Sacituzumab Govitecan and Q901 in Advanced TNBC

Multi-center, Open-label, Single-arm Phase II Clinical Trial of Sacituzumab-Govitecan Plus Q901 in Advanced TNBC

This is a multicenter, open-label, single-arm phase II clinical trial designed to evaluate the efficacy and safety of Sacituzumab govitecan (SG) in combination with Q901 in patients with advanced (metastatic/recurrent/unresectable) triple-negative breast cancer (TNBC) whose disease has progressed following prior therapy, in the third-line treatment setting.

Subjects enrolled in this trial must be patients diagnosed with advanced TNBC who have received at least 2 prior lines of systemic anticancer therapy, which may include chemotherapy, targeted therapy, or immunotherapy. However, for subjects who received adjuvant/neoadjuvant chemotherapy for resectable-stage breast cancer and relapsed within 12 months after completion of the last chemotherapy, the adjuvant/neoadjuvant chemotherapy is counted as one line of therapy. There are no restrictions on the type or sequence of prior therapies, but all subjects must have measurable disease per RECIST 1.1 criteria at the time of enrollment.

Subjects will be assigned to a single treatment arm and will receive the following combination regimen:

Sacituzumab govitecan (SG): 10 mg/kg administered intravenously on Day 1 and Day 8 of each 21-day cycle Q901: 126 mg/m² administered intravenously on Day 1 and Day 8 of each 21-day cycle

Each treatment cycle is defined as 21 days, and study drug administration will continue until disease progression, unacceptable toxicity, discontinuation of treatment at the discretion of the investigator or subject, withdrawal of consent, or death.

Prior to full-scale phase II enrollment, this trial includes a safety run-in phase to evaluate the initial safety and dose appropriateness of the SG plus Q901 combination.

In the safety run-in phase, a small number of subjects will receive the combination regimen to assess the occurrence of dose-limiting toxicities (DLTs); if DLTs are observed, dose de-escalation of Q901 will be considered.

Based on the results of the safety run-in, the final combination dose to be used in the phase II portion will be determined, after which expansion enrollment will proceed.

The target number of subjects to be enrolled in this trial is a maximum of 6-18 in the safety run-in phase and 30 in the phase II portion, for a total maximum enrollment of 48 subjects across the entire trial.

The primary endpoint is objective response rate per RECIST v1.1; secondary endpoints include progression-free survival, overall survival, duration of response, disease control rate, safety, and quality of life.

1. Study design: A multicenter, open-label, single-arm Phase II study conducted at six institutions in Korea.

   This is a multicenter, open-label, single-arm phase II clinical trial designed to evaluate the efficacy and safety of Sacituzumab govitecan (SG) in combination with Q901 in patients with advanced (metastatic/recurrent/unresectable) triple-negative breast cancer (TNBC) whose disease has progressed following prior therapy, in the third-line treatment setting.

   Subjects enrolled in this trial must be patients diagnosed with advanced TNBC who have received at least 2 prior lines of systemic anticancer therapy, which may include chemotherapy, targeted therapy, or immunotherapy. However, for subjects who received adjuvant/neoadjuvant chemotherapy for resectable-stage breast cancer and relapsed within 12 months after completion of the last chemotherapy, the adjuvant/neoadjuvant chemotherapy is counted as one line of therapy. There are no restrictions on the type or sequence of prior therapies, but all subjects must have measurable disease per RECIST 1.1 criteria at the time of enrollment.

2. Study Treatment Arm

   Subjects will be assigned to a single treatment arm and will receive the following combination regimen:

   • Sacituzumab govitecan (SG): 10 mg/kg administered intravenously on Day 1 and Day 8 of each 21-day cycle
   • Q901: 126 mg/m² administered intravenously on Day 1 and Day 8 of each 21-day cycle

   Each treatment cycle is defined as 21 days, and study drug administration will continue until disease progression, unacceptable toxicity, discontinuation of treatment at the discretion of the investigator or subject, withdrawal of consent, or death.

3. Safety Run-in Phase

   Prior to full-scale phase II enrollment, this trial includes a safety run-in phase to evaluate the initial safety and dose appropriateness of the SG plus Q901 combination.

   In the safety run-in phase, a small number of subjects will receive the combination regimen to assess the occurrence of dose-limiting toxicities (DLTs); if DLTs are observed, dose de-escalation of Q901 will be considered.

   Based on the results of the safety run-in, the final combination dose to be used in the phase II portion will be determined, after which expansion enrollment will proceed.

   The key items to be assessed during the safety run-in phase are as follows:

   Occurrence and characteristics of DLTs Frequency and severity of treatment-related adverse events Initial tolerability of the SG plus Q901 combination regimen

4. Principles for Management of Adverse Events

   If adverse events occur during administration of the combination regimen in this trial, Sacituzumab govitecan (SG) will be dose-reduced, delayed, or discontinued in accordance with the prescribing information and standard clinical guidelines, while Q901 will follow the dose modification and reduction principles established in its phase I clinical trial.

   When adverse events occur, independent dose reduction or schedule adjustment for the relevant study drug may be applied based on the assessed relationship (attribution) of the event to each drug.

5. Target Number of Subjects and Primary Endpoint

The target enrollment for this trial is a total of 36-48 subjects (6-18 in safety run-in + 30 in phase II), which has been set taking the dropout rate into consideration.

This trial is designed as a single-arm study, with the Objective Response Rate (ORR) of the combination regimen set as the primary efficacy endpoint.

Tumor response will be assessed according to RECIST version 1.1 criteria, with computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis performed at baseline prior to enrollment and repeated every 8 weeks thereafter until disease progression.

Safety will be assessed continuously throughout the study drug administration period, with a defined safety follow-up period conducted after the last dose of study drug.

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.