Phase II Trial of Trilaciclib, Pembrolizumab, Gemcitabine and Carboplatin in Metastatic Triple-Negative Breast Cancer

The goal of this phase II study is to test the combination of trilaciclib, pembrolizumab, gemcitabine, and carboplatin in locally advanced unresectable or metastatic triple-negative breast cancer.

The main questions it aims to answer are:

* to evaluate the anti-cancer efficacy (assess how well it works)
* to evaluate the safety and tolerability (how well the body can handle the treatment) of this combination of anti-cancer therapy

This is an open label, single-arm, phase II trial designed to evaluate the efficacy of trilaciclib, pembrolizumab, gemcitabine and carboplatin in participants with locally advanced unresectable or metastatic triple-negative breast cancer. Pembrolizumab will be given for a maximum of 2 years. Eligible participants will receive the study treatment until disease progression, unacceptable toxicity, or withdrawal for any reason. A tumor biopsy will be collected from participants in which it can be safely obtained before the first dose of treatment, prior to Cycle 3 Day 1, and at the time of disease progression (optional). Blood specimens for correlative studies will be collected pre-treatment Cycle 1 Day 1, prior to treatment Cycle 2 Day 1, prior to treatment Cycle 3 Day 1, 3 months after the start of study treatment, and 6 months after the start of study treatment.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information signed by the patient
2. Male or female with locally advanced unresectable or metastatic TNBC
3. Age ≥ 18 years at the time of consent
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1 evaluated within 28 days prior to day 1 of study treatment
5. Histological or cytological confirmation of estrogen negative and progesterone negative tumor, defined as \< 10% staining on immunohistochemistry (IHC) and human epidermal growth factor receptor type 2 (HER2)-negative, defined as HER 2 IHC 0 or 1+ or IHC 2+ with no amplification. Patients may be enrolled regardless of their PD-L1 (programmed death ligand-1) status.
6. Measurable disease according to response evaluation criteria in solid tumors
7. Demonstrate adequate organ function
8. Female patients: All females of childbearing potential must have a negative serum β-human chorionic gonadotropin (hCG) test result at Screening and negative serum or urine pregnancy test results within 72 hours prior to day 1 of study treatment.
9. Subject agrees to use contraception
10. As determined by the enrolling physician, the ability of the subject to understand and comply with study procedures for the entire length of the study
11. Tumor tissue: Willing to provide tumor tissue for research purposes
12. Subject has a life expectancy of ≥ 12 weeks

Exclusion Criteria:

1. More than 3 prior lines of chemotherapy for locally advanced unresectable or triple-negative metastatic disease
2. Prior therapy with the concurrent combination of gemcitabine and carboplatin in the metastatic setting
3. Active, symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis or CNS metastases that are progressing on screening magnetic resonance imaging (MRI) brain.
4. Prior systemic anti-cancer therapy within 3 weeks, prior stereotactic radiotherapy within 1 week, and radiation within 2 weeks of day 1 of study treatment. 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 to non-CNS disease.
5. Major surgery, defined by the investigator's discretion, within 3 weeks of day 1 of study treatment
6. Not recovered from all reversible acute toxic effects of prior therapy, including non-hematologic toxicities related to prior systemic therapy to ≤ Grade 1. Participants with less than Grade 2 neuropathy or alopecia of any grade are an exception
7. Active infection requiring systemic therapy
8. Pregnant or breastfeeding
9. Participants previously diagnosed with an additional malignancy must be disease-free for at least five years prior to enrollment. Exceptions include basal cell or squamous cell skin cancer and in situ cervical or bladder cancer.
10. Treatment with any investigational drug within 30 days or at least 5 half-lives, whichever is longer, prior to day 1 of study treatment
11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled symptomatic congestive heart failure (Class III or IV as defined by the New York Heart Association (NYHA) functional classification system), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations/substance abuse that would limit compliance with study requirements as determined by the investigator
12. Known history of stroke or cerebrovascular event within 6 months prior to the day 1 of study treatment
13. Known hypersensitivity to carboplatin or other platinum-containing compounds, gemcitabine, mannitol, or pembrolizumab
14. History of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids or current ILD/ pneumonitis.
15. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) prior to day 1 of study treatment. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
16. Prior hematopoietic stem cell or bone marrow transplant or allogenic tissue/solid organ transplant
17. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
18. Has known active hepatitis B (e.g., hepatitis B surface antigen \[HBsAg\] reactive).
19. Has known active hepatitis C (e.g., hepatitis C virus (HCV) ribonucleic acid (RNA) \[qualitative\] is detected).
20. Receipt of a live, attenuated vaccine within 30 days prior to day 1 of study treatment or anticipation that such a live, attenuated vaccine will be required during the study treatment period. Administration of killed vaccines is allowed. Exception: Monkeypox vaccine may be given if there are at least 3 days between the vaccine and initiation of study treatment.