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) |
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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 |
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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) |
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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) |
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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) |
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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 after at least 2, and no more than 4, prior chemotherapy regimens for MBC.
- To assess and compare objective (overall) response rate (ORR) between treatment arms as determined by blinded independent central review (BICR) using RECIST 1.1. |
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E.2.2 | Secondary objectives of the trial |
- To assess and compare Sacituzumab Govitecan to TPC in overall survival (OS) in subjects with HR+/HER2- MBC after at least 2, and no more than 4, prior chemotherapy treatment regimens for MBC.
- To assess and compare duration of response (DOR) and clinical benefit rate (CR+PR+SD with a duration of > 6 months) between treatment arms as determined by LIR using RECIST 1.1
- To assess and compare the impact of treatment on Health-Related Quality of Life (HRQoL) between treatment arms, using EORTC questionnaire version 30 (QLQ-C30) and the EuroQOL 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) version 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female or male subjects aged ≥18 years at the time of signing the informed consent form (ICF).
2. Documented evidence of hormone receptor-positive HER2-negative (HR+/HER2-) MBC confirmed (local laboratory) with the most recently available or newly obtained tumor biopsy (within 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 (within 12 months prior to randomization) or newly acquired biopsy from a metastatic site.
4. Refractory to or relapsed after at least 2, and no more than 4, prior systemic chemotherapy regimens for MBC.
5. Subjects should have been previously treated with:
- Taxanes in any setting.
- At least 1 prior anticancer hormonal treatment.
- At least 1 cyclin-dependent kinase inhibitor 4/6 in the metastatic setting.
6. Eligible for one of the chemotherapy options listed in the TPC arm.
7. Documented disease progression after the most recent therapy.
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 (LN) lesion that measures at least one dimension as ≥1.5 cm in the short axis.
- Non-nodal lesion that measures ≥1.0 cm in the longest diameter.
- The lesion is suitable for repeat measurement using CT/MRI.
- Lesions that have had EBRT or locoregional therapy must show radiographic evidence of disease progression based on RECIST 1.1 to be deemed a target lesion.
9. Brain MRI must be conducted for subjects with a history of brain metastasis. The subject must have had stable CNS disease for at least 4 weeks.
10. Life expectancy of ≥3 months from randomization based on the PI’s assessment.
11. ECOG performance status of 0 or 1 (as assessed within 10 days prior to the start of study treatment).
12. Adequate renal function.
13. Adequate bone marrow function
Note: Blood transfusion or growth factor support is not allowed within 14 days prior to screening labs.
14. Adequate liver function.
15. Resolution of all systemic anticancer therapy-related or radiation-related toxicities to Grade 1 severity or lower, except for stable sensory neuropathy (≤Grade 2) and alopecia. Subjects with Grade 2 neuropathy are eligible but may not receive vinorelbine as TPC.
16. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative ß-hCG or hCG) test. A separate baseline assessment is required if a negative screening serum pregnancy test was obtained more than 72 hours before the first dose of study drug.
- All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically.
17. 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 120 days after study drug discontinuation. For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception.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 120 days after study drug discontinuation.
18. 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(s), throughout the entire study period, and for 6 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. No sperm donation is allowed during the study period or for 6 months after study drug discontinuation.
19. Subject must be willing and able to comply with all aspects of the protocol.
20. Subject must voluntarily agree to provide written informed consent.
21. Subjects could have received an unlimited number of prior endocrine, biological, or targeted therapies (including taxanes and CD 4/6 inhibitors) in the absence of co-administered chemotherapy; all of these therapies must have been completed 14 days prior to randomization. |
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E.4 | Principal exclusion criteria |
1. Previous treatment with Topoisomerase 1 Inhibitors as a free form or as other formulations.
2. Current enrollment in another clinical study or used any investigational drug or device within the past 28 days preceding informed consent.
3. Treatment with chemotherapy or biological therapy within 3 weeks prior to the first dose of study treatment, or radiation or small molecule targeted therapy within 2 weeks prior to the first dose of study treatment.
4. Existing anticancer treatment-related AEs of Grade ≥2 (except for alopecia and Grade 2 sensory 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 CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to the first dose of study drug and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastases, and are taking ≤10mg/day of prednisone or its equivalent. All subjects with carcinomatous meningitis are excluded regardless of clinical stability.
9. Active hepatitis B virus (positive hepatitis B surface antigen) or active hepatitis C virus (measurable viral 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 infection requiring IV systemic therapy.
12. Subjects with active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) and subjects with a history of bowel obstruction.
13. Subjects who have received a live vaccine within 30 days of randomization.
14. Known hypersensitivity or intolerance to either 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. Has Gilbert’s disease. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Progression-free survival (PFS) as determined by a local investigator
review [LIR].
- Objective (overall) response rate (ORR) between treatment arms as determined by blinded independent central review (BICR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout the study |
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E.5.2 | Secondary end point(s) |
- Overall survival (OS) as determined by time from start of study for a subject until their death or lost to follow-up.
- Duration of Overall Response (DOR) as determined by a local investigator review [LIR].
- Clinical benefit rate (CBR) as assessed by overall response of complete response (CR) or response (PR) or durable stable disease (duration more than 6 months) determined by a local investigator review [LIR].
- Quality of life assessed by HRQoL, EORTC, QLQ-C30 and PRO-CTCAE.
- Safety and tolerability as assessed by adverse events, safety laboratories and evaluations, incidence of dose delays and dose reductions, and treatment discontinuations due to adverse events |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Monitored throughout the study |
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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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 62 |
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 |
Hong Kong |
Italy |
Korea, Republic of |
Netherlands |
Spain |
United Kingdom |
United States |
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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
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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. The primary analyses are expected to occur a minimum of 9 months after the last subject is randomized to the study. Survival data may continue to be collected after End of Study. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |