Comparative Study of Sacituzumab Govitecan Versus Sacituzumab Govitecan Plus Pembrolizumab in Low-Risk Triple-Negative Early Breast Cancer
- Trial ID
- 2023-508787-29-00
- Protocol
- WSG-AM13
Trial statistics
Objectives
The primary objectives of this study are twofold: firstly, to demonstrate the superiority of treatment with **sacituzumab govitecan** plus **pembrolizumab** compared to sacituzumab govitecan alone in achieving higher pathological complete response (pCR) rates in patients with low-risk, triple-negative early breast cancer. Secondly, the study aims to establish that the 3-year invasive disease-free survival (iDFS) rate in the entire study cohort, which includes both treatment arms, exceeds 88% as compared to historical controls. These objectives are clinically relevant as they aim to improve treatment outcomes and long-term survival in this patient population.
The secondary objectives include: - Assessing the clinical response in both treatment arms. - Evaluating 3-year distant disease-free survival (dDFS), distant disease-free interval (dDFI), relapse-free survival (RFS), locoregional relapse-free survival (LRFS), breast cancer-free interval (BCFI), and overall survival (OS) across the entire study and within each treatment arm. - Assessing health-related quality of life using the EORTC-QLQ-C30 and EORTC QLQ-BR45 questionnaires. These secondary objectives provide a comprehensive evaluation of the treatment's impact on disease progression, survival, and patient quality of life.
Participants
The clinical trial involves participants diagnosed with **triple-negative early breast cancer** with a low risk for recurrence. The study population includes both female and male subjects, with an age range starting from 18 years and above. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on specific criteria, including histologically confirmed unilateral, primary invasive carcinoma of the breast, and no clinical evidence of distant metastasis. The trial includes individuals with a performance status of ECOG ≤ 1 or KI ≥ 80%. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The study population includes a vulnerable population, and both genders are represented. The trial's inclusion criteria emphasize the need for participants to have a negative pregnancy test within seven days prior to registration for premenopausal patients and to meet specific laboratory and clinical assessment requirements.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **sacituzumab govitecan** alone versus in combination with **pembrolizumab** in patients with low-risk, triple-negative early breast cancer. This is a randomized, double-blind, controlled trial with a phase II classification. The trial aims to demonstrate the superiority of the combination treatment in achieving higher pathological complete response (pCR) rates and to assess the 3-year invasive disease-free survival (iDFS) rate. The trial is expected to commence recruitment on June 30, 2024, and conclude by June 30, 2030, with an estimated participant involvement duration of up to 18 months.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including histologically confirmed unilateral, primary invasive carcinoma of the breast, and laboratory assessments. Following randomization, participants will receive treatment via intravenous infusion, with follow-up visits scheduled to monitor clinical response and safety. These visits will include assessments through palpation, ultrasound, and mammography, as well as evaluations of overall survival and health-related quality of life at defined intervals. The end-of-study visit will occur after the final treatment cycle, where the primary and secondary endpoints will be assessed.
The expected length of participant involvement is contingent upon the treatment regimen, with a maximum treatment period of 18 months. Conditions that may lead to early termination from the study include non-compliance with protocol requirements, adverse events, or withdrawal of consent. Participants are required to adhere to contraceptive guidelines and refrain from donating ova or sperm during the study and for a specified period after the last dose of the investigational medicinal product. The trial's primary endpoints include achieving pCR and evaluating the 3-year iDFS, while secondary endpoints focus on clinical response, overall survival, and quality of life changes.
Treatment
The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a concentration of 25 mg/mL and is administered via **intravenous infusion**. The maximum daily dose is 200 mg, with a total maximum dose of 1200 mg over the treatment period. The treatment duration is set for a maximum of 18 months. Pembrolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF02. The product is manufactured by Merck Sharp & Dohme B.V. and is labeled specifically for the study.
Another experimental medication used in the trial is **Trodelvy** (sacituzumab govitecan), which is provided as a **powder for concentrate for solution for infusion**. This medication is also administered via **intravenous infusion**. The dosing regimen involves a maximum daily dose of 10 mg/kg, with a total maximum dose of 60 mg/kg over the treatment period. The treatment duration is similarly set for a maximum of 18 months. Sacituzumab govitecan is a protein-based therapeutic agent, classified under the ATC code L01FX17. The product is manufactured by Gilead Sciences Ireland Unlimited Company and is labeled specifically for the study.
Both medications are utilized in the trial to evaluate their efficacy in treating low-risk, triple-negative early breast cancer. The trial aims to compare the effectiveness of sacituzumab govitecan alone versus in combination with pembrolizumab. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in the clinical trial titled "NeoAdjuvant Dynamic marker - Adjusted Personalized Therapy comparing sacituzumab govitecan versus sacituzumab govitecan+pembrolizumab in low-risk, triple-negative early breast cancer (ADAPT-TN-III)" will be assessed using two primary endpoints. The first primary endpoint is the **pathological complete response (pCR)**, defined as the absence of invasive tumor in both the breast and lymph nodes (ypT0/is, ypN0). The second primary endpoint is the 3-year invasive disease-free survival (iDFS), which is defined as the time from the date of first diagnosis to any invasive breast cancer event, death, or secondary malignancy, according to STEEP 2.0 criteria.
Secondary endpoints include clinical response measured by palpation, ultrasound, and mammography, overall survival defined as the time from the date of first diagnosis to death, and various 3-year survival metrics such as distant disease-free survival (dDFS), distant disease-free interval (dDFI), recurrence-free survival (RFS), locoregional recurrence-free survival (LRFS), and breast cancer-free interval (BCFI). Additionally, changes in health-related quality of life will be evaluated between baseline and after defined timepoints: after 2, 4, and 6 cycles (if applicable), before surgery, every 6 months in follow-up until year 3, and yearly thereafter.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ER + PR negative or low positive (≤10% positive cells in IHC), and HER2 negative (i.e., IHC 0 – 1+ or IHC 2+ with FISH negative) breast cancer
- All patients, independent from gender
- ≥18 years at diagnosis
- Histologically confirmed unilateral, primary invasive carcinoma of the breast Note: bilateral, multicentric, or multifocal carcinoma may be included, if there is a clear target (primary) lesion, that is subject to treatment decisions and solely evaluated and documented for study purposes.
- Clinical stage I: cT1a-c/cN0,(clinical stage II only, if patient does not qualify for neoadjuvant polychemotherapy+PEM, e.g., elderly population, per investigator´s decision)
- No clinical evidence for distant metastasis (M0)
- Tumour block available for central pathology review
- Performance Status ECOG ≤ 1 or KI ≥ 80 %
- Negative pregnancy test (urine or serum) within 7 days prior to registration in premenopausal patients
- Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
- The patient must be willing and able to comply with the requirements and restrictions in this protocol and accessible for treatment and follow-up
- Laboratory requirements: • Leucocytes 3.5 109/L, • Neutrophils >1.5 109/L, • Platelets 100 109/L, • Haemoglobin 10 g/dL, • AP < 5.0 ULN, • AST 2.5 x ULN, • ALT 2.5 x ULN, • Total bilirubin 1 x ULN, • Creatinine ≤1.5 × ULN OR clearance ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
- Clinical assessments: • LVEF within normal limits of each institution, measured by echocardiography and normal ECG (within 42 days prior to treatment)
- The following age-specific requirements apply: • Women aged <50 years will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site. • Women aged ≥ 50 years will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments.
- Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential and need to discontinue HRT to allow confirmation of post-menopausal status prior to randomization/study enrolment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can participate in the study without use of a contraceptive method.
- Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 3 (see Section 3.8.2), from the time of enrolment and must agree to continue using such precautions for 7 months after the last dose of investigational medicinal product (IMP). Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of IMP. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient’s usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic, or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.
- Female patients must not donate, or retrieve for their own use, ova from the time of randomisation and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrolment in this study.
- A male participant must agree to use a contraception as detailed in Appendix C of this protocol during the treatment period and for at least 7 months after the last dose of study treatment and refrain from donating sperm during this period.
Exclusion Criteria
- Known hypersensitivity reaction to the compounds or incorporated substances of the IMPs
- Prior malignancy with a disease-free survival of < 5 years, except curatively treated basalioma of the skin or pTis of the cervix uteri
- Any history of invasive breast cancer
- Previous or concurrent treatment with cytotoxic agents for any reason unless clarified with sponsor
- Concurrent treatment with other experimental drugs.
- Participation in another interventional clinical trial with or without any investigational not marketed drug within 30 days prior to study entry
- Concurrent pregnancy; patients of childbearing potential or potentially childbearing partners of male patients must implement a highly effective (less than 1% failure rate) non-hormonal contraceptive measures during the study treatment
- Breast feeding woman
- Reasons indicating risk of poor compliance
- Patients not able to consent
- Known polyneuropathy ≥ grade 2
- Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including recovery from major surgery, autoimmune disease, known psychiatric/substance abuse disorders, acute cystitis, ischuria, and chronic kidney disease
- Uncontrolled infection requiring i.v. antibiotics, antivirals, or antifungals
- History of pneumonitis haemolytic anaemia, myocarditis, sclerosing cholangitis and exocrine pancreatic insufficiency, medical history of allogenic stem cell transplants, or solid organ transplant
- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection,. Patients should be tested for HIV prior to randomisation if required by local regulations or ethics committee (EC). Patients who test positive for HIV-antibody are excluded.
- Active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded. • Patients who test positive for hepatitis B surface antigen (HBsAg). Patients who test positive for hepatitis B core antibody (anti-HBc) will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease. • Patients who test positive for HCV antibody will require HCV RNA by quantitative PCR for confirmation of active disease. Patients with a known history of HCV or a positive HCV antibody test will not require a HCV antibody at enrolment and will only require HCV RNA by quantitative PCR for confirmation of active disease.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 30 Jun 2024 | 348 |
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 |
|---|---|---|---|---|---|---|
Trodelvy 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 10 | 18 | PRD9351384 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 200 | 18 | PRD4323105 |