Study of Sacituzumab Govitecan-hziy and Pembrolizumab Versus Treatment of Physician's Choice and Pembrolizumab in Patients With Previously Untreated, Locally Advanced Inoperable or Metastatic Triple-Negative Breast Cancer

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

13 Sep 2022 → ongoing

Decision date (initial)

2024-11-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-504194-21-00

EudraCT number

2021-005742-14

ClinicalTrials.gov

NCT05382286

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacodynamic, Safety, Efficacy, Therapy

To compare PFS as assessed by BICR between SG and pembrolizumab versus treatment of physician’s choice (TPC) and pembrolizumab

Secondary objectives 7

1. To compare OS between the 2 arms.
2. To compare ORR as assessed by BICR between the 2 arms.
3. To evaluate DOR as assessed by BICR between the 2 arms
4. To evaluate TTR as assessed by BICR between the 2 arms
5. To evaluate safety and tolerability between the 2 arms.
6. To compare time to deterioration (TTD) in physical functioning as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [Version 3.0]) between the 2 arms.
7. To evaluate TTD in role functioning, global health status/quality of life (QOL), pain, and fatigue as measured by the EORTC QLQ-C30 (Version 3.0) between the 2 arms.

Conditions and MedDRA coding

PD-L1 Positive Metastatic Triple-Negative Breast Cancer

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 12

1. Participants must meet all of the following inclusion criteria to be eligible for participation in this study (no waivers for participant eligibility will be offered or permitted): Female or male participants, regardless of race and/or ethnic group, who are 18 years of age or older, able to understand and give written informed consent.
2. Participants with locally advanced inoperable or metastatic TNBC who have not received previous systemic therapy for advanced disease and whose tumors are PD-L1 positive at screening. a) Participants must have completed treatment for Stage I to III breast cancer, if indicated, and ≥ 6 months must have elapsed between completion of treatment with curative intent (eg, date of primary breast cancer surgery or date of last (neo)adjuvant chemotherapy administration [including anti-PD-(L)1 treatment], whichever occurred last) and first documented local or distant disease recurrence. Dates of postoperative radiotherapy are not included in this calculation. Prior use of an anti-PD(L)1 agent in the curative TNBC setting is permitted. i) Participants who received taxane, gemcitabine, or platinum agents in the (neo)adjuvant setting can be treated with same class of chemotherapy (taxane or gemcitabine/carboplatin) if ≥ 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 first documented local or distant disease recurrence. ii) Participants enrolled should have received prior anthracycline in the (neo)adjuvant setting or be considered not eligible for anthracyclines as assessed by the treating physician. b) Participants presenting with de novo metastatic TNBC are eligible for this study. c) TNBC status and tumor PD-L1 CPS will be confirmed centrally on a recent or archival tumor specimen. Participants must have histologically or cytologically documented TNBC, according to current ASCO/CAP criteria, defined as negative for ER, progesterone receptor, and HER2 {Allison 2020, Wolff 2018}. Participants initially diagnosed with hormone receptor-positive or HER2-positive breast cancer must have central confirmation of TNBC in a tumor biopsy obtained from a local recurrence or distant metastasis site prior to study entry. Tumor CPS ≥ 10 using the PD-L1 IHC 22C3 assay will be required for eligibility. d) Participants must have measurable disease by CT or MRI as per RECIST Version 1.1 criteria (Appendix 11.7) as evaluated locally. Tumor lesions situated in a previously irradiated area are considered measurable if unequivocal progression has been documented in such lesions since radiation.
3. Have provided representative formalin-fixed paraffin-embedded (FFPE) tumor specimen in blocks (preferably) or have at least 20 to 25 freshly sectioned unstained slides from fresh biopsy tissue (preferred) or archival tissue block for central testing of ER, progesterone receptor, HER2, PD-L1, Trop-2, and additional biomarker testing. A baseline biopsy is required if archival tissue is not available and this procedure must be performed prior to the first dose of study treatment and after the participant provides written informed consent. Fine needle aspirates and bone biopsies are not suitable samples. Note: Tumor tissue quality must be confirmed by the central laboratory. Submission of another tumor specimen may be required if provided specimen is not adequate for assessment. A discussion with the medical monitor is required if only 15 to 19 unstained slides are available and it is not clinically feasible to obtain a new biopsy.
4. ECOG performance status score of 0 or 1 (Appendix 11.6).
5. Life expectancy ≥ 3 months.
6. Recovered from major surgery for ≥ 2 weeks.
7. Adequate hematologic counts without transfusional or growth factor support within 2 weeks of study treatment initiations (hemoglobin ≥ 9 g/dL, ANC ≥ 1500/mm3, and platelets ≥ 100,000/μL).
8. Adequate hepatic function (bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN if known liver metastases, and serum albumin > 3 g/dL).
9. Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation {Cockcroft 1976}.
10. International normalized ratio (INR)/PT and PTT or aPTT ≤ 1.5 ULN unless participant is currently receiving therapeutic anticoagulant therapy.
11. Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.4.
12. Participants with HIV must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: a) Participants on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening. b) Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (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) Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1). d) The combination ART regimen must not contain any medications that may interfere with SN-38 metabolism

Exclusion criteria 21

1. Participants who meet any of the following exclusion criteria are not eligible to be enrolled in this study (no waivers for participant eligibility will be offered or permitted): Positive serum pregnancy test (Appendix 11.4) or women who are lactating.
2. Known or severe (≥ Grade 3) hypersensitivity or allergy to SG, pembrolizumab, and/or the chemotherapy regimen of choice in the TPC arm (eg, nab-paclitaxel, paclitaxel, gemcitabine, or carboplatin), their metabolites, or formulation excipient.
3. Have received prior therapy with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
4. Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.6.1.
5. Participants may not have received systemic anticancer treatment (with the exception of endocrine therapy) within the previous 6 months or radiation therapy within 2 weeks prior to enrollment. Participants must have recovered from AEs due to a previously administered agent to ≤ Grade 1 or baseline at the time of study entry. Note: participants with ≤ Grade 2 neuropathy or any grade alopecia are an exception to this criterion and will qualify for the study. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible. Note: if participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
6. Participants may not be participating in a study with an investigational agent or investigational device within 4 weeks prior to randomization. Participants participating in observational studies are eligible.
7. Have previously received topoisomerase 1 inhibitors or antibody drug conjugates containing a topoisomerase inhibitor.
8. Have an active second malignancy. Note: participants with a history of malignancy that has been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or participants with surgically cured tumors with low risk of recurrence (eg, nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.
9. Have known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate (with the exception of those treated with chemotherapy) provided they have stable CNS disease (defined as radiographic stability demonstrated with a minimum of 2 post-treatment brain imaging assessments; one performed during screening) 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 have also been clinically stable for at least 2 weeks while taking ≤ 10 mg/day of prednisone or its equivalent. All participants with carcinomatous meningitis are excluded regardless of clinical stability.
10. Have undergone an allogenic tissue or solid organ transplant.
11. Met any of the following criteria for cardiac disease: 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%.
12. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or GI perforation within 6 months of enrollment.
13. Have active serious infection requiring systemic antimicrobial therapy.
14. Participants positive for HIV-1 or 2 with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
15. Have active HBV (defined as having a positive HBsAg test) or HCV. a) For participants with a history of HBV infection, a hepatitis B core antibody test should be conducted at screening. If positive, hepatitis B DNA testing will be performed and if active HBV infection is ruled out, the participant may be eligible. b) Participants who are HCV antibody positive with undetectable HCV viral load may be eligible.
16. Have 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.
17. Has a diagnosis of immunodeficiency or receiving systemic corticosteroid therapy (higher than physiologic doses) ≥ 10 mg of prednisone per day or equivalent] or any other form of immunosuppressive therapy within 14 days prior to randomization.
18. Has received a live or live-attenuated vaccine within 30 days prior to randomization. Administration of killed vaccines are allowed.
19. Has an active autoimmune disease that has required systemic treatment in the past 2 years (eg, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
20. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
21. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (2 weeks of radiotherapy) to non-CNS disease.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS is defined as the time from the date of randomization until the date of objective progressive disease (PD), as assessed by BICR per RECIST Version 1.1, or death (whichever comes first)

Secondary endpoints 7

1. OS is defined as the time from the date of randomization until death due to any cause.
2. ORR is defined as the proportion of participants who achieve CR or PR that is confirmed at least 4 weeks after initial documentation of response as assessed by BICR per RECIST Version 1.1.
3. 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 per RECIST Version 1.1.
4. TTR is defined as the time from the date of randomization until the first documentation of CR or PR as assessed by BICR per RECIST Version 1.1.
5. Incidence of TEAEs and clinical laboratory abnormalities.
6. TTD of physical functioning domain of the EORTC QLQ-C30.
7. TTD of role functioning, global health status/QOL, pain, and fatigue subscale domains of the EORTC QLQ-C30.

Investigational products

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

Test 1

Comparator 5

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 4

Locations

10 EU/EEA countries · 56 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

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

Documents 114 files

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

Application history

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