Phase III Evaluation of Sacituzumab Govitecan Versus Physician's Choice in HER2-Negative Breast Cancer with High Relapse Risk Post-Neoadjuvant Therapy
- Trial ID
- 2023-510390-33-00
- Protocol
- GBG102-SASCIA
- Sponsor
- GBG Forschungs GmbH
Trial statistics
Objectives
The primary objective of this Phase III study is to compare **invasive disease-free survival (iDFS)** between patients treated with sacituzumab govitecan and those receiving the treatment of physician's choice. This is clinically relevant as it aims to determine the efficacy of sacituzumab govitecan in reducing the risk of invasive disease recurrence in patients with **HER2-negative breast cancer** who are at high risk of relapse following standard neoadjuvant treatment.
Secondary objectives include:
- Comparing overall survival (OS) between both groups.
- Comparing distant disease-free survival (DDFS) between both groups.
- Comparing invasive breast cancer-free survival (iBCFS) between both groups.
- Comparing locoregional recurrences-free interval (LRRFI) between both groups.
- Comparing iDFS and OS in stratified subgroups: HR-negative vs. HR-positive; ypN+ vs. ypN0.
- Comparing iDFS and OS in exploratory subgroups, including prior platinum therapy and immune-checkpoint inhibitor therapy in triple-negative breast cancer (TNBC), and evaluating TROP2-expression levels.
- Comparing safety between both groups.
- Assessing and comparing compliance on the treatment between both arms.
- Assessing Patient Reported Outcome (PRO) and Quality of Life (QoL) between both groups.
Participants
The clinical trial involves a total of **5 participants** diagnosed with **HER2-negative breast cancer**, specifically those at high risk of relapse following standard neoadjuvant treatment. The study population includes both **male and female** subjects, aged 18 years and older, reflecting a diverse age range. Participants were selected based on specific inclusion criteria, ensuring they have undergone complete staging work-up and received neoadjuvant taxane-based chemotherapy. The trial population is characterized by a requirement for adequate surgical treatment and no clinical evidence of locoregional or distant relapse during or after preoperative chemotherapy. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to contraceptive measures if of childbearing potential. The trial includes individuals with a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale, indicating a generally good health status. The study also accommodates a vulnerable population, ensuring comprehensive ethical oversight.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of **sacituzumab govitecan** in patients with **HER2-negative breast cancer** who are at high risk of relapse following standard neoadjuvant treatment. The primary objective is to compare invasive disease-free survival (iDFS) between patients treated with sacituzumab govitecan and those receiving treatment of the physician's choice. The trial is expected to run until March 2027, with recruitment having commenced in August 2020. Participants will be involved in the study for a maximum treatment period of 24 months.
The study involves a sequence of visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, staging work-up, and histological confirmation of **HER2-negative** status. Following randomization, participants will undergo regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments of cardiac function, laboratory tests, and imaging studies as required. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by factors such as disease progression, unacceptable toxicity, or withdrawal of consent.
Participants are required to adhere to specific conditions, including the use of effective contraception for those of childbearing potential, and must meet laboratory and performance status criteria throughout the study. The trial will assess primary and secondary endpoints, including overall survival (OS), distant disease-free survival (DDFS), and patient-reported quality of life measures. The study will also evaluate the frequency and severity of adverse events, as well as treatment adherence and modifications. Early termination from the study may occur if participants experience significant adverse effects or if the investigator deems it necessary for the participant's safety.
Treatment
The clinical trial involves the administration of several treatments, including **Cisplatin**, marketed as Cisplatin NeoCorp 1 mg/ml. This is a **solution for infusion** with the active substance **cisplatin**, a platinum-based drug. The pharmaceutical form is a concentrate for the preparation of an infusion solution, administered via **intravenous use**. The maximum daily dose is 120 mg/m², and the treatment period is up to 24 months. The product is manufactured by HEXAL AG and is not a pediatric formulation.
Another treatment used in the trial is **Capecitabine**, available as Xeloda 150 mg and 500 mg film-coated tablets. This **chemotherapy** agent, an antimetabolite and 5-FU prodrug, is administered **orally**. The maximum daily dose for capecitabine is 2000 mg/m², with a treatment duration of up to 24 months. The manufacturer is CHEPLAPHARM ARZNEIMITTEL GMBH, and the formulation is not intended for pediatric use.
**Sacituzumab Govitecan**, marketed as Trodelvy 200 mg, is a powder for concentrate for solution for infusion. It is an **antibody-drug conjugate** composed of hRS7, a humanized IgG1κ monoclonal antibody that recognizes Trop-2. The administration route is **intravenous**, with a maximum daily dose of 10 mg/kg. The treatment period is up to 24 months. The product is manufactured by GILEAD SCIENCES IRELAND UNLIMITED COMPANY and is relabeled for use in clinical studies.
**Carboplatin**, marketed as Carbomedac® 10 mg/ml, is another **solution for infusion** used in the trial. It is a platinum-based drug with the active substance **carboplatin**. The administration is via **intravenous** route, with a maximum daily dose of 750 mg. The treatment duration is up to 24 months. The product is manufactured by MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE MBH (WEDEL) and is not a pediatric formulation.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the evaluation of **invasive disease-free survival (iDFS)**. iDFS is defined as the time from randomization until the first occurrence of events such as 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. Secondary endpoints include overall survival (OS), defined as the time from randomization until death from any cause, and distant disease-free survival (DDFS), which is 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.
Additional secondary endpoints include invasive breast cancer-free survival (iBCFS), which is the time from randomization until the first iDFS event excluding any second non-breast primary cancer, and loco-regional recurrence-free interval (LRRFI), defined as the time from randomization until any loco-regional recurrence of disease or any invasive contralateral breast cancer, with distant recurrence, secondary malignancy, and death considered as competing risks. The frequency and severity of adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patient-reported outcomes will be measured using the FACT–B for breast cancer-specific quality of life, FACT-Cog for cognitive function, and EQ-5D-5L for global quality of life. The trial will also monitor dose-density, dose reductions, dose delays, treatment interruptions, and treatment discontinuation rates.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Women or men with age at diagnosis at least 18 years.
- Patients with known gBRCA1/2 mutation without indication to adjuvant olaparib therapy are allowed to participate in the trial.
- 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.
- 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.
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- 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).
- 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.
- 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)).
- Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
- 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.
- Complete staging work-up prior to the initiation of neoadjuvant chemotherapy. Missing staging investigations must be performed prior to randomization.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- Immune checkpoint inhibitor / immunotherapy during (neo)adjuvant therapy is allowed until the completion of radiotherapy.
- Inclusion criterium specific for France due to a request of the French ethics committee
- Inclusion criterium specific for France due to a request of the French ethics committee
Exclusion Criteria
- Known hypersensitivity reaction to one of the compounds or substances used in this protocol.
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving chemotherapy.
- History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
- Known allergic reactions to irinotecan.
- 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.
- Patients with definitive clinical or radiologic evidence of stage IV cancer (metastatic disease) are not eligible.
- Patients with known gBRCA1/2 mutation and indicated or planned adjuvant olaparib therapy if available.
- 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.
- 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.
- 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.
- 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.
- 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.
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis or active pneumonitis on chest CT scan.
- Exclusion criterium specific for France due to a request of the French ethics committee
- Exclusion criterium specific for France due to a request of the French ethics committee
- Exclusion criterium specific for France due to a request of the French ethics committee
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 03 Aug 2020 | 34 |
 Belgium | Not Recruiting | 03 Aug 2020 | 3 |
 France | Not Recruiting | 03 Aug 2020 | 247 |
 Germany | Not Recruiting | 03 Aug 2020 | 760 |
 Ireland | Not Recruiting | 03 Aug 2020 | 46 |
 Spain | Not Recruiting | 03 Aug 2020 | 296 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Carbomedac® 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS | 750 | 24 | PRD536350 |
Cisplatin NeoCorp 1 mg/ml - Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | 120 | 24 | PRD759858 |
Xeloda 500 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL | 2000 | 24 | PRD9863934 |
Trodelvy 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 10 | 24 | PRD9351384 |
Xeloda 150 mg film-coated tablets | Other | FILM-COATED TABLETS | ORAL | 2000 | 24 | PRD9863933 |