This is an open-label, investigator-initiated phase II clinical trial designed to evaluate the efficacy and safety of Sacituzumab Tirumotecan (sac-TMT) monotherapy in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) of salivary gland origin and papillary thyroid carcinoma (PTC). A total of 68 patients will be enrolled over in 18-month period, with 34 patients in Cohort A (ACC) and 34 in Cohort B (PTC). All participants will receive sac-TMT at a dose of 4 mg/kg administered intravenously on Days 1 and 15 of each 28-day cycle. The primary endpoint is the objective response rate (ORR), defined as the proportion of patients achieving a complete or partial response as assessed by the site investigators. Secondary endpoints include progression-free survival, overall survival, disease control rate, safety and tolerability, dose intensity, and relative dose intensity.
\<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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
68
Sacituzumab Tirumotecan 4 mg/kg is administered on Days 1 and 15 of each 28-day (4 week) cycle until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation. The duration of Sacituzumab Tirumotecan infusions should be 90 minutes (±15 minutes) and infusion-related reactions will be monitored. The infusion duration may be adjusted to be longer than 105 minutes at the discretion of the investigator, but the infusion of Sacituzumab Tirumotecan needs to be completed within the timeframe specified in the Pharmacy Manual. After at least 4 administrations and in the absence of either infusion-related reactions or hypersensitivity reactions, the infusion may be shortened at the discretion of the investigator but cannot be shorter than 60 minutes.
National Cancer Center Hospital
Tokyo, Japan
Sarawak General Hospital
Kuching, Sarawak, Malaysia
University of Malaya Medical Center
Kuala Lumpur, Malaysia
National Cancer Centre Singapore
Singapore, Singapore
Tan Tock Seng Hospital
Singapore, Singapore
National Cancer Center Korea
Gyeonggi-do, South Korea
Seoul National University Hospital
Seoul, South Korea
Objective Response Rate (ORR) as assessed by the investigator (site assessment).
The objective response rate is defined as the proportion of patients in the full analysis set whose best overall response is a complete response (CR) or partial response (PR) assessed by the investigator (site assessment).
Time frame: Every 8 weeks until 48 weeks, then every 12 weeks after 49 weeks after the initiation of protocol treatments, until disease progression, initiation of post-study treatment, or study completion, approximately 2.5 years.
Progression-free survival.
The duration from the date of enrollment to the date of the judgement of progression or death from any cause, whichever comes first. The analysis will rely exclusively on these site assessments (no central review).
Time frame: From date of enrollment until disease progression or death, whichever occurs first, through study completion, approximately 2.5 years.
Overall survival.
The duration from the date of enrollment to the date of death from any cause.
Time frame: From date of enrollment until death, through study completion, approximately 2.5 years.
Disease control rate.
Among full analysis set, the proportion of subjects with either CR, PR, SD best overall response assessed by the investigator.
Time frame: From date of enrollment until disease progression, initiation of post-study treatment, or study completion, approximately 2.5 years.
Proportion of patients with adverse events.
Among safety analysis set, the proportion of subjects with each adverse event. For each adverse event, determine the frequency of the worst Grade by CTCAE v5.0.
Time frame: From date of first dose of study drug until 30 days after the last dose of study drug or initiation of post-study treatment, whichever comes first. Assessed up to approximately 2.5 years.
Proportion of patients with adverse drug reactions.
Among safety analysis set, the proportion of subjects who experienced adverse drug reactions that were judged to be related to the study interventions. For each adverse drug reaction, determine the frequency of the worst Grade by CTCAE v5.0.
Time frame: From date of first dose of study drug until 30 days after the last dose of study drug or initiation of post-study treatment, whichever occurs first. Assessed up to approximately 2.5 years.
Proportion of patients with serious adverse events/adverse drug reactions.
Among safety analysis set, the proportion of subjects who experienced serious adverse events will be determined. The proportion of subjects who experienced serious adverse drug reactions, defined as serious adverse events judged to be related to the study intervention, will also be determined. For each serious adverse event or adverse drug reaction, the frequency of the worst Grade will be determined according to CTCAE v5.0.
Time frame: From date of first dose of study drug until study completion, approximately 2.5 years.
Dose Intensity.
Denominator = (date of last course start - date of 1st course start +28 days)/7 \[week\] Numerator = actual dose \[mg\] from the first day of treatment to the last day of treatment/body weight at enrollment \[kg\]
Time frame: From date of first dose until discontinuation of study treatment. Assessed up to approximately 2.5 years.
Relative Dose Intensity.
Denominator = (planned dose in 1st course \[mg\]/body weight at enrollment \[kg\])/planned duration of one course \[week\] Numerator =DI×100
Time frame: From date of first dose until discontinuation of study treatment. Assessed up to approximately 2.5 years.
Darren Wan-Teck Lim, MBBS (S'pore), MRCP (UK), FAMS
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