A Randomized, Open-label, Phase 3 Study of Sacituzumab Govitecan Versus Treatment of Physician’s Choice in Patients With Hormone Receptor-Positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2−) (HER2 IHC0 or HER2-low [IHC 1+, IHC 2+/ISH−]) Inoperable, Locally Advanced, or Metastatic Breast Cancer and Have Received Endocrine Therapy
- Trial ID
- 2022-502593-17-00
- Protocol
- GS-US-598-6168
- Sponsor
- Gilead Sciences Inc.
Trial statistics
Objectives
The primary objective of this study is to compare the effect of **sacituzumab govitecan** (SG) relative to the treatment of physician's choice (TPC) on progression-free survival (PFS) in patients with locally advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who have received an endocrine-based regimen. This objective is clinically relevant as PFS is a critical endpoint in oncology trials, reflecting the time during which a patient's disease does not worsen, thereby providing insights into the efficacy of the treatment.
Secondary objectives include comparing the effect of SG relative to TPC on overall survival (OS), objective response rate (ORR), and changes from baseline in the physical functioning domain. Additionally, the study aims to evaluate the time to definitive deterioration in global health status and quality of life (QoL) as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30). These secondary objectives are important for understanding the broader impact of the treatment on patient outcomes beyond disease progression, including survival and quality of life metrics.
Participants
The clinical trial involves a total of **439 participants** diagnosed with **locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer**. The study population includes both male and female subjects, aged 18 years and older, who have previously received an endocrine-based regimen. Participants were selected based on their ability to provide informed consent and meet specific health criteria, including a life expectancy of at least three months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial includes individuals with a history of HIV, provided they are on a stable antiretroviral therapy regimen with well-controlled infection. Lifestyle factors such as diet and physical activity are not specified, but participants must comply with protocol requirements, including the use of contraception if applicable. The trial population is not limited to a specific gender, and vulnerable populations are included. Key inclusion criteria require participants to have measurable disease per RECIST v1.1 criteria and documented evidence of HR+ metastatic breast cancer, with HER2-negative status confirmed by local or central testing. Participants must have completed any prior anticancer treatment at least 14 days before randomization, with any treatment-related toxicity resolved or clinically stable.
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 hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) inoperable, locally advanced, or metastatic breast cancer who have previously received endocrine therapy. The primary objective is to compare the effect of sacituzumab govitecan relative to the treatment of physician's choice on progression-free survival (PFS). The trial is expected to conclude by December 29, 2028, with recruitment starting on August 22, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, previous treatment history, and disease status. Following randomization, participants will receive either sacituzumab govitecan or a treatment of the physician's choice, which may include **capecitabine**, **nab-paclitaxel**, or **paclitaxel**. The trial will involve regular follow-up visits to monitor treatment response and safety, with assessments conducted according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement in the trial is contingent upon the treatment regimen, with a maximum treatment period of 21 to 28 days for sacituzumab govitecan and other chemotherapeutic agents. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will also evaluate secondary endpoints such as overall survival (OS), objective response rate (ORR), and the incidence of adverse events (AEs) and serious adverse events (SAEs).
Treatment
The clinical trial involves several treatments, including both experimental and non-experimental medications. **Sacituzumab govitecan** is an experimental medication used in this study. It is administered as a **powder for concentrate for solution for infusion**. The active substance, sacituzumab govitecan, is an **antibody-drug conjugate**. The maximum daily dose is 10 mg/kg, with a total maximum dose of 20 mg/kg over a treatment period of 21 days. The route of administration is **intravenous infusion**.
**Capecitabine** is used as a comparator treatment in the form of **film-coated tablets**. It is a **cytostatic** agent, with a maximum daily dose of 2500 mg/m² and a total maximum dose of 35000 mg/m² over a 21-day treatment period. The administration route is **oral**.
**Paclitaxel albumin-bound** is another comparator treatment, provided as a **powder for dispersion for infusion**. It is classified as an **antineoplastic agent**. The maximum daily dose is 100 mg/m², with a total maximum dose of 300 mg/m² over a 28-day treatment period. The administration is via **intravenous administration**.
**Paclitaxel** is also used as a comparator, available as a **concentrate for solution for infusion**. It is an **antineoplastic agent** with a maximum daily dose of 80 mg/m² and a total maximum dose of 240 mg/m² over a 28-day treatment period. The route of administration is **intravenous administration**.
Non-experimental treatments include **corticosteroids, plain**, administered orally, and **antiemetics and antinauseants**, administered via injection. These auxiliary treatments are used to manage side effects and support the primary treatment regimen. Additionally, **immunostimulants** are administered via injection, and **antipsychotics** are administered orally, both serving as auxiliary treatments to support patient care during the trial.
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 first occurrence of objective progressive disease or death from any cause, as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). Secondary endpoints include Overall Survival (OS), which measures the time from randomization to death from any cause, and Objective Response Rate (ORR), defined as the percentage of patients achieving a complete or partial response confirmed at least four weeks after initial documentation, as assessed by BICR per RECIST v1.1.
Additional secondary endpoints include the change from baseline in the physical functioning domain at Week 16, and Time to Deterioration (TTD) of Global Health Status/Quality of Life (QoL) domain of the EORTC QLQ-C30. This is defined as the time from randomization to the first occurrence of a change from baseline equal to or greater than a pre-specified threshold for worsening or death. The Duration of Response (DOR) is also evaluated, defined as the time from the first documentation of complete or partial response to the first documentation of objective progressive disease or death, assessed by both BICR and the investigator per RECIST v1.1.
The incidence of adverse events (AEs) and serious adverse events (SAEs) will be monitored, along with the percentage of patients experiencing clinically significant laboratory and/or vital sign abnormalities. These efficacy parameters will be measured and analyzed at various timepoints throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on patients with hormone receptor-positive, HER2-negative inoperable, locally advanced, or metastatic breast cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Assigned male or female at birth, 18 years of age or older (or minimum age according to country-specific requirements), able to understand and give written informed consent.
- Must have adequate tumor tissue sample preferably from locally recurrent or metastatic site, either in a formalin-fixed, paraffin-embedded block or newly sectioned, unstained slides for HER2 status and other biomarker assessments.
- Documented evidence of HR+ metastatic breast cancer (mBC) confirmed with the most recently available tumor biopsy preferably from a locally recurrent or metastatic site and defined per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria as HR+ (a tumor is considered HR+ if at least 1% of the cells examined have estrogen or progesterone receptors) by local assessment using the most recent biopsy from a non–bone lesion.
- Documented evidence of HER2− status according to ASCO-CAP guidelines. HER2− status including HER2 IHC0 or HER2-low (IHC 1+, IHC 2+/ISH−) should be documented by local testing at the time of eligibility review. If HER2 IHC is not locally available, central testing can be requested in discussion with the sponsor
- Documented PD by computed tomography (CT) or magnetic resonance imaging during or after the most recent therapy per RECIST v1.1 criteria.
- Candidate for the first chemotherapy in the locally advanced or metastatic setting a) Patients may have received prior anthracycline in the (neo)adjuvant setting or were considered not eligible or not a candidate for anthracyclines as assessed by the treating physician.
- Eligible for capecitabine, nab-paclitaxel, or paclitaxel. a) Patients who received taxane in the (neo)adjuvant setting can be treated with the same class of chemotherapy (taxane) if at least 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 the first documented local or distant disease recurrence. b) If required per local guidelines, any patient with a blood uracil level ≥ 150 ng/mL is excluded from receiving capecitabine as TPC. If required per local guidelines, patients with known dihydropyrimidine dehydrogenase deficiency (by genotyping) are also excluded from receiving capecitabine and do not need to have blood uracil level assessed at screening.
- Patients must have at least one of the following: a) Disease progression on at least 2 or more previous lines of ET with or without a targeted therapy in the metastatic setting Disease recurrence while on the first 24 months of starting adjuvant ET will be considered a line of therapy; these patients will only require 1 line of ET in the metastatic setting. b) Disease progression within 6 months of starting first-line ET with a CDK 4/6 inhibitor or without a CDK 4/6 inhibitor (if ineligible or if unable to access a CDK 4/6 inhibitor) in the metastatic setting. c) Disease recurrence while on the first 24 months of starting adjuvant ET with CDK 4/6 inhibitor and if the patient is no longer a candidate for additional ET in the metastatic setting.
- Patients may have received prior targeted therapies, including but not limited to poly adenosine diphosphate-ribose polymerase (PARP) inhibitors (for those with germline BRCA1 or BRCA2 mutations), PI3K inhibitors (for those with PIK3CA mutations), or mTOR inhibitors. However, patients can no longer be candidates for additional endocrine treatment with or without targeted therapies.
- Patients must have completed any anticancer treatment at least 14 days prior to randomization. Any toxicity experienced on prior treatment must have resolved or be considered clinically stable prior to randomization.
- 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 at least 350 cells/mm3 at the 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 quantitation (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 randomization. d) The combination ART regimen must not contain any medications that may interfere with SN-38 metabolism.
- Meet the organ function requirements as per study protocol section 4.2
- Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception. For sites in South Korea, see Appendix11.15.2.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Life expectancy of at least 3 months.
- Willing and able to comply with the requirements and restrictions in this protocol.
- Patients must have measurable disease per RECIST v1.1 criteria.
Exclusion Criteria
- Progressive disease within 6 months of completing (neo)adjuvant chemotherapy.
- Previously HER2+ (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO-CAP guidelines).
- Locally advanced mBC (Stage IIIc) in patients who are candidates for curative intent therapy at the time of study enrollment.
- Current enrollment in another clinical study and use of any investigational device or drug (drugs not marketed for any indication) either within 5 half-lives or 28 days prior to randomization, whichever is longer. a) Use of investigational drugs in the category of Selective Estrogen Receptor Degraders are acceptable if last dose was longer than 14 days prior to randomization.
- Treatment with definitive radiation within 2 weeks prior to the first dose of study drug administration. (Note: palliative radiation therapy for treatment of bone pain secondary to metastases is allowed.)
- Received any prior treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I.
- Received any prior treatment with a Trop-2–directed ADC
- Have a need for ongoing systemic anticancer therapies aside from the study drug.
- Have a need for ongoing therapy of any prohibited medications.
- Have not recovered (ie, ≥ Grade 2) from AEs due to a previously administered agent, with the exception of any grade alopecia or Grade 1 neuropathy. 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 who underwent major surgery within 3 weeks of enrollment are not eligible.
- Have known active, symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis that requires treatment. Patients with previously treated brain metastases may participate provided they have stable CNS disease 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 are taking no more than 10 mg/day of prednisone or its equivalent. All patients with carcinomatous meningitis are excluded regardless of clinical stability.
- 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, nonmelanoma skin cancer, histologically confirmed complete excision carcinoma in situ, or similar) are eligible
- Have a history of significant cardiovascular disease, defined as: 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%.
- Clinically significant ECG abnormality, including any of the following: a) Marked baseline prolonged QT/QT corrected (QTc) interval (ie, a repeated demonstration of a QTc interval > 500 ms) demonstrated on ECG at screening. b) History of risk factors for torsade de pointes (eg, heart failure, hypokalemia, family history of long QT Syndrome) or a history of torsade de pointes
- Have an active serious bacterial, fungal, or viral infection requiring antibiotics.
- Have active hepatitis B virus (HBV) (defined as having a positive hepatitis B surface antigen test) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded. a) Patients who test positive for hepatitis B surface antigen will be excluded. b) Patients who test positive for hepatitis B core antibody will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease. Patients with positive hepatitis B core antibody but negative viral load by PCR may be eligible if they are being monitored for potential viral reactivation or are willing to start or maintain antiviral treatment during study conduction (as dictated by their local and institutional standard practice or guidelines). A patient with a history of HBV infection and presence of hepatitis B surface antibody may participate in the study. In this last scenario, viral load (HBV DNA) is not mandated. For sites in South Korea, see Appendix 11.15.2. c) 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 an HCV antibody at screening and will only require HCV RNA by quantitative PCR for confirmation of active disease.
- Patients positive for HIV-1 or -2 with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
- Criterion removed.
- Scheduled surgery during the study, other than minor surgery which would not delay study drug (eg, port insertion, tooth extraction, any procedure that requires < 1-hour general anesthesia. Procedures performed under local or IV/monitored sedation that lasts < 2 hours are acceptable).
- Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or history of bowel obstruction within 6 months prior to enrollment.
- Have a positive serum pregnancy test or are breastfeeding for patients who are assigned female at birth.
- Have other concurrent medical or psychiatric conditions that, in the investigator’s or sponsor’s opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
- Known or severe (≥ Grade 3) hypersensitivity or allergy to SG and/or the chemotherapy regimen of choice in the TPC arm (eg, paclitaxel, nab-paclitaxel, capecitabine), their metabolites, or formulation excipient.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 22 Aug 2023 | 11 |
 Belgium | Not Recruiting | 22 Aug 2023 | 16 |
 Czechia | Not Recruiting | 22 Aug 2023 | 18 |
 France | Not Recruiting | 22 Aug 2023 | 62 |
 Germany | Not Recruiting | 22 Aug 2023 | 34 |
 Greece | Not Recruiting | 22 Aug 2023 | 18 |
 Hungary | Not Recruiting | 22 Aug 2023 | 7 |
 Italy | Not Recruiting | 22 Aug 2023 | 90 |
 Poland | Not Recruiting | 22 Aug 2023 | 24 |
 Portugal | Not Recruiting | 22 Aug 2023 | 18 |
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 |
|---|---|---|---|---|---|---|
- | Other | - | INJECTION | 00 | 14 | L03A |
Trodelvy 200 mg powder for concentrate for solution for infusion. | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 10 | 21 | PRD9351384 |
- | Other | PHF00169MIG | ORAL | 00 | 12 | A07DA |
Xeloda 500 mg film-coated tablets | Comparator | FILM-COATED TABLETS | ORAL | 2500 | 21 | PRD9863934 |
- | Other | - | ORAL | 00 | 12 | N05A |
- | Other | PHF00170MIG | ORAL | 00 | 12 | SCP5488912 |
- | Other | - | INTRAVENOUS USE | 00 | 12 | M05B |
- | Other | PHF00082MIG | ORAL | 00 | 12 | R06A |
- | Other | PHF00231MIG | INTRAVENOUS | 00 | 12 | B03XA |
Paclitaxel 6 mg/ml concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS ADMINISTRATION | 80 | 28 | PRD7486025 |