| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Hormonal Receptor-Positive (HR+) Human Epidermal Growth Factor
Receptor 2 (HER2) Negative Metastatic Breast Cancer (MBC) |
|
| E.1.1.1 | Medical condition in easily understood language |
Hormonal Receptor-Positive (HR+) Human Epidermal Growth Factor
Receptor 2 (HER2) Negative Metastatic Breast Cancer (MBC) who has progressed or returned |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006198 |
| E.1.2 | Term | Breast cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess and compare efficacy of Sacituzumab Govitecan to treatment of physician’s choice (TPC) as measured by progression-free survival (PFS) as determined by local investigator review [LIR] using Response Evaluation Criteria in Solid Tumors Version 1.1 [RECIST1.1]) in subjects with HR+/HER2- MBC who have progressed after CDK 4/6 inhibitor, endocrine therapy, taxane, and at least 2 but no more than 4 prior chemotherapy regimens for metastatic disease.
- To assess and compare objective (overall) response rate (ORR) between treatment arms as determined by blinded independent central review (BICR) using RECIST 1.1. |
|
| E.2.2 | Secondary objectives of the trial |
-To assess and compare Sacituzumab Govitecan to TPC in overall
survival(OS) in subjects withHR+/HER2-MBC who have progressed
after CDK4/6inhibitor,endocrine therapy,taxane and at least2,but no more than4 prior chemotherapy treatment regimens for metastatic disease
-To assess and compare duration of response(DOR) and clinical benefit rate(CBR) between treatment arms as determined by LIR using RECIST1.1
-To assess and compare the impact of treatment on Health-Related Quality of Life between treatment arms,using quality of life
questionnaire v30(QLQ-C30) and theEuroQOL EQ-5D-5L instruments to assess and compare the impact of treatment-related symptoms using a set of 9 relevant symptom concepts from the Patient-Reported Outcomes(PRO)ver.of the Common Terminology Criteria for Adverse Events(PRO-CTCAE™)item library(decreased appetite,nausea,vomiting,constipation,diarrhea,abdominal pain,shortness of breath,hair loss,and fatigue)
-To assess and compare the overall safety and tolerability |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female or male subjects, adult or aged ≥18 years at the time of
signing the informed consent form (ICF)
2. Documented evidence of HR+/HER2- MBC confirmed by a local
laboratory with the most recently available or newly obtained tumor
biopsy (preferably within the last 12 months) from a locally recurrent or metastatic site(s) and defined per ASCO/CAP criteria as: HR positive and HER2-negative.
3. Availability of archival tumor tissue in a formalin-fixed, paraffin
embedded (FFPE) block (preferably within 12 months prior to consent) or newly acquired biopsy (FFPE block) from a metastatic site. Note: bone biopsies are not allowed.
4. Refractory to or relapsed after at least 2, but no more than 4 prior
systemic chemotherapy regimens for metastatic disease.
5. Should have been previously treated with:
- At least 1 taxane in any setting.
- At least 1 prior anticancer hormonal treatment in any setting .
- At least 1 cyclin-dependent kinase inhibitor 4/6 in any setting.
6. Eligible for one of the chemotherapy options listed in the TPC arm.
7. Documented disease progression after the most recent therapy by
CT/MRI.
8. At least 1 measurable target lesion according to RECIST 1.1 (bony
disease only is not allowed) meeting all of the following criteria:
• Lymph node lesion that measures at least ≥1.5 cm in the short axis
• Non-nodal lesion that measures ≥1.0 cm in the longest diameter in the plane of measurement
• The lesion is suitable for repeat measurement using CT/MRI. Historical CT/MRI scans performed within 28 days of C1D1 may be used as screening scans to demonstrate eligibility by local radiology review as long as they meet minimum standards as separately defined by the central imaging vendor.
• Lesions that have had external beam radiotherapy or locoregional
therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion
• Brain CT/MRI must be conducted for subjects with a history of brain metastasis. The subject must have had stable* brain metastasis for at least 4 weeks. Target lesions cannot be from brain.
* Stable brain metastasis is defined as the following:
- Prior local treatment by radiation, surgery, or stereotactic surgery.
- Imaging – stable or decreasing size after such local treatment.
- Clinically stable signs and symptoms for at least 4 weeks.
- ≥2 weeks from discontinuation of antiseizure medication
- Low and stable doses of corticosteroids ≤20 mg prednisone or
equivalent daily are permitted
9. ECOG performance status of 0 or 1
10. Adequate renal function: calculated creatinine clearance ≥30 mL/minute according to the Cockcroft and Gault formula
11. Adequate bone marrow function
Note: Blood transfusion or growth factor support is not allowed within 14 days prior to screening labs.
12. Adequate liver function.
13. Resolution of all systemic anticancer therapy-related or radiationrelated toxicities to Grade 1 severity or lower, except for neuropathy (≤ Grade 2) and alopecia. Subjects with Grade 2 neuropathy are eligible but should not receive vinorelbine as TPC.
14. Females must not be lactating or pregnant at Baseline (as
documented by a negative ß-hCG or hCG) test.
- All females will be considered to be of childbearing potential unless
they are postmenopausal or have been sterilized surgically.
15. Females of childbearing potential must not have had unprotected
sexual intercourse within 30 days before study entry and must agree to use a highly effective method of contraception throughout the entire study period and for 6 months after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 28 days before dosing and must continue to use the same contraceptive during the study and for 6 months after study drug discontinuation.
16. Male subjects who are partners of women of childbearing potential must use a condom and spermicide and their female partners, if of childbearing potential, must use a highly effective method of contraception beginning at least 1 menstrual cycle prior to starting study drug, throughout the entire study period, and for 3 months after the last dose of study drug, unless the male subjects are totally sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia or unless the female partners have been sterilized surgically or are otherwise proven sterile.
17. Must be willing and able to comply with all aspects of the protocol.
18. Must voluntarily agree to provide written informed consent.
19. Could have received an unlimited number of prior endocrine,
biological, or targeted therapies in the absence of co-administered
chemotherapy; all of these therapies must have been completed 14 days prior to randomization, except biological therapy which must have been completed 28 days prior to randomization. |
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with a topoisomerase 1 inhibitor as a free form or as other formulations
2. Current enrollment in another clinical study or used any
investigational device or drug either within 5 half-lives or 28 days prior to randomization, whichever is longer
3. Treatment with chemotherapy, radiation, or small molecule targeted therapy within 2 weeks and biological therapy within 4 weeks prior to the first dose of study treatment
4. Existing anticancer treatment-related AEs of Grade ≥2 (except for
alopecia and Grade 2 neuropathy) according to NCI-CTCAE v5.0.
5. Any other malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 5 years prior to enrollment in this study.
6. History of significant cardiovascular disease, defined as:
- Congestive heart failure greater than New York Heart Association
(NYHA) Class II according to the NYHA Functional Classification.
- Unstable angina or myocardial infarction within 6 months before
enrollment.
- Serious cardiac arrhythmia.
7. Clinically significant ECG abnormality, including:
- Marked Baseline prolonged QT/QTc interval (ie, a repeated
demonstration of a QTc interval >500 ms) demonstrated on ECG at
Screening.
- History of risk factors for torsade de pointes (eg, heart failure,
hypokalemia, family history of long QT Syndrome).
8. Has known active central nervous system metastases and/or
carcinomatous meningitis. Subjects may participate provided they have stable brain metastasis. All subjects with carcinomatous meningitis are excluded regardless of clinical stability. Stable brain metastasis is defined in inclusion criterion 8
9. Active hepatitis B virus (positive hepatitis B surface antigen) or active hepatitis C virus (measurable viral ribonucleic acide (RNA) load with polymerase chain reaction) infection.
10. Scheduled surgery during the study, other than minor surgery which would not delay study treatment.
11. Has an active serious infection requiring antibiotics
12. Has active chronic inflammatory bowel disease (ulcerative colitis,
Crohn's disease) and subjects with a history of bowel obstruction.
13. Have received a live vaccine within 30 days of randomization.
14. Known hypersensitivity or intolerance to any of the study drugs or any of the excipients.
15. Any medical or other condition which, in the opinion of the
Investigator, causes the subject to be medically unfit to receive
sacituzumab govitecan or unsuitable for any other reason.
16. Is receiving any medication prohibited in combination with the study treatment(s) as described in the respective product labels, unless medication was stopped within 7 days prior to randomization.
17. Locally-advanced MBC (stage IIIc) in subjects who are candidates
for curative intent therapy at the time of study enrollment.
18. If required per local guidelines, any subject with a blood uracil level ≥ 150 ng/mL is excluded from receiving capecitabine as TPC (Note: blood uracil level will be assessed at Screening for all subjects eligible to be randomized to capecitabine as TPC) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Progression-free survival (PFS) as determined by a local investigator
review [LIR] using RECIST1.1.
- Objective (overall) response rate (ORR) between treatment arms as determined by blinded independent central review (BICR) using RECIST1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Duration of Overall Response (DOR)
- Clinical benefit rate (CBR)
- EORTC QLQ-C30 and EuroQOL EQ-5D-5L
- PRO-CTCAE
- Safety and tolerability will be assessed based on the incidence of AEs and SAEs, review of clinical laboratory data (i.e., hematology, chemistry, and urinalysis), electrocardiogram (ECG) monitoring, Eastern Cooperative Oncology Group (ECOG) performance status, vital signs (i.e., heart rate, systolic and diastolic blood pressure, respiratory rate, and body temperature), and ADA. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Monitored throughout the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 55 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of study is defined as the point in time when the number of progression events required for the primary analyses have been reached or if the Sponsor terminates the study, whichever comes first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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