Trial of Sacituzumab Govitecan in Participants With Refractory/Relapsed Metastatic Triple-Negative Breast Cancer (TNBC)

Study Overview
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Brief Summary
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The primary objective of this study is to compare the efficacy of sacituzumab govitecan to the treatment of physician's choice (TPC) as measured by independently-reviewed Independent Review Committee (IRC) progression-free survival (PFS) in participants with locally advanced or metastatic triple-negative breast cancer (TNBC) previously treated with at least two systemic chemotherapy regimens for unresectable, locally advanced or metastatic disease, and without brain metastasis at baseline.

Official Title
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An International, Multi-Center, Open-Label, Randomized, Phase III Trial of Sacituzumab Govitecan Versus Treatment of Physician Choice in Patients With Metastatic Triple-Negative Breast Cancer Who Received at Least Two Prior Treatments

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Sacituzumab govitecan
* Drug: Eribulin
* Drug: Capecitabine
* Drug: Gemcitabine
* Drug: Vinorelbine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically or cytologically confirmed TNBC based on the most recent analyzed biopsy or other pathology specimen. Triple negative is defined as <1% expression for estrogen receptor (ER) and progesterone receptor (PR) and negative for human epidermal growth factor receptor 2 (HER2) by in-situ hybridization. Refractory to or relapsed after at least two prior standard therapeutic regimens for advanced/metastatic TNBC. Prior exposure to a taxane in localized or advanced/metastatic setting. Eligible for one of the chemotherapy options listed as TPC (eribulin, capecitabine, gemcitabine, or vinorelbine) as per investigator assessment. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Bone-only disease is not permitted. At least 2 weeks beyond prior anti-cancer treatment (chemotherapy, endocrine therapy, radiotherapy, and/or major surgery), and recovered from all acute toxicities to Grade 1 or less (except alopecia and peripheral neuropathy). At least 2 weeks beyond high dose systemic corticosteroids (however, low dose corticosteroids < 20 mg prednisone or equivalent daily are permitted provided the dose is stable for 4 weeks). Adequate hematology without ongoing transfusional support (hemoglobin > 9 g/dL, absolute neutrophil count (ANC) > 1,500 per mm^3, platelets > 100,000 per mm^3). Adequate renal and hepatic function (creatinine clearance [CrCL] > 60 mL/min, bilirubin ≤ 1.5 institutional upper limit of normal [IULN], aspartate aminotransferase [AST] and alanine aminotransferase [ALT] ≤ 2.5 x IULN or ≤ 5 x IULN if known liver metastases and serum albumin ≥3 g/dL). Recovered from all toxicities to Grade 1 or less by National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) v4.03 (except alopecia or peripheral neuropathy that may be Grade 2 or less) at the time of randomization. Participants with Grade 2 neuropathy are eligible but may not receive vinorelbine as TPC. Participants with treated, non-progressive brain metastases, off high-dose steroids (>20 mg prednisone or equivalent) for at least 4 weeks can be enrolled in the trial. Key Exclusion Criteria: Women who are pregnant or lactating. Women of childbearing potential or fertile men unwilling to use effective contraception during study and up to three months after treatment discontinuation in women of child-bearing potential and six months in males post last study drug. Participants with Gilbert's disease. Participants with non-melanoma skin cancer or carcinoma in situ of the cervix are eligible, while participants with other prior malignancies must have had at least a 3-year disease-free interval. Participants known to be human immunodeficiency (HIV) positive, hepatitis B positive, or hepatitis C positive. Infection requiring antibiotic use within one week of randomization. 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. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacituzumab Govitecan<br>Participants will receive sacituzumab govitecan on Days 1 and 8 of a 21-day treatment cycle for up to 29.6 months. Participants will continue treatment until progression of disease requiring treatment discontinuation or occurrence of unacceptable adverse events (AEs). | Drug: Sacituzumab govitecan<br>* 10 mg/kg administered as a slow intravenous (IV) infusion either by gravity or with an infusion pump. Infusion rate for the first 15 minutes will start with 50 mg/hour or less with a subsequent infusion of 100 to 200 mg/hour up to a maximum recommended rate (advanced every 15 to 30 minutes) of 500 mg/hour with a subsequent infusion of 1000 mg/hour.<br>* Other names: Trodelvy®;|
| Active Comparator: Treatment of Physician's Choice (TPC)<br>Participants will receive TPC (ie, eribulin, capecitabine, gemcitabine, or vinorelbine), administered as a single-agent regimen that is selected by the investigator before participant randomization. Participants will continue treatment until progression of disease requiring treatment discontinuation or occurrence of unacceptable AEs. | Drug: Eribulin<br>* Administered IV over 2 to 5 minutes at a dose 1.4 mg/m^2 at North American sites and 1.23 mg/m^2 at European sites on Days 1 and 8 of a 21-day cycle for up to 15.3 months. Lower doses will be administered on the same schedule to participants with moderate hepatic impairment (ie, Child-Pugh B; 0.7 mg/m^2 and 0.67 mg/m^2 for North American and European sites, respectively).<br>* Other names: Halaven;Drug: Capecitabine<br>* 1000 to 1250 mg/m^2 will be administered in a 21-day cycle, with capecitabine administered orally twice daily for 2 weeks followed by 1-week rest period for up to 10.6 months.<br>* Other names: Xeloda;Drug: Gemcitabine<br>* 800 to 1200 mg/m^2 will be administered IV over 30 minutes on Days 1, 8, and 15 of a 28-day cycle for up to 8.1 months.<br>* Other names: Gemzar;Drug: Vinorelbine<br>* 25 mg/m^2 will be administered as a weekly IV injection over 6-10 minutes for up to 11.5 months. Vinorelbine will not be allowed as TPC for any participant with Grade 2 neuropathy.<br>* Other names: Navelbine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) by Independent Review Committee (IRC) Assessment in Brain Metastasis Negative (BM-ve) Population | PFS was defined as the time from randomization until objective tumor progression by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death, whichever came first. The date of progression was date of the last observation or radiological assessment of target lesions that either showed a predefined increase (greater than or equal to [≥] 20%) in the sum of the target lesions or the appearance of new non-target lesions. PFS was estimated using Kaplan-Meier estimate. | From randomization until objective tumor progression or death (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) by IRC Assessment in the ITT Population | PFS was defined as the time from randomization until objective tumor progression by RECIST v1.1 or death, whichever came first. The date of progression was date of the last observation or radiological assessment of target lesions that either showed a predefined increase (≥20%) in the sum of the target lesions or the appearance of new non-target lesions. PFS was estimated using Kaplan-Meier estimate. | From randomization until objective tumor progression or death (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Overall Survival (OS) in BM-ve Population | Overall survival (OS) was defined as the time from the randomization to death from any cause. OS was estimated using Kaplan-Meier estimate. | From the randomization to death from any cause (maximum follow-up duration: 30.8 months) | 
| Overall Survival (OS) in ITT Population | Overall survival (OS) was defined as the time from the randomization to death from any cause. OS was estimated using Kaplan-Meier estimate. | From the randomization to death from any cause (maximum follow-up duration: 30.8 months) | 
| Objective Response Rate (ORR) by IRC and Investigator Assessment in BM-ve Population | ORR was defined as the percentage of participants who had the overall best response as either a confirmed complete response (CR) or partial response (PR) relative to the size of population under evaluation. CR: Disappearance of all target and non-target lesions; and normalization of tumor marker levels initially above upper limits of normal; and no new lesions. PR: ≥30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; and no new lesions. | From randomization to the date of progression or death (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Time to Objective Response by the Investigator Assessment in BM-ve Population | Time to response was defined as the time from randomization to the first recorded objective response (ie, CR or PR). CR: Disappearance of all target and non-target lesions; and normalization of tumor marker levels initially above upper limits of normal; and no new lesions. PR: ≥30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; and no new lesions. | From randomization to the first recorded objective response (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Time to Objective Response by the IRC Assessment in BM-ve Population | Time to response was defined as the time from randomization to the first recorded objective response (ie, CR or PR). CR: Disappearance of all target and non-target lesions; and normalization of tumor marker levels initially above upper limits of normal; and no new lesions. PR: ≥30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; and no new lesions. | From randomization to the first recorded objective response (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Duration of Response (DOR) by IRC and Investigator Assessment in BM-ve Population | DOR was defined as the number of days between the first date showing a documented response of CR or PR and the date of progression or death. CR: Disappearance of all target and non-target lesions; and normalization of tumor marker levels initially above upper limits of normal; and no new lesions. PR: ≥30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; and no new lesions. The date of progression was date of the last observation or radiological assessment of target lesions that either showed a predefined increase (≥20%) in the sum of the target lesions or the appearance of new non-target lesions. | From the first date of documented response of CR or PR to the date of progression or death (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Time to Progression (TTP) by Investigator Assessment in BM-ve Population | Time to Progression (TTP) was defined as the time from the date of randomization to the date of the first evidence of disease progression as assessed using RECIST 1.1 criteria. The date of progression was date of the last observation or radiological assessment of target lesions that either showed a predefined increase (≥20%) in the sum of the target lesions or the appearance of new non-target lesions. Participants without progression were censored. | From randomization until disease progression (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Time to Progression (TTP) by IRC Assessment in BM-ve Population | Time to Progression (TTP) was defined as the time from the date of randomization to the date of the first evidence of disease progression as assessed using RECIST 1.1 criteria. The date of progression was date of the last observation or radiological assessment of target lesions that either showed a predefined increase (≥20%) in the sum of the target lesions or the appearance of new non-target lesions. Participants without progression were censored. | From randomization until disease progression (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Clinical Benefit Rate (CBR) by IRC and Investigator Assessment in BM-ve Population | CBR was defined as the percentage of participants with best response as either CR, PR, or stable disease (SD) with a duration of ≥6 months. CR: Disappearance of all target and non-target lesions; and normalization of tumor marker levels initially above upper limits of normal; and no new lesions. PR: ≥30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD; and no new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started; and Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. PD: ≥20% increase in the sum of LD of target lesions, taking as reference the smallest sum LD recorded since treatment started or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | From randomization to the date of progression or death (assessed every 6 weeks for 9 months and then every 9 weeks thereafter until the occurrence of progression of disease; maximum exposure: 29.6 months) | 
| Percentage of Participants Experiencing Any Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and TEAEs Leading to Discontinuation of Study Drug | Treatment-emergent adverse events (TEAEs) were defined as any adverse events (AEs) that begin or worsen on or after the start of study drug through 30 days after the last dose of study drug. The severity was graded based on the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 4.03. An AE that met one or more of the following outcomes was classified as serious: Fatal Life-threatening Disabling/incapacitating Results in hospitalization or prolongs a hospital stay A congenital abnormality Other important medical events may also be considered serious AEs if they may require medical or surgical intervention to prevent one of the outcomes listed above | First dose date up to last follow-up (maximum up to 30.8 months) | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30) Score | The EORTC QLQ-C30 is a questionnaire to assess quality of life (QoL), it is composed of 30 questions (items) resulting in 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, pain), and 6 single items (dyspnea, insomnia, loss of appetite, constipation, diarrhea, financial difficulties). All of the scales and single-item measures range in score from 0 to 100. Higher score for the functioning scales and global health status indicate a better quality of life; a positive change from baseline indicates improvement. Lower scores on the symptom and single-item scales indicate a better quality of life; a negative change from baseline indicates improvement. | Baseline; End of Treatment (EOT) (up to 29.6 months) | 
| Percentage of Participants Experiencing the Worst Laboratory Abnormalities Grade 3 or 4 Post-Baseline | Blood samples were collected for hematology, serum chemistry and the laboratory abnormalities were assessed. The most severe graded abnormality observed post-baseline for each graded test was counted for each participant. Safety as assessed by grading of laboratory values and AEs according to the National Cancer Institutes' Common Terminology Criteria for Adverse Events (NCI CTCAE) covering grades 0-5 (0=Normal, 1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening, 5=Death). The percentage of participants with worst postbaseline grades 3 or 4 are reported. | First dose date up to last follow-up (maximum up to 30.8 months) |