Trilaciclib in Patients Receiving Sacituzumab Govitecan-hziy for Triple Negative Breast Cancer

A Phase 2, Single-Arm, Open-Label Study of Trilaciclib Administered Prior to Sacituzumab Govitecan-hziy in Patients With Unresectable Locally Advanced or Metastatic Triple-Negative Breast Cancer Who Received at Least Two Prior Treatments, at Least One in the Metastatic Setting

This was a Phase 2, multicenter, open-label, single-arm study evaluating the safety and efficacy of trilaciclib administered prior to sacituzumab govitecan-hziy in participants with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC) who received at least 2 prior treatments, at least 1 in the metastatic setting.

The study included 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase began on the day of the first dose of study treatment and was completed at the Safety Follow-up Visit. Trilaciclib and sacituzumab govitecan-hziy were administered intravenously (IV) in 21-day cycles. Study drug administration continued until progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as determined by the Investigator, unacceptable toxicity, withdrawal of consent, Investigator decision, or the end of the study, whichever occurred first. The first Survival Follow-up assessment occurred approximately 3 months after the Safety Follow-Up Visit and continued every 3 months until the end of the study (or death).

Inclusion Criteria:

1. Adult ( ≥18 years of age), female or male participant with measurable (per RECIST v1.1), unresectable locally advanced or metastatic TNBC

2. Documentation of histologically or cytologically confirmed ER-negative, PR-negative, and HER2-negative tumor per the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (ASCO/CAP) criteria.

3. Measurable disease as defined by RECIST v1.1.

4. Considered to be eligible to receive sacituzumab govitecan-hziy treatment, in the Investigator's judgment.

5. Participants must have received 2 or more prior lines of systemic therapy, at least one of them in the metastatic setting.

6. Radiation therapy for metastatic disease is permitted as long as the participant has at least 1 measurable lesion that has not been irradiated. Participants should be sufficiently recovered from the effects of radiation as determined by the Investigator but must have completed radiotherapy at least 2 weeks prior to enrollment.

7. ECOG performance status of 0 or 1.

8. Adequate organ function as demonstrated by the following laboratory values:

   • Hemoglobin ≥9.0 g/dL
   • Absolute neutrophil count (ANC) ≥1.5 × 10^9/L;
   • Platelet count ≥100 × 10^9/L;
   • Estimated glomerular filtration rate ≥30 mL/minute/1.73 m^2;
   • Total bilirubin ≤1.5 × upper limit of normal (ULN);
   • ALT and AST ≤3 × ULN in the absence of liver metastasis or ≤5 × ULN in the presence of liver metastasis.

9. Resolution of nonhematologic toxicities from prior systemic therapy, radiation therapy, or surgical procedures to Common Terminology Criteria for Adverse Events (CTCAE) ≤ Grade 1 (except alopecia or peripheral neuropathy that may be Grade 2 or less).

10. Predicted life expectancy of ≥3 months.

11. Contraceptive use by men or women should be consistent with local guidelines regarding the methods of contraception for those participating in clinical studies.

12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol.

Exclusion Criteria:

1. Prior treatment with trilaciclib, sacituzumab govitecan-hziy, irinotecan, Trop-2 antibody drug conjugate, or any therapy with a topoisomerase-1 payload.

2. Participants with known brain metastasis at enrollment.

3. Participants with known Gilbert's disease or known homozygous for the UGT1A1*28 allele.

4. Participants with bone-only disease.

5. Malignancies other than TNBC within 3 years prior to enrollment. Participants with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death <5% at 5 years as determined by the Investigator) are eligible provided they meet all of the following criteria:

   1. Malignancy treated with expected curative intent (e.g., adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent);
   2. No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers.

6. History of clinically significant gastrointestinal bleeding, intestinal obstruction, or gastrointestinal perforation within 6 months of enrollment.

7. Receipt of any investigational medication within 4 weeks, or at least 5 half-lives, whichever is greater, prior to the first dose of study treatment.

8. Receipt of any cytotoxic chemotherapy within 2 weeks or antibody treatment for cancer within 3 weeks prior to the first dose of study treatment.

9. Receipt of any high dose systemic corticosteroids within 2 weeks prior to the first dose of study treatment.

   1. Low dose corticosteroids (≤20 mg prednisone or equivalent daily) are permitted if the dose is stable for 4 weeks, or if medically indicated as part of their pre-medications for infusions.
   2. Topical steroids and corticosteroid inhalers are allowed.

10. Current use of immunosuppressive medication, except for the following:

    1. Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
    2. Systemic corticosteroids at physiological doses ≤10 mg/day of prednisone or equivalent;
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).

11. Use of oral or IV antibiotics within 2 weeks prior to enrollment.

12. QT corrected interval using Fridericia's formula (QTcF) >480 msec at screening (confirmed on repeat). For participants with ventricular pacemakers, QTcF >500 msec.

13. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure (Class III or IV as defined by the New York Heart Association functional classification system).

14. History of stroke or cerebrovascular accident within 6 months prior to first dose of study treatment.

15. Known serious active infection such as, but not limited to, human immunodeficiency virus (HIV) (e.g., viral load indicative of HIV, HIV 1/2 antibodies), Hepatitis B (e.g., Hepatitis B surface antigen reactive or Hepatitis B DNA detected), Hepatitis C (e.g., Hepatitis C ribonucleic acid [quantitative] is detected) or tuberculosis.

16. Severe infection within 4 weeks prior to enrollment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

17. Other uncontrolled serious chronic disease or psychiatric condition that in the Investigator's opinion could affect participant safety, compliance, or follow-up in the protocol.

18. Known hypersensitivity or allergy to irinotecan, SN-38, trilaciclib, or sacituzumab govitecan-hziy or any excipients of the aforementioned medications

19. Prior hematopoietic stem cell or bone marrow transplantation.

20. Pregnant or lactating women

21. Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.

22. Received a live, attenuated vaccine within 4 weeks prior to the first dose of study treatment or anticipation that such a vaccine will be required during the study treatment period:

    a. Influenza vaccination should be given during influenza season only (approximately October through May in the Northern Hemisphere).

23. Legal incapacity or limited legal capacity.

24. Participants who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or participants who are employees of G1 Therapeutics, Inc. directly involved in the conduct of the study.