Sacituzumab Govitecan and Q901 in Advanced TNBC

Inclusion Criteria:

1. Patients with histologically or cytologically confirmed triple-negative breast cancer (TNBC) who have received at least 2 prior lines of systemic anticancer therapy for recurrent, metastatic, or unresectable disease. TNBC is defined as estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative status.

   ER-negative and PR-negative are defined as nuclear staining in \<1% of cells by immunohistochemistry (IHC).

   HER2-negative is defined by any of the following:
   * IHC 0 or 1+ without in-situ hybridization (ISH) results, or
   * IHC 2+ with negative ISH (single-probe ISH average HER2 gene copy number \<4 signals/cell, or dual-probe ISH HER2/CEP17 ratio \<2.0 with average HER2 gene copy number \<4 signals/cell), or
   * Negative ISH without IHC results.
2. Male or female patients aged ≥19 years.
3. Patients who have received at least 2 prior lines of systemic anticancer therapy for recurrent, metastatic, or unresectable TNBC.

   Prior therapy may include chemotherapy, immunotherapy, or targeted therapy. There is no restriction on the type or sequence of prior therapies (however, prior treatment with a taxane-based regimen is required).

   \*Patients who received adjuvant/neoadjuvant therapy for surgically resectable breast cancer and relapsed within 12 months after completion of the last chemotherapy are considered to have received 1 line of chemotherapy.
4. Patients who have provided written informed consent prior to any study-specific procedures.
5. Patients with at least 1 measurable lesion per RECIST 1.1 on baseline CT.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Patients with adequate organ function as defined below. Transfusion or growth factor support is not permitted within 14 days prior to screening laboratory tests.

   A. Absolute Neutrophil Count (ANC) ≥ 1,500 cells/mm³ B. Platelets ≥ 100,000/mm³ C. Hemoglobin ≥ 9.0 g/dL D. Total bilirubin ≤ 1.5 × ULN E. AST (SGOT) ≤ 2.5 × ULN (≤ 5.0 × ULN if liver metastases are present) F. ALT (SGPT) ≤ 2.5 × ULN (≤ 5.0 × ULN if liver metastases are present) G. Creatinine clearance ≥ 60 mL/min calculated using the Cockcroft-Gault equation, or serum creatinine ≤ 1.5 × ULN
8. 12-lead ECG showing normal findings or non-clinically significant changes not requiring medical intervention.
9. QTc interval ≤ 470 msec and no history of Torsades de pointes.
10. Women of childbearing potential who are not pregnant or breastfeeding must use an effective method of contraception from 2 weeks before the start of study treatment, during treatment, and until 7 months after completion of study treatment.

    Women of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to the first dose of study drug. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test must be performed.

    Women of childbearing potential must agree to use an adequate method of contraception (as described in Section 11.13), be surgically sterile, or abstain from heterosexual intercourse during the study and until 7 months after the last dose of study drug.

    Women considered to be of non-childbearing potential are defined as follows; patients not meeting these criteria are considered to be of childbearing potential:
    * Women who have undergone surgical sterilization (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy)
    * Women aged ≥55 years with no spontaneous menstruation for ≥12 months prior to randomization
    * Women aged \<55 years with no spontaneous menstruation for ≥12 months prior to randomization and a postmenopausal follicle-stimulating hormone (FSH) level \>30 IU/L (or meeting the local laboratory's criteria for postmenopausal status)
11. Subjects infected with human immunodeficiency virus (HIV) must be receiving anti-retroviral therapy (ART) and have well-controlled HIV infection/disease, defined as follows:

    Subjects on ART must have a CD4+ T-cell count \>350 cells/mm³ at screening. Subjects on ART must have achieved and maintained virologic suppression, defined as HIV RNA \<50 copies/mL or below the limit of quantification (below the limit of detection) using a locally available assay, at screening and for at least 12 weeks prior to screening.

    Subjects on ART must have been on a stable regimen without any change in drugs or dose adjustment for at least 4 weeks prior to study enrollment (Day 1).

    Concomitant ART must not include any antiretroviral agents other than abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenofovir.
12. Patients without severe or uncontrolled disease that could interfere with study participation.
13. Adequate washout periods prior to enrollment are as follows:

Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy ≥ 4 weeks (≥ 2 weeks for stereotactic radiotherapy for palliative purposes)

Exclusion Criteria:

1. Prior treatment with a TROP2-targeted antibody-drug conjugate, or a history of receiving a selective CDK7 inhibitor including Q901.
2. Severe cardiac disease (e.g., uncontrolled hypertension, congestive heart failure \[NYHA class ≥2\], ventricular arrhythmia, active ischemic heart disease, or history of myocardial infarction within the past 1 year).
3. Current active hepatic or biliary disease (Gilbert's syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease may be excluded from this criterion at the investigator's discretion).
4. Patients with a clinically significant, uncontrolled medical condition that limits the ability to comply with study procedures, or other medical conditions that place the patient at an unacceptable risk of toxicity.
5. Patients with symptomatic CNS metastases, or CNS metastases requiring local treatment (e.g., radiotherapy or surgery). Patients previously treated for brain metastases must be clinically and radiologically stable (no evidence of disease progression and all neurological symptoms returned to baseline from ≥4 weeks after treatment until study enrollment; no evidence of new or progressive brain metastases) and must not have received steroid therapy exceeding physiological doses (\>10 mg prednisolone/day) for at least 2 weeks prior to administration of the study drug. Regardless of the above conditions, subjects with leptomeningeal carcinomatosis are not permitted.
6. Concomitant use of known strong CYP3A4/5 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, and nelfinavir.
7. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients who have completed curative therapy for HCV are eligible. For patients with evidence of chronic HBV infection, the HBV viral load must be undetectable at the time of enrollment.
8. Patients with significantly impaired mental status, or psychological, familial, sociological, or geographical conditions that impede understanding of the study or potentially interfere with compliance with the study protocol and follow-up schedule.
9. Patients diagnosed with another malignancy within 5 years. Exceptions are non-melanoma skin cancer treated with curative intent, in-situ disease treated with curative intent, thyroid cancer, or cervical intraepithelial carcinoma.
10. Patients who are pregnant or breastfeeding, or who plan to conceive during the scheduled study period from the screening visit until 7 months after the last dose of study drug.
11. Patients who received a live or live-attenuated vaccine within 30 days prior to the scheduled first dose of the study drug.
12. Unresolved active systemic infection.
13. In addition to the above criteria, the investigator may exclude a subject from the study if the subject is judged to have conditions that may compromise subject safety or the scientific validity of the study.