Phase 3 Randomized Study of Sacituzumab Govitecan vs. Physician's Choice in PD-L1 Negative or Anti-PD-(L)1 Treated Metastatic Triple-Negative Breast Cancer
- Trial ID
- 2023-504195-14-00
- Protocol
- GS-US-592-6238
- Sponsor
- Gilead Sciences Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **progression-free survival** (PFS) as assessed by blinded independent central review (BICR) between sacituzumab govitecan and treatment of physician's choice in patients with previously untreated, locally advanced, inoperable, or metastatic triple-negative breast cancer. This objective is clinically relevant as PFS is a critical endpoint in oncology trials, providing insights into the efficacy of the treatment in delaying disease progression.
Secondary objectives include:
- Comparing overall survival (OS) between the two arms, which is essential for understanding the long-term benefits of the treatment.
- Comparing objective response rate (ORR) as assessed by BICR, which evaluates the proportion of patients with tumor size reduction.
- Comparing duration of response (DOR) as assessed by BICR, which measures the time period during which a tumor continues to respond to treatment.
- Comparing time to response (TTR) as assessed by BICR, which assesses the time taken for a response to occur after treatment initiation.
- Comparing safety and tolerability between the two arms, which is crucial for assessing the treatment's risk-benefit profile.
- Comparing mean change from baseline in the physical functioning domain and time to deterioration (TTD) in fatigue as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core Questionnaire, Version 3.0 (EORTC QLQ-C30) between the two arms, which provides insights into the impact of treatment on patients' quality of life.
Participants
The clinical trial involves a total of **562 participants** diagnosed with **metastatic triple-negative breast cancer** (TNBC), either PD-L1-negative or PD-L1-positive, who have previously been treated with an anti-PD-(L)1 agent in a curative setting. The study population includes both **female and male subjects** aged 18 years and older, without restrictions on race or ethnic group. Participants were selected based on specific inclusion criteria, including the ability to provide informed consent and meet health status requirements such as an **ECOG performance status** score of 0 or 1, adequate hematologic and hepatic function, and a life expectancy of at least 3 months. The trial also considers lifestyle factors, requiring participants to adhere to protocol-specified contraception methods if engaging in heterosexual intercourse. The study population includes individuals with well-controlled HIV on antiretroviral therapy, provided they meet specific virologic and immunologic criteria. Participants must have measurable disease as per RECIST Version 1.1 criteria and have recovered from major surgery for at least 2 weeks. The trial does not exclude vulnerable populations, indicating a comprehensive approach to participant selection.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **sacituzumab govitecan** compared to the treatment of physician's choice in patients with previously untreated, locally advanced, inoperable, or metastatic **triple-negative breast cancer** (TNBC). The trial targets patients whose tumors do not express PD-L1 or those previously treated with anti-PD-(L)1 agents in the early setting whose tumors do express PD-L1. The primary objective is to compare progression-free survival (PFS) as assessed by blinded independent central review (BICR) between the two treatment groups. The trial is expected to conclude by May 31, 2027, with recruitment having commenced on July 20, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, performance status, and tumor characteristics. Following randomization, participants will receive treatment according to their assigned group, with regular follow-up visits scheduled to monitor treatment response and safety. These visits will include assessments such as imaging studies to evaluate measurable disease by CT or MRI, laboratory tests, and physical examinations. The end-of-study visit will occur after the completion of the treatment period or upon early termination, which may result from disease progression, unacceptable toxicity, or withdrawal of consent.
The expected length of participant involvement in the study is determined by the treatment regimen and the individual's response to therapy, with a maximum treatment period of 21 to 28 days per cycle, depending on the specific medication administered. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, non-compliance with study procedures, or the investigator's decision based on the participant's best interest. The study aims to provide comprehensive data on the safety and efficacy of sacituzumab govitecan in comparison to standard treatments, contributing valuable insights into the management of metastatic TNBC.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Gemcitabine**, marketed as "Gemcitabine 38 mg/mL concentrate for solution for infusion," is a nucleoside metabolic inhibitor. It is provided in a concentrate form for solution for infusion and is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of 1000 mg/m². The treatment period for gemcitabine is up to 21 days. This medication is used in combination with carboplatin in the study.
**Abraxane**, containing the active substance **paclitaxel albumin-bound**, is provided as a "5 mg/mL powder for dispersion for infusion." It is an antineoplastic agent administered through intravenous infusion. The dosage is also based on body surface area, with a maximum daily dose of 100 mg/m², and the treatment period is up to 21 days. Abraxane serves as a comparator in the trial.
**Trodelvy**, with the active substance **sacituzumab govitecan**, is provided as a "200 mg powder for concentrate for solution for infusion." It is an antibody-drug conjugate administered via intravenous infusion. The dosage is calculated based on body weight, with a maximum daily dose of 10 mg/kg, and the treatment period is up to 21 days. Trodelvy is the test drug in this clinical trial.
**Paclitaxel**, marketed as "Paclitaxel 6 mg/mL concentrate for solution for infusion," is another antineoplastic agent used in the study. It is administered through intravenous infusion, with a dosage based on body surface area, and a maximum daily dose of 90 mg/m². The treatment period for paclitaxel is up to 28 days. This medication is used as a comparator in the trial.
**Carboplatin**, provided as "Carboplatin 10 mg/mL concentrate for solution for infusion," is an antineoplastic agent administered via intravenous infusion. The dosage is based on body surface area, with a maximum daily dose of 1000 mg/m², and the treatment period is up to 21 days. Carboplatin is used in combination with gemcitabine in the study.
All medications are administered intravenously, and participant compliance is monitored throughout the trial. The study aims to compare the progression-free survival (PFS) between sacituzumab govitecan and the treatment of physician's choice in patients with previously untreated, locally advanced, inoperable, or metastatic triple-negative breast cancer.
Efficacy
Efficacy in this clinical trial will be assessed using several key endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, which is defined as the time from the date of randomization until the date of objective progressive disease (PD), as assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, or death, whichever occurs first. Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DOR), Time to Response (TTR), and the incidence of treatment-emergent adverse events (TEAEs) and clinical laboratory abnormalities. ORR is defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) that is confirmed at least 4 weeks after initial documentation of response, as assessed by BICR per RECIST Version 1.1. DOR is the time from the first documentation of CR or PR to the earlier of the first documentation of definitive PD or death from any cause. TTR is the time from the date of randomization until the first documentation of CR or PR.
Additional assessments include the mean change from baseline in the physical functioning domain of the EORTC QLQ-C30 at Week 25 and the Time to Deterioration (TTD) of the fatigue domain of the EORTC QLQ-C30, defined as the time between the date of randomization and the date of assessment at which a patient experienced a deterioration (≥ 10 points worsening from baseline in the fatigue domain) or death. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, with the use of validated scales and laboratory tests to ensure accuracy and reliability of the data. The analysis of these endpoints will provide comprehensive insights into the efficacy of the investigational treatment in patients with previously untreated, locally advanced, inoperable, or metastatic triple-negative breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must meet all of the following inclusion criteria to be eligible for participation in this study (no waivers for patient eligibility will be offered or permitted): Female or male patients, regardless of race and ethnic group, who are 18 years of age or older, able to understand and give written informed consent.
- Patients with locally advanced, inoperable, or metastatic TNBC who have not received previous systemic therapy for advanced disease and whose tumors are PD-L1 negative at screening. Alternatively, patients whose tumors are PD-L1 positive at screening will be eligible if they received an anti-programmed death (ligand) 1 (anti-PD-[L]1) agent (ie, checkpoint inhibitor) in the adjuvant or neoadjuvant setting or if they cannot be treated with an anti-PD-(L)1 agent due to a comorbidity. a) Patients must have completed treatment for Stage I-III breast cancer, if indicated, and ≥ 6 months must have elapsed between completion of treatment with curative intent (eg, date of primary breast cancer surgery or date of last (neo)adjuvant chemotherapy administration [including anti-PD-(L)1 treatment], whichever occurred last) and first documented local or distant disease recurrence. Dates of postoperative radiotherapy are not included in this calculation. i) Patients who received taxane, gemcitabine, or platinum agents in the (neo)adjuvant setting can be treated with same class of chemotherapy (taxane or gemcitabine/carboplatin) if ≥ 12 months have elapsed between the completion of treatment with curative intent (eg, date of primary breast tumor surgery or date of last (neo)adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence. ii) Patients enrolled should have received prior anthracycline in the (neo)adjuvant setting or be considered not eligible for anthracyclines as assessed by the treating physician. b) Patients presenting with de novo metastatic TNBC are eligible for this study. c) TNBC status and tumor PD-L1 CPS will be confirmed centrally on a recent or archival tumor specimen. Patients must have histologically or cytologically documented TNBC, according to current ASCO/CAP criteria, defined as negative for ER, progesterone receptor, and HER2 {Allison 2020, Wolff 2018}. Patients initially diagnosed with hormone receptor-positive or HER2-positive breast cancer must have central confirmation of TNBC in a tumor biopsy obtained from a local recurrence or distant metastasis prior to entry. Tumor combined positive score (CPS) < 10 using the PD-L1 IHC 22C3 assay will be required for eligibility. Alternatively, patients with tumor CPS ≥ 10 will be eligible if they received an anti-PD-(L)1 agent (ie, checkpoint inhibitor) in the adjuvant or neoadjuvant setting or if they cannot be treated with an anti-PD-(L)1 agent due to a comorbidity. d) Patients must have measurable disease by CT or MRI as per RECIST Version 1.1 criteria (Appendix 11.6) as evaluated locally. Tumor lesions situated in a previously irradiated area are considered measurable if unequivocal progression has been documented in such lesions since radiation.
- Have provided representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in blocks (preferred) or have at least 20 to 25 freshly sectioned unstained slides from fresh biopsy tissue (preferred) or archival tissue block for central testing of ER, progesterone receptor, HER2, and PD-L1 and additional biomarker testing. A baseline biopsy is required if archival tissue is not available and this procedure must be performed prior to the first dose of study treatment and after the patient provides written informed consent. Fine needle B12aspirates and bone biopsies are not suitable samples. Note: Tumor tissue quality must be confirmed by the central laboratory. Submission of another tumor specimen may be required if provided specimen is not adequate for assessment. A discussion with the medical monitor is required if only 15 to 19 unstained slides are available and it is not clinically feasible to obtain a new biopsy.
- ECOG performance status score of 0 or 1 (see Appendix 11.5).
- Life expectancy ≥ 3 months.
- Recovered from major surgery for ≥ 2 weeks.
- Adequate hematologic counts without transfusional or growth factor support within 2 weeks of study treatment initiation (hemoglobin ≥ 9 g/dL, ANC ≥ 1500/mm3, and platelets ≥ 100,000/μL).
- Adequate hepatic function (bilirubin ≤ 1.5 ULN, AST and ALT ≤ 2.5 ULN or ≤ 5 ULN if known liver metastases, and serum albumin > 3 g/dL).
- Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation {Cockcroft 1976}.
- International Normalized Ratio (INR)/PT and PTT or aPTT ≤ 1.5 ULN unless patient is currently receiving therapeutic anticoagulant therapy.
- Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.3.
- Patients with HIV must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: a) Patients on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening. b) Patients on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening. c) Patients on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1). d) The combination ART regimen must not contain any medications that may interfere with SN-38 metabolism.
Exclusion Criteria
- Patients who meet any of the following exclusion criteria are not eligible to be enrolled in this study (no waivers for patient eligibility will be offered or permitted): Positive serum pregnancy test or women who are lactating (see Appendix 11.3).
- Known or severe (≥ Grade 3) hypersensitivity or allergy to sacituzumab govitecan and/or the chemotherapy regimen of choice in the TPC arm (eg, nab-paclitaxel, paclitaxel, gemcitabine, or carboplatin), their metabolites, or formulation excipient.
- Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.1.
- Patients may not have received systemic anticancer treatment (with the exception of endocrine therapy) within the previous 6 months or radiation therapy within 2 weeks prior to enrollment. Patients must have recovered (ie, > Grade 2 is considered not recovered) from AEs due to a previously administered agent at the time of study entry. Note: patients with any grade neuropathy or alopecia are an exception to this criterion and will qualify for the study. Note: if patients received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Patients may not be participating in a study with an investigational agent or investigational device within 4 weeks prior to randomization. Patients participating in observational studies are eligible.
- Have previously received topoisomerase 1 inhibitors or antibody drug conjugates containing a topoisomerase inhibitor.
- Have an active second malignancy. Note: patients with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or patients with surgically cured tumors with low risk of recurrence (eg, non-melanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
- Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate (with the exception of those treated with chemotherapy) provided they have stable CNS disease (defined as radiographic stability demonstrated with a minimum of 2 posttreatment brain imaging assessments; one performed during screening) for at least 4 weeks prior to enrollment and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and have also been clinically stable for at least 2 weeks while taking ≤ 10 mg/day of prednisone or its equivalent. All patients with carcinomatous meningitis are excluded regardless of clinical stability.
- Met any of the following criteria for cardiac disease: a) Myocardial infarction or unstable angina pectoris within 6 months of enrollment. b) History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication); history of QT interval prolongation. c) New York Heart Association Class III or greater congestive heart failure or known left ventricular ejection fraction of < 40%.
- Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or GI perforation within 6 months of enrollment.
- Have active serious infection requiring antibiotics.
- Patients positive for HIV-1 or 2 with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
- Have active HBV (defined as having a positive HBsAg test) or HCV. a) For patients with a history of HBV infection, a hepatitis B core antibody test should be conducted at screening. If positive, hepatitis B DNA testing will be performed and if active HBV infection is ruled out, the patient may be eligible. b) Patients who are HCV antibody positive with undetectable HCV viral load may be eligible.
- Have other concurrent medical or psychiatric conditions that, in the investigator’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
- Has received a live vaccine within 30 days prior to randomization.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 20 Jul 2022 | 4 |
 Belgium | Not Recruiting | 20 Jul 2022 | 7 |
 Czechia | Not Recruiting | 20 Jul 2022 | 9 |
 France | Not Recruiting | 20 Jul 2022 | 22 |
 Germany | Not Recruiting | 20 Jul 2022 | 15 |
 Hungary | Not Recruiting | 20 Jul 2022 | 8 |
 Italy | Not Recruiting | 20 Jul 2022 | 36 |
 The Netherlands | Not Recruiting | 20 Jul 2022 | — |
 Poland | Not Recruiting | 20 Jul 2022 | 8 |
 Romania | Not Recruiting | 20 Jul 2022 | 10 |
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 |
|---|---|---|---|---|---|---|
Paclitaxel 6 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 90 | 28 | PRD7486025 |
Trodelvy 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 10 | 21 | PRD9351384 |
Abraxane 5 mg/ml powder for dispersion for infusion. | Comparator | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS INFUSION | 100 | 21 | PRD9254301 |
Gemcitabine 38 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 21 | PRD1164506 |
Carboplatin 10 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 21 | PRD7277959 |