Trilaciclib, Pembrolizumab, Gemcitabine and Carboplatin for the Treatment of Patients with Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information signed by the patient
• Male or female with locally advanced unresectable or metastatic triple negative breast cancer (TNBC)
• Age ≥ 18 years at the time of consent
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 evaluated within 28 days prior to day 1 of study treatment
• Histological or cytological confirmation of estrogen negative and progesterone negative tumor, defined as < 10% staining on immunohistochemistry (IHC) and HER2-negative, defined as HER2 IHC 0 or 1+ or IHC 2+ with no amplification. Patients may be enrolled regardless of their PD-L1 status
• Measurable disease according to response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening)
• Platelet count ≥ 100 x 10^9/L (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening)
• Hemoglobin (Hgb) ≥ 9.0 g/dL (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening). Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 14 days prior to day 1 of study treatment
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl) ≥ 30 ml/min for subjects with creatinine levels > 1.5 x ULN (CrCl should be calculated per institutional standard); OR glomerular filtration rate (GFR) ≥ 30 mL/minute/1.73 m^2 can be used in place of creatinine for CrCl (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening) * NOTE: Must meet at least one of these parameters
• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN (< 3 ULN if Gilbert’s disease) (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases) (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening)
• International normalized ratio (INR) ≤ 1.5; Patients receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation per investigator discretion (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening)
• Prothrombin time (PT) AND activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN; subjects receiving anticoagulant therapy are eligible if PT or PTT is within the therapeutic range of intended use of anticoagulants per investigator discretion (to be obtained within 28 days prior to day 1 of study treatment. The most recent labs prior to day 1 of study treatment will be used to evaluate for eligibility if labs drawn more than once during screening)
• Female patients: All females of childbearing potential must have a negative serum beta human chorionic gonadotropin (beta-hCG) test result at screening and negative serum or urine pregnancy test results within 72 hours prior to day 1 of study treatment. NOTE: Pregnancy test will be repeated before each cycle and at the end of treatment visit. * Woman of childbearing potential ** A woman is considered fertile following menarche and until becoming postmenopausal unless permanently sterile. If fertility is unclear (e.g., amenorrhea in adolescents or athletes), additional evaluation should be considered * Women in the following categories are not considered woman of childbearing potential: ** Premenopausal female with 1 of the following acceptable surgical sterilization techniques: complete or partial hysterectomy, bilateral tubal ligation, or occlusion with surgery at least 6 months prior to day 1 of study treatment, or bilateral oophorectomy with surgery at least 2 months prior to day 1 of study treatment ** Postmenopausal female: defined as spontaneous amenorrhea for > 12 months prior to screening without alternative cause (e.g., implantable contraceptive, a side effect of medication, etc.) with a serum follicle-stimulating hormone (FSH) within the laboratory’s reference range for postmenopausal females if subject is < 45 years old. In the absence of 12 months of amenorrhea, confirmation with a FSH measurement in the postmenopausal range is required. FSH testing not required for subjects ≥ 45 years old
• Subject agrees to use contraception per guidance below: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. * Male patients: Males must be surgically sterile prior to screening with appropriate documentation (absence of sperm in ejaculate 6 months after the procedure) or have a female partner(s) who is either postmenopausal, surgically sterile, or using a male condom plus one of the forms of contraception for females as defined below. Male patients with female partners of childbearing potential may also be eligible to participate if they agree to be abstinent if this is their usual and preferred lifestyle and agree to remain abstinent. ** In addition, males must also agree to refrain from sperm donation during the study and utilize a barrier method with intercourse during the study and for 6 months following discontinuation of trilaciclib and gemcitabine, and for 4 months after last dose of pembrolizumab. * Females must be either postmenopausal, surgically sterile, or agree to use a highly effective method of contraception consistently and correctly during the study and for 6 months following the last dose of trilaciclib and gemcitabine, and for 4 months after last dose of pembrolizumab. Acceptable forms of contraception include: ** Non-hormonal intrauterine device (IUD) or intrauterine system (IUS) ** Male partner sterilization prior to screening with the appropriate postvasectomy documentation (absence of sperm in the ejaculate 6 months after the procedure). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject. ** True abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * For subjects who are exclusively in same-sex relationships, contraceptive requirements do not apply. If a subject who is in a same-sex relationship at the time of signing the informed consent form (ICF) becomes engaged in a heterosexual relationship, they must agree to use contraception as described previously. If a subject who is abstinent at the time of signing the informed consent form (ICF) becomes sexually active, they must agree to use contraception as described above
• 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
• Tumor tissue: Willing to provide tumor tissue for research purposes Note: Fresh biopsy of the metastatic lesion prior to day 1 of study treatment preferred if feasible. If a fresh biopsy of the metastatic lesion (preferred) is not feasible, a fresh biopsy can be obtained from the primary tumor (i.e., breast), if present. Tumor tissue from bone metastases is not acceptable. If a fresh biopsy is not possible to obtain due to inaccessible tumor, subject safety concern, or bone-only disease, an archived tumor specimen may be submitted if it was collected within 6 months prior to enrollment. For archived tissue, metastatic site is preferred over primary site, if both are available. It is also acceptable to use tissue obtained from a biopsy performed within 6 months prior to enrollment and that the subject has not received any anti-cancer therapy since the time of the biopsy. If tissue is not available for the subject or unable to obtain the tissue within the required timeframe (i.e., either fresh or archival), the subject will still be eligible for the trial
• Subject has a life expectancy of ≥ 12 weeks

Exclusion Criteria

• More than 3 prior lines of chemotherapy for locally advanced unresectable or metastatic triple-negative disease
• Prior therapy with the concurrent combination of gemcitabine and carboplatin in the metastatic setting
• Active, symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis or CNS metastases that are progressing on screening magnetic resonance imaging (MRI) brain. NOTE: A subject with previously treated brain metastasis may be considered if they have completed their CNS-directed treatment for brain metastasis at least 4 weeks prior to day 1 of treatment and have no requirement for steroids. Patients with brain metastases will have a brain MRI performed during the screening phase to confirm the stable disease
• 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
• Major surgery, defined by the investigator’s discretion, within 3 weeks of day 1 of study treatment
• Not recovered from all reversible acute toxic effects of prior therapy, including nonhematologic toxicities related to prior systemic therapy to ≤ grade 1. Subjects with ≤ grade 2 neuropathy or alopecia of any grade are an exception
• Active infection requiring systemic therapy (NOTE: at the discretion of the investigator, subjects receiving treatment for uncomplicated urinary tract infections may be eligible.)
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on the study)
• Subjects 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
• Treatment with any investigational drug within 30 days or at least 5 half-lives, whichever is longer, prior to day 1 of study treatment
• 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
• Known history of stroke or cerebrovascular event within 6 months prior to the day 1 of study treatment
• Known hypersensitivity to carboplatin or other platinum-containing compounds, gemcitabine, mannitol, or pembrolizumab
• History of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids or current ILD/ pneumonitis
• 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
• Prior hematopoietic stem cell or bone marrow transplant or allogenic tissue/solid organ transplant
• Has a known history of human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive). Hepatitis testing is not required but in the event a potential subject has had prior hepatitis testing, the following parameters apply: Subjects who are polymerase chain reaction (PCR) positive will be excluded. Subjects who are HbsAg positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to day 1 of study treatment. Subjects should remain on anti-viral therapy throughout study intervention and follow institutional guidelines for HBV anti-viral therapy post completion of study intervention
• Has known active hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). Subjects with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening, however, must have completed curative anti-viral therapy at least 4 weeks prior to day 1 of study treatment NOTE: Subjects who were treated for HBV or HCV, enrolled in the study, and present with elevated transaminases according to the protocol should be evaluated for viral hepatitis exacerbation/reactivation
• 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. Note: please refer to the protocol for information on COVID-19 vaccines