Sacituzumab Tirumotecan in Recurrent/Metastatic Adenoid Cystic Carcinoma and Papillary Thyroid Carcinoma (STRAP)

<Background and Rationale>

Adenoid cystic carcinoma (ACC) and papillary thyroid carcinoma (PTC) are uncommon malignancies that present distinct clinical challenges in the recurrent or metastatic setting. Although their biological behaviors differ, both diseases share a lack of well-established, effective systemic treatment options once standard therapies have failed.

ACC is a rare epithelial malignancy arising most frequently from the salivary glands. It is characterized by slow initial growth, perineural invasion, and a high propensity for distant metastasis, particularly to the lungs and bones. Despite its relatively indolent nature, ACC is ultimately associated with poor long-term outcomes due to relentless disease progression and resistance to conventional cytotoxic chemotherapy. No systemic therapy has been established as a standard of care for patients with unresectable or metastatic ACC, and treatment decisions are often based on limited evidence derived from small, single-arm studies.

PTC is the most common subtype of thyroid cancer and generally has a favorable prognosis following surgery and radioactive iodine (RAI) therapy. However, a subset of patients develops recurrent or metastatic disease that is refractory to RAI and other standard treatments. In this population, disease control becomes increasingly difficult, and available systemic therapies may offer limited efficacy or be associated with cumulative toxicity. Patients with progressive disease after multiple lines of therapy represent an area of significant unmet medical need.

Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein involved in cell signaling, proliferation, and survival. Overexpression of TROP2 has been reported across a wide range of epithelial malignancies and is associated with tumor aggressiveness and poor clinical outcomes. These biological features make TROP2 an attractive therapeutic target.

Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate composed of a humanized IgG1 monoclonal antibody directed against TROP2, linked via a cleavable linker to a potent topoisomerase I inhibitor payload (KL610023). Upon binding to TROP2-expressing tumor cells, sac-TMT is internalized through the endosomal-lysosomal pathway, releasing the cytotoxic payload intracellularly. This results in DNA damage, cell cycle arrest in the S or G2/M phase, and apoptosis. In addition to direct cytotoxicity, sac-TMT exhibits antibody-dependent cell-mediated cytotoxicity and a bystander effect, potentially extending antitumor activity to neighboring tumor cells with lower or heterogeneous TROP2 expression.

Early-phase clinical studies of sac-TMT have demonstrated antitumor activity and a manageable safety profile in multiple solid tumors. Pharmacokinetic, safety, and efficacy data from dose-escalation and dose-expansion cohorts supported the selection of a 4 mg/kg every-2-week dosing regimen as an appropriate balance between efficacy and tolerability. These data provide the scientific and clinical rationale for evaluating sac-TMT in patients with ACC and PTC.

<Study Objectives>

The primary objective of this study is to evaluate the antitumor activity of sac-TMT monotherapy in patients with unresectable locally advanced or recurrent/metastatic AdCC or PTC.

Secondary objectives include evaluation of progression-free survival, overall survival, disease control rate, safety and tolerability, and treatment feasibility, including dose intensity and relative dose intensity.

Exploratory objectives include the assessment of associations between clinical outcomes and TROP2 expression using archival tumor specimens, where available.

<Study Design>

The STRAP study is an international, multicenter, open-label, investigator-initiated Phase II clinical trial

The study employs a single-arm design with two disease-specific cohorts:

• Cohort A: Patients with adenoid cystic carcinoma (ACC)
• Cohort B: Patients with papillary thyroid carcinoma (PTC)

The study is conducted in multiple Asian countries, including Japan, Singapore, Malaysia, and South Korea, in accordance with the protocol, ICH-GCP, the Declaration of Helsinki, and applicable national regulations.

<Study Treatment>

All participants receive sacituzumab tirumotecan (sac-TMT) at a dose of 4 mg/kg, administered as an intravenous infusion on Day 1 and Day 15 of each 28-day cycle.

Treatment is initiated within 14 days of registration and is continued until one or more of the following occur:

• Radiographic or clinical disease progression
• Unacceptable toxicity
• Withdrawal of consent
• Investigator or Steering Committee decision based on participant safety or protocol-defined criteria

<Efficacy Assessments>

Tumor assessments are performed using contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. Imaging of the head or bones is performed as clinically indicated.

Tumor response and disease progression are evaluated according to RECIST version 1.1. Imaging assessments are scheduled every 8 weeks until Week 48 and every 12 weeks thereafter.

All efficacy assessments are conducted by site investigators. No central imaging review is used for the primary efficacy analysis. Confirmation imaging is required to confirm complete or partial responses.

<Endpoints>

Primary Endpoint

• Objective Response Rate (ORR): Proportion of patients achieving a best overall response of complete response (CR) or partial response (PR), as assessed by the investigator.

Secondary Endpoints

• Progression-free survival (PFS)
• Overall survival (OS)
• Disease control rate (DCR)
• Incidence and severity of adverse events and adverse drug reactions (CTCAE v5.0)
• Dose intensity (DI)
• Relative dose intensity (RDI)

<Study Oversight and Funding>

The trial is conducted as a registration-directed study and overseen by a Steering Committee composed of investigators from participating institutions. National Cancer Center Hospital (NCCH), Japan is the Coordinating Sponsor and responsible for overall trial coordination, data management, monitoring, and analysis.

Merck Sharp & Dohme LLC provides the investigational product and research funding for the study.

Inclusion criteria

Common Eligibility Criteria for Cohorts A and B

• Unresectable locally advanced or recurrent/metastatic adenoid cystic carcinoma or papillary thyroid carcinoma.
• Trophoblast cell-surface antigen 2 (TROP2) expression testing by immunohistochemistry or other methods is not required for enrollment. Provision of archival tumour tissue (where available) will be requested to support retrospective analysis. Waiver for tissue submission may be granted by the Steering Committee on a case-by-case basis if archival tissue is unavailable or insufficient for analysis.
• Age ≥18 years at the time of enrollment (≥21 years in Singapore)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• At least one target lesion *identified on contrast-enhanced CT (head, neck, chest, abdomen, pelvis with ≤5 mm slice thickness) performed within 14 days prior to enrollment (same day of the week within 14 days is acceptable; this applies similarly to other time-based criteria below).

• A non-lymph node lesion with a longest diameter of ≥10 mm or a lymph node lesion with a short axis of ≥15 mm
• No prior treatment with Trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugates or antibody-drug conjugates containing anti-topoisomerase I agents.
• Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or pre-treatment baseline level (except for alopecia and vitiligo). Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible.
• No administration of anticancer therapies (e.g., chemotherapy, targeted therapy, immunotherapy) within 13 days prior to enrollment.
• No major surgery under general anesthesia within 27 days prior to enrollment.
• No radiotherapy (including Gamma Knife or CyberKnife) within 13 days prior to enrollment. Thirteen days or fewer of palliative radiotherapy for non-CNS disease prior to enrollment is permitted. The last radiotherapy treatment must have been performed at least 7 days before enrollment.Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.
• Laboratory values within the following criteria based on testing within 14 days prior to enrollment.

• Neutrophil count≥1,500/mm3
• Platelet count≥10x10^4/mm3
• Hemoglobin≥9.0 g/dL
• AST<100 U/L
• ALT<100 U/L
• Total bilirubin<1.5 mg/dL
• Creatinine<1.5 mg/dL, if >1.5 mg/dL, estimated creatinine clearance ≥30 ml/min. If an estimated value is used, it should be calculated using the Cockcroft-Gault formula.
• Peripheral oxygen saturation (SpO₂) ≥92% on room air within 14 days prior to enrollment.
• For male patients: Must agree to use acceptable contraception (refer to Notes 1,2,3) and refrain from sperm donation for at least 120 days after the last dose of study drug.

For female patients: Must not be pregnant or breastfeeding and must meet one of the following conditions:

• Not of childbearing potential; or
• If of childbearing potential:

• Agrees to use effective contraception (refer to Note 2) from the time of informed consent through at least 210 days after the last dose of study drug. If breastfeeding, agrees to discontinue breastfeeding from the first dose of the study drug through at least 10 days after the last dose.
• Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 19.3.2 of the study protocol during the intervention period and for at least the time needed to eliminate the study intervention after the last dose of study intervention. The participant agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for each study intervention is: sac-TMT: 210 days
• The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.
• Additional requirements for pregnancy testing during and after study intervention are in Appendix 19.3 of the study protocol
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.

Note 1: The patient must not be currently pregnant and, when engaging in penile-vaginal intercourse with a partner who is capable of becoming pregnant, must use a condom (male or female type). In addition, because condoms may break or leak, the partner must also use an additional effective contraceptive method (see Appendix 19.3.3 of the study protocol).

Note 2: The use of contraception must comply with local regulations regarding contraceptive practices for clinical trial participants. If local labeling requirements related to study treatment are more stringent than the above, those local requirements must be followed.

Note 3: If the patient is confirmed to be azoospermic-either due to vasectomy or secondary to a medical condition-based on medical records, physical examination, or medical history as documented by site personnel, additional contraception is not required.

• Written informed consent obtained from the patient.

Cohort A-Specific Eligibility Criteria

• Diagnosis of adenoid cystic carcinoma of salivary gland origin confirmed by histological examination of the primary or metastatic lesion and the diagnosis has been confirmed by central pathology review, based on pathological images of the primary or metastatic lesion (including virtual slides or low- and high-power images of H&E-stained specimens).
• No history of receiving two or more lines of systemic anticancer therapy (excluding adjuvant therapy). Due to no standard care for these patients, patients without prior systemic therapy may also be included.
• Tumor growth has been observed within the past 6 months.

Cohort B-Specific Eligibility Criteria

• Diagnosis of PTC confirmed by histological examination of the primary or metastatic lesion. If this histological diagnosis was performed at the referring institution (i.e., a center not participating in the study), it must be reviewed and verified by a pathologist at the participating study site.
• Patients must have received at least one prior line of standard therapy for recurrent/metastatic disease and no more than two prior lines (RAI therapy is not counted as a prior line).

Exclusion criteria

• Active central nervous system (CNS) metastases - including brain metastases, carcinomatous (leptomeningeal) meningitis, or symptomatic spinal metastases that require radiotherapy or surgical intervention. However, patients with previously treated brain metastases may be enrolled if imaging performed at screening shows radiographic stability for at least 28 days with no evidence of progression, they are clinically stable, and they have not required steroid therapy for at least 14 days before enrollment.
• Clinically significant pericardial effusion, pleural effusion, or ascites requiring treatment.
• Has a current and past history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or severe corneal disease that prevents/delays corneal healing.
• Has uncontrolled, significant cardiovascular disease or cerebrovascular disease, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >480 ms, prior treatment history with cardiotoxic agents and/or other serious cardiovascular and cerebrovascular diseases within 6 months before enrollment.
• Received a live or live-attenuated vaccine within 30 days before enrollment. Administration of inactivated vaccines are allowed.
• Is currently receiving a strong inducer/inhibitor of CYP3A4 that cannot be discontinued for the duration of treatment with study intervention. The required washout period before starting study intervention is 2 weeks.

Note: A list of strong inducers/inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Please note that this list is not exhaustive and that investigators should review the locally-approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor of CYP3A4.

• Is currently participating in another therapeutic clinical trial. Concurrent enrollment on another therapeutic clinical trial or any trial designed to impact the efficacy of anti-cancer therapy is prohibited.
• Has received an investigational agent or has used an investigational device within 28 days before enrollment.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

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

Note: Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.

• Has an active infection requiring systemic therapy except those permitted in the exclusion criteria 15), 16), and 17) (e.g., HIV, HBV, HCV)
• 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 treating investigator.
• Severe hypersensitivity (Grades ≥3) to study intervention, any of their excipients, and/or to another biologic therapy.
• Has had major surgery or significant traumatic injury within 27 days before enrollment. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary.

Note: Participants who underwent major surgery must have adequately recovered from toxicity and/or complications from the surgery before starting study intervention.

• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Participants with HIV infection will be excluded unless all of the following conditions are met:

• Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening
• Having achieved and maintained virologic suppression, defined as confirmed HIV RNA level below 50 or the LLOQ using the locally available assay, at the time of screening and for at least 12 weeks before screening
• Absence of any AIDS-defining opportunistic infections within the past 12 months
• Being on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before registration and agreeing to continue ART throughout the study Note: The ART regimen must not contain any antiretroviral medications that are strong CYP3A4 inducers/inhibitors/substrates. Refer to https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. Please note that this list is not exhaustive and that investigators should review the locally-approved label for all concomitant therapy to ensure it is not a strong inducer/inhibitor/substrate of CYP3A4.
• Positive for HCV RNA, or, if HCV RNA is negative, has not completed curative antiviral therapy at least 28 days prior to enrollment. HCV RNA testing is required only for patients who test positive for HCV antibodies or as mandated by local regulations.
• Positive for HBs antigen, or negative for HBs antigen but positive for either HBs antibody or HBc antibody and positive for HBV DNA quantification. Patients are eligible if HBV DNA is below the lower limit of quantification; however, they will be excluded if they have not received at least 4 weeks of antiviral therapy prior to enrollment.
• Patients with active gastrointestinal ulcers.