Study of Sacituzumab Govitecan Versus Treatment of Physician’s Choice in Patients With HR+/HER2− Metastatic Breast Cancer Who Have Received Endocrine Therapy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Gilead Sciences Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Sep 2023 → ongoing

Decision date (initial)

2023-08-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Gilead Sciences, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To compare the effect of SG relative to the TPC on PFS

Secondary objectives 1

1. To compare the effect of SG relative to TPC on the following: - OS - ORR - Change from baseline in physical functioning domain and time to definitive deterioration (TTDD TTD) in Global Health Status/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)

Conditions and MedDRA coding

Locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in patients who have received an endocrine-based regimen

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 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.
2. 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.
3. 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.
4. 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
5. Documented PD by computed tomography (CT) or magnetic resonance imaging during or after the most recent therapy per RECIST v1.1 criteria.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Meet the organ function requirements as per study protocol section 4.2
13. 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.
14. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
15. Life expectancy of at least 3 months.
16. Willing and able to comply with the requirements and restrictions in this protocol.
17. Patients must have measurable disease per RECIST v1.1 criteria.

Exclusion criteria 23

1. Progressive disease within 6 months of completing (neo)adjuvant chemotherapy.
2. Previously HER2+ (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO-CAP guidelines).
3. Locally advanced mBC (Stage IIIc) in patients who are candidates for curative intent therapy at the time of study enrollment.
4. 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.
5. 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.)
6. Received any prior treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I.
7. Received any prior treatment with a Trop-2–directed ADC
8. Have a need for ongoing systemic anticancer therapies aside from the study drug.
9. Have a need for ongoing therapy of any prohibited medications.
10. 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.
11. 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.
12. 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
13. 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%.
14. 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
15. Have an active serious bacterial, fungal, or viral infection requiring antibiotics.
16. 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.
17. Patients positive for HIV-1 or -2 with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
18. Criterion removed.
19. 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).
20. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or history of bowel obstruction within 6 months prior to enrollment.
21. Have a positive serum pregnancy test or are breastfeeding for patients who are assigned female at birth.
22. 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.
23. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS is the time from the date of randomization until the date of first objective progressive disease (PD) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), or death from any cause, whichever comes first

Secondary endpoints 9

1. OS is the time from randomization until the date of death from any cause
2. ORR is defined as the percentage of patients who have achieved a complete response (CR) or partial response (PR) that is confirmed at least 4 weeks after initial documentation of response as assessed by BICR per RECIST v1.1
3. Change from baseline in the physical functioning domain at Week 16
4. TTD of Global Health Status/QoL domain of the EORTC QLQ-C30 is defined as the time from date of randomization to the first time a patient experienced change from baseline equal or greater than the pre-specified threshold value for worsening or death
5. PFS is the time from the date of randomization until the date of first objective PD as assessed by the investigator per RECIST v1.1, or death from any cause, whichever comes first
6. ORR is defined as the percentage of patients who have achieved CR or PR that is confirmed at least 4 weeks after initial documentation of response as assessed by the investigator per RECIST v1.1
7. DOR is defined as the time from the first documentation of CR or PR to the earlier of the first documentation of objective PD or death from any cause (whichever comes first) as assessed by BICR and the investigator per RECIST v1.1
8. The incidence of adverse events (AEs) and serious adverse events (SAEs)
9. Percentage of patients who experience clinically significant laboratory and/or vital sign abnormalities

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 5

Auxiliary 10

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Gilead Sciences Inc.

Sponsor organisation

Gilead Sciences Inc.

Address

333 Lakeside Drive

City

Foster City

Postcode

94404-1147

Country

United States

Scientific contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Public contact point

Organisation

Gilead Sciences Inc.

Contact name

EU CT Support

Third parties 11

Locations

11 EU/EEA countries · 81 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 262 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

14 submissions — initial application plus substantial / non-substantial modifications