) and/or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of prior infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP >150/90 mmHg under treatment with at maximum three antihypertensive drugs), rhythm abnormalities requiring permanent treatment (excluding chronic atrial fibrillation not requiring a pacemaker), clinically significant valvular heart disease, supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker.\n- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitis on chest CT scan.\n- Exclusion criterium specific for France due to a request of the French ethics committee\n- Exclusion criterium specific for France due to a request of the French ethics committee\n- Exclusion criterium specific for France due to a request of the French ethics committee\n- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving chemotherapy.\n- History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.\n- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.\n- Known allergic reactions to irinotecan.\n- Concurrent treatment with chronic corticosteroids prior to study entry with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or equivalent corticosteroid.\n- Patients with definitive clinical or radiologic evidence of stage IV cancer (metastatic disease) are not eligible.\n- Patients with known gBRCA1/2 mutation and indicated or planned adjuvant olaparib therapy if available.\n- Patients with a history of any malignancy are ineligible with the following exceptions: patient has been disease-free for at least 5 years and is at low risk for recurrence of that malignancy; CIS of the cervix, basal cell and squamous cell carcinomas of the skin."}

Primary endpoints

• {"endpoint_text":"- iDFS is defined as time from randomization until first iDFS event: local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause.","definition_or_measurement_approach":"iDFS defined as time from randomization until first iDFS event (local invasive recurrence after mastectomy, local invasive recurrence in ipsilateral breast after lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer [excluding squamous or basal cell carcinoma of skin], or death from any cause)."}

Secondary endpoints

• {"endpoint_text":"- OS is defined as the time from randomization until death from any cause.","definition_or_measurement_approach":"Overall survival (OS): time from randomization until death from any cause."}
• {"endpoint_text":"- DDFS is defined as the time from randomization until distant recurrence of disease, second primary invasive cancer (non-breast, excluding squamous or basal cell carcinoma of the skin), and death due to any cause.","definition_or_measurement_approach":"Distant disease-free survival (DDFS): time from randomization until distant recurrence, second primary invasive non-breast cancer (excluding skin squamous/basal cell carcinoma), or death from any cause."}
• {"endpoint_text":"- iBCFS is defined as the time from randomization until first iDFS event excluding any second non-breast primary cancer.","definition_or_measurement_approach":"Invasive breast cancer-free survival (iBCFS): time from randomization until first iDFS event excluding second non-breast primary cancers."}
• {"endpoint_text":"- LRRFI is defined as the time from randomization until any loco-regional (ipsilateral breast (invasive), chest wall, local/regional lymph nodes) recurrence of disease or any invasive contralateral breast cancer whichever occurs first. Distant recurrence, secondary malignancy and death are considered as competing risks and will be accounted for in the analysis.","definition_or_measurement_approach":"Locoregional recurrence-free interval (LRRFI): time from randomization until loco-regional recurrence (ipsilateral invasive breast, chest wall, local/regional lymph nodes) or invasive contralateral breast cancer. Distant recurrence, secondary malignancy and death considered competing risks."}
• {"endpoint_text":"- Frequency and severity of adverse events graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.","definition_or_measurement_approach":"Safety: frequency and severity of adverse events graded per NCI CTCAE v5.0."}
• {"endpoint_text":"- Dose-density, dose reductions, dose delays, treatment interruptions and treatment discontinuation rates.","definition_or_measurement_approach":"Treatment adherence and modifications: measurement of dose-density, reductions, delays, interruptions and discontinuation rates as recorded in treatment records."}
• {"endpoint_text":"- Patient reported breast cancer specific QoL as measured by FACT–B; functional assessment of cognitive function assessed by FACT-Cog; patient reported global QoL assessed by EQ-5D-5L.","definition_or_measurement_approach":"Patient-reported outcomes and QoL measured using FACT-B (breast cancer specific), FACT-Cog (cognitive function) and EQ-5D-5L (global QoL) questionnaires at specified timepoints."}

Austria

Latest Decision Or Authorization Date

26-08-2024

Number Of Participants

34

France

Latest Decision Or Authorization Date

26-08-2024

Number Of Participants

247

Spain

Latest Decision Or Authorization Date

20-08-2024

Number Of Participants

296

Belgium

Latest Decision Or Authorization Date

22-08-2024

Number Of Participants

3

Germany

Latest Decision Or Authorization Date

03-09-2024

Number Of Participants

760

Ireland

Latest Decision Or Authorization Date

20-08-2024

Number Of Participants

46

Primary sponsor

Full Name

GBG Forschungs GmbH

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"Clinigen Clinical Supplies Management GmbH","duties_or_roles":"Labeling, IMP-distribution EU, storage, destruction, final QP batch release","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"Fundacion Grupo Espanol De Investigacion En Cancer De Mama","duties_or_roles":"code 5","organisation_type":"Patient organisation/association"}
• {"country":"Austria","full_name":"Verein Zur Praevention Und Therapie Boesartiger Erkrankungen Austrian Breast And Colorectal Cancer Study Group","duties_or_roles":"code 5","organisation_type":"Patient organisation/association"}
• {"country":"Germany","full_name":"Philipps-Universitaet Marburg","duties_or_roles":"Central pathology testing","organisation_type":"Educational Institution"}
• {"country":"Germany","full_name":"Dr. Nibler & Partner mbB Aerzte","duties_or_roles":"Qualified Person for Pharmacovigilance; code 8","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"BioKryo GmbH","duties_or_roles":"storage of frozen blood samples","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"ETOP IBCSG Partners Foundation","duties_or_roles":"code 5","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"France","full_name":"Unicancer","duties_or_roles":"code 5","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Ireland","full_name":"Cancer Trials Ireland","duties_or_roles":"code 5","organisation_type":"Patient organisation/association"}