A Phase II, Investigator-Initiated Exploratory Study of Sacituzumab Tirumotecan for Previously Treated Unresectable Thymic Carcinomas

Inclusion criteria

• Pathologically diagnosed (histological or cytological examination) as thymic carcinoma originating in the thymus or from a metastatic site Immunohistochemical staining including diagnostic marker testing is recommended. If performed prior to registration, the timing is not restricted. However, if histological examination was conducted at another institution, the pathological diagnosis must generally be obtained by a pathologist at the study site, e.g., by requesting the pathological specimen.)
• Meets any of the following criteria:

• Thymic carcinoma was classified as Stage IV by the Masaoka-Koga staging at initial diagnosis
• Thymic carcinoma was classified as Stage III by the Masaoka-Koga staging at initial diagnosis and was judged to be unresectable with curative resection
• The disease is a postoperative recurrence of thymic carcinoma
• The patients do not have symptomatic brain metastases, carcinomatous meningitis, or spinal metastases requiring radiation therapy or surgical intervention
• The patients do not have pericardial effusion, pleural effusion, or ascites requiring treatment
• Age ≥ 18 years at registration
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
• At least one measurable lesion on contrast-enhanced CT (brain, neck, chest, abdomen, pelvis: slice thickness ≤ 5 mm) performed within 14 days prior to registration (same day of the week 2 weeks prior to registration date is acceptable; same applies below)
• History of combination chemotherapy including platinum agents for unresectable thymic carcinoma (treatment in this study will be second-line or later)
• No administration of anticancer drugs (chemotherapy, molecularly targeted therapy, immunotherapy, etc.) or other investigational drugs within 28 days prior to the registration date (same day of the week 4 weeks prior to registration date is acceptable; same applies below)
• No surgery under general anesthesia within 28 days prior to the registration date
• No radiation therapy (including gamma knife, cyberknife) within 14 days prior to the registration date
• Laboratory tests performed within 14 days prior to the registration date meet the following criteria #1 to #8. However, no administration of granulocyte colony-stimulating factor (G-CSF) or blood transfusion within 14 days prior to the blood draw date

• Neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 10 × 10⁴/mm³
• Hemoglobin ≥ 9.0 g/dL
• AST ≤ 75 U/L (up to 150 U/L allowed if liver metastases are present)
• ALT ≤ 75 U/L (up to 150 U/L allowed if liver metastases are present)
• Total bilirubin ≤ 1.5 mg/dL
• PT-INR ≤ 1.5
• Creatinine ≤ 1.5 mg/dL (If creatinine > 1.5 mg/dL, eligibility is confirmed if creatinine clearance (CrCl)* ≥ 30 mL/min) *CrCl is calculated using the Cockcroft-Gault formula: [[140-age (years)] × weight (kg)] / [72 × serum creatinine (mg/dL) × 0.85 (for females)]. Alternatively, CrCl may be measured from a 24-hour urine collection.
• Percutaneous oxygen saturation (SpO2) ≥ 92% under room air within 14 days prior to registration date
• Patients with adverse events from prior anticancer therapy must have recovered to Grade 1 or below or to baseline values (excluding alopecia and leukoplakia). If endocrine-related adverse events are present, they must be adequately managed with hormone replacement therapy.
• For males: Agree to the following for at least 120 days after the last dose of study drug:

Refrain from sperm donation Use condoms during sexual intercourse with non-study participants of childbearing potential, and have the partner use an additional contraceptive method as described in the Appendix 18.2

• For females: Not pregnant or breastfeeding, and meeting at least one of the following conditions:

• The patients do not fall under the definition of a woman of childbearing potential (POCBP, Appendix 18.2)
• Falls under the definition of a woman of childbearing potential and has agreed to the following:

For at least 210 days from consent to the final study drug administration, use a highly effective (failure rate <1% per year) and low user-dependent contraceptive method as listed in the Appendix 18.2, or have permanently and continuously abstained from penile-vaginal intercourse as a preferred and habitual lifestyle. During this period, the patient agrees not to donate or freeze/store eggs (ova, oocytes) to others. The period required to maintain contraception for the study treatment is from day 0 (final dose) to day 210. The investigator will assess compliance with the contraception requirements (Appendix 18.2) prior to the first study drug dose.

A negative pregnancy test must be confirmed using either a urine hCG pregnancy test within 14 days prior to the date of enrollment Refer to Appendix 18.2 for additional requirements regarding pregnancy testing during and after study treatment.

To reduce the risk of including women with very early, undetected pregnancies, the investigator is responsible for confirming the patient's medical history, menstrual history, and recent sexual activity.

For lactating patients, they must agree not to breastfeed for at least 10 days after the final study drug dose.

• Written informed consent for study participation has been obtained from the patient.
• Patients who have undergone cancer genomic profiling testing and have agreed to provide their C-CAT ID (limited to patients registered within Japan). For patients enrolled in South Korea, genomic profiling results, if available, may be provided for supplementary analyses.

Exclusion criteria

• Patients with thymoma and immune complications associated with thymoma (such as myasthenia gravis, aplastic anemia, hypogammaglobulinemia (Good syndrome), etc.)
• Patients with intestinal paralysis or intestinal obstruction
• Patients with a history of severe dry eye syndrome, severe meibomian gland disease, or severe corneal disease (impeding or delaying corneal healing)
• Uncontrolled major cardiovascular or cerebrovascular disease (NYHA Class III or IV heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, QTcF interval >480 ms, or other major cardiovascular or cerebrovascular disease within 6 months prior to enrollment
• Patients with unresolved stomatitis greater than Grade 1 at the time of registration are excluded. Prophylactic supportive care measures for stomatitis are permitted, provided there are no active stomatitis-related symptoms.
• Previous treatment history with a TROP2-targeted ADC (such as sacituzumab govitecan)
• Previous treatment history with topoisomerase I inhibitors (irinotecan, topotecan) or ADCs containing topoisomerase I inhibitors (e.g., trastuzumab deruxtecan)
• Received a live or live-attenuated vaccine within 30 days prior to the registration date. Inactivated vaccines may be administered.
• Currently receiving a strong CYP3A4 inducer/inhibitor (Appendix 18.4) that cannot be discontinued during the treatment period of the protocol treatment. The required washout period prior to the registration date is 14 days.
• Known malignancy that has progressed or required active treatment within the past 3 years.

Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (except carcinoma in situ of the bladder) who have undergone curative resection are not excluded.

Note: Untreated patients with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤ 6, PSA < 10 ng/mL) who have undergone curative treatment or whose disease is stable under active surveillance are not excluded.

• Active infection requiring systemic therapy.
• Positive for HIV antibody, HBs antigen, or HCV-RNA (HCV-RNA measured only if HCV antibody is positive).
• HBs antigen negative, HBs antibody or HBc antibody positive, and HBV-DNA quantitative positive (not excluded if below detection limit).
• Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual's ability to cooperate with the requirements of the study, or interfere with the individual's participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the investigator or sub-investigator.
• Has a history of severe hypersensitivity (Grade 3 or higher) to the study drug, its excipients, or other biological therapies.
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids, has current pneumonitis/interstitial lung disease, or has suspected ILD or pneumonitis that cannot be ruled out by standard diagnostic assessments at Screening.