Phase 3 Randomized Study of Sacituzumab Govitecan and Pembrolizumab Versus Physician's Choice and Pembrolizumab in PD-L1 Positive Metastatic Triple-Negative Breast Cancer
- Trial ID
- 2023-504194-21-00
- Protocol
- GS-US-592-6173
- 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 the combination of sacituzumab govitecan and pembrolizumab versus the treatment of physician's choice and pembrolizumab in patients with previously untreated, locally advanced inoperable or metastatic **triple-negative breast cancer** expressing **PD-L1**. This objective is clinically relevant as PFS is a critical endpoint in oncology trials, providing insights into the efficacy of the treatment regimen in delaying disease progression.
Secondary objectives include:
- Comparing overall survival (OS) between the two arms.
- Comparing objective response rate (ORR) as assessed by BICR between the two arms.
- Evaluating duration of response (DOR) as assessed by BICR between the two arms.
- Evaluating time to response (TTR) as assessed by BICR between the two arms.
- Evaluating safety and tolerability between the two arms.
- Comparing time to deterioration (TTD) in physical functioning as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [Version 3.0]) between the two arms.
- Evaluating TTD in role functioning, global health status/quality of life (QOL), pain, and fatigue as measured by the EORTC QLQ-C30 (Version 3.0) between the two arms.
Participants
The clinical trial involves a total of **329 participants** diagnosed with **PD-L1 Positive Metastatic Triple-Negative Breast Cancer**. The study population includes both female and male subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, ensuring they have not received previous systemic therapy for advanced disease and have PD-L1 positive tumors at screening. The trial includes individuals with a well-controlled HIV infection, provided they are on antiretroviral therapy. Participants are required to have an **ECOG performance status** score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population is characterized by a life expectancy of at least three months and adequate hematologic and hepatic function. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use protocol-specified contraception methods if applicable. The selection process ensures a diverse group, including vulnerable populations, to comprehensively assess the trial's objectives.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **sacituzumab govitecan** in combination with **pembrolizumab** compared to the treatment of physician's choice with **pembrolizumab** in patients with previously untreated, locally advanced inoperable or metastatic triple-negative breast cancer expressing PD-L1. This is a randomized, open-label, Phase 3 study. The trial aims to assess progression-free survival (PFS) as the primary endpoint, with secondary endpoints including overall survival (OS), objective response rate (ORR), duration of response (DOR), time to response (TTR), and the incidence of treatment-emergent adverse events (TEAEs). The trial is expected to conclude by February 2027, with recruitment having commenced in September 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and specific medical history. Following randomization, participants will receive treatment according to their assigned group. Regular follow-up visits will be scheduled to monitor treatment response and safety, with assessments conducted using imaging techniques such as CT or MRI per RECIST Version 1.1 criteria. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected duration of participant involvement in the study is contingent upon the treatment regimen and individual response, with a maximum treatment period of 28 days for certain regimens. Conditions that may lead to early termination from the study include the occurrence of unacceptable adverse events, disease progression, or withdrawal of consent. Participants will be closely monitored throughout the trial to ensure adherence to protocol and to address any safety concerns promptly.
Treatment
The clinical trial involves the administration of several experimental and comparator medications, each with specific pharmaceutical forms, dosages, and administration routes. **Carboplatin** is provided as a 10 mg/mL concentrate for solution for infusion. It is administered via **intravenous infusion** with a maximum daily dose of 1000 mg/m². The treatment period for Carboplatin is set at 21 days. This medication is classified as an antineoplastic agent and is produced by Fresenius Kabi Deutschland GmbH.
**Pembrolizumab**, marketed as KEYTRUDA, is a 25 mg/mL concentrate for solution for infusion. It is also administered through intravenous infusion, with a maximum daily dose of 200 mg. The treatment period is 21 days. Pembrolizumab is a monoclonal antibody produced by Merck Sharp & Dohme B.V.
**Paclitaxel** is available as a 6 mg/mL concentrate for solution for infusion, administered via intravenous infusion. The maximum daily dose is 90 mg/m², with a treatment period of 28 days. It is classified as an antineoplastic agent and is manufactured by Fresenius Kabi Deutschland GmbH.
**Sacituzumab Govitecan**, marketed as Trodelvy, is provided as a 200 mg powder for concentrate for solution for infusion. It is administered intravenously with a maximum daily dose of 10 mg/kg. The treatment period is 21 days. Sacituzumab Govitecan is an antibody-drug conjugate produced by Gilead Sciences Ireland Unlimited Company.
**Paclitaxel Albumin-Bound**, marketed as Abraxane, is a 5 mg/mL powder for dispersion for infusion. It is administered via intravenous infusion with a maximum daily dose of 100 mg/m². The treatment period is 28 days. This medication is classified as an antineoplastic agent and is produced by Bristol-Myers Squibb Pharma EEIG.
**Gemcitabine** is available as a 38 mg/mL concentrate for solution for infusion, administered through intravenous infusion. The maximum daily dose is 1000 mg/m², with a treatment period of 21 days. It is classified as a nucleoside metabolic inhibitor and is produced by Hospira UK Limited, Walton Oaks.
All medications are administered via intravenous infusion, and participant compliance is monitored throughout the trial. The trial aims to compare the progression-free survival (PFS) between the combination of Sacituzumab Govitecan and Pembrolizumab versus the treatment of physician's choice and Pembrolizumab in patients with previously untreated, locally advanced inoperable or metastatic triple-negative breast cancer, whose tumors express PD-L1.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from randomization to the date of objective progressive disease or death, whichever occurs first. This will be assessed by Blinded Independent Central Review (BICR) according to RECIST Version 1.1 criteria.
Secondary endpoints include **Overall Survival (OS)**, which measures the time from randomization until death from any cause, and **Objective Response Rate (ORR)**, defined as the proportion of participants achieving a complete response (CR) or partial response (PR) confirmed at least four weeks after initial documentation. The **Duration of Response (DOR)** is also evaluated, measuring the time from the first documentation of CR or PR to the first documentation of objective progressive disease or death. Additionally, **Time to Response (TTR)** and the incidence of treatment-emergent adverse events (TEAEs) and clinical laboratory abnormalities will be assessed. The trial will also evaluate the time to deterioration (TTD) of physical functioning and other domains of the EORTC QLQ-C30, including role functioning, global health status/quality of life, pain, and fatigue.
These efficacy parameters will be measured and analyzed at various timepoints throughout the trial, with assessments conducted by BICR to ensure objectivity and consistency. The use of validated scales and criteria, such as RECIST Version 1.1, ensures that the efficacy assessments are standardized and reliable.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must meet all of the following inclusion criteria to be eligible for participation in this study (no waivers for participant eligibility will be offered or permitted): Female or male participants, regardless of race and/or ethnic group, who are 18 years of age or older, able to understand and give written informed consent.
- Participants with locally advanced inoperable or metastatic TNBC who have not received previous systemic therapy for advanced disease and whose tumors are PD-L1 positive at screening. a) Participants must have completed treatment for Stage I to 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. Prior use of an anti-PD(L)1 agent in the curative TNBC setting is permitted. i) Participants 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) Participants 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) Participants 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. Participants 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}. Participants 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 site prior to study entry. Tumor CPS ≥ 10 using the PD-L1 IHC 22C3 assay will be required for eligibility. d) Participants must have measurable disease by CT or MRI as per RECIST Version 1.1 criteria (Appendix 11.7) 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 (preferably) 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, PD-L1, Trop-2, 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 participant provides written informed consent. Fine needle aspirates 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 (Appendix 11.6).
- 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 initiations (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 participant is currently receiving therapeutic anticoagulant therapy.
- Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.4.
- Participants with HIV must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: a) Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening. b) Participants 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) Participants 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
- Participants who meet any of the following exclusion criteria are not eligible to be enrolled in this study (no waivers for participant eligibility will be offered or permitted): Positive serum pregnancy test (Appendix 11.4) or women who are lactating.
- Known or severe (≥ Grade 3) hypersensitivity or allergy to SG, pembrolizumab, and/or the chemotherapy regimen of choice in the TPC arm (eg, nab-paclitaxel, paclitaxel, gemcitabine, or carboplatin), their metabolites, or formulation excipient.
- Have received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
- Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.1.
- Participants 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. Participants must have recovered from AEs due to a previously administered agent to ≤ Grade 1 or baseline at the time of study entry. Note: participants with ≤ Grade 2 neuropathy or any grade alopecia are an exception to this criterion and will qualify for the study. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. Note: if participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
- Participants may not be participating in a study with an investigational agent or investigational device within 4 weeks prior to randomization. Participants 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: participants with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or participants with surgically cured tumors with low risk of recurrence (eg, nonmelanoma 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. Participants 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 post-treatment 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 participants with carcinomatous meningitis are excluded regardless of clinical stability.
- Have undergone an allogenic tissue or solid organ transplant.
- 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 systemic antimicrobial therapy.
- Participants 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 participants 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 participant may be eligible. b) Participants 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 a diagnosis of immunodeficiency or receiving systemic corticosteroid therapy (higher than physiologic doses) ≥ 10 mg of prednisone per day or equivalent] or any other form of immunosuppressive therapy within 14 days prior to randomization.
- Has received a live or live-attenuated vaccine within 30 days prior to randomization. Administration of killed vaccines are allowed.
- Has an active autoimmune disease that has required systemic treatment in the past 2 years (eg, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
- Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
- Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (2 weeks of radiotherapy) to non-CNS disease.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 13 Sept 2022 | 3 |
 Belgium | Not Recruiting | 13 Sept 2022 | 3 |
 Czechia | Not Recruiting | 13 Sept 2022 | 6 |
 France | Not Recruiting | 13 Sept 2022 | 25 |
 Germany | Not Recruiting | 13 Sept 2022 | 11 |
 Hungary | Not Recruiting | 13 Sept 2022 | 3 |
 Italy | Not Recruiting | 13 Sept 2022 | 19 |
 The Netherlands | Not Recruiting | 13 Sept 2022 | — |
 Poland | Not Recruiting | 13 Sept 2022 | 4 |
 Spain | Not Recruiting | 13 Sept 2022 | 32 |
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 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 200 | 21 | PRD4323105 |
Abraxane 5 mg/ml powder for dispersion for infusion. | Comparator | POWDER FOR DISPERSION FOR INFUSION | INTRAVENOUS INFUSION | 100 | 28 | PRD9254301 |
Gemcitabine 38 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 21 | PRD1164506 |
Trodelvy 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 10 | 21 | PRD9351384 |
Carboplatin 10 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 21 | PRD7277959 |