A Multicenter, Multi-Cohort, Phase II Study of Sacituzumab Tirumotecan With or Without Tislelizumab in Patients With Advanced Thyroid Cancer
Phase: NA
Conditions: Advanced Thyroid Carcinoma, Radioiodine-refractory Differentiated Thyroid Cancer, Poorly Differentiated Thyroid Carcinoma
Sponsor: Zhejiang Provincial People's Hospital

Official Title: 
A Multicenter, Multi-Cohort, Phase II Study of Sacituzumab Tirumotecan with 
or Without Tislelizumab in Patients with Advanced Thyroid Cancer 
NCT Number: 
NCT07068542 
Document Type: 
Study Protocol 
Version Number: 
Version 4.0 
Document Date: 
December 1, 2025 
 
 
 

Background 
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid 
malignancies, characterized by rapid local invasion, early metastasis, and a 
median overall survival of less than one year despite multimodal therapy. Poorly 
differentiated thyroid carcinoma (PDTC) represents an intermediate biological 
entity between differentiated thyroid carcinoma (DTC) and ATC and is 
associated with significantly worse outcomes compared to well-differentiated 
disease. 
Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) 
develops resistance to radioactive iodine (RAI) therapy and carries a markedly 
reduced survival compared with RAI-sensitive DTC. Although multi-target 
tyrosine kinase inhibitors (TKIs) provide modest progression-free survival 
benefit, durable responses remain limited, and treatment resistance frequently 
occurs. 
ATC is characterized by high tumor mutational burden, frequent PD-L1 
expression, and substantial immune cell infiltration, suggesting potential 
sensitivity to immune checkpoint blockade. However, single-agent PD-1/PD-L1 
inhibitors have demonstrated limited efficacy in this setting. 
Sacituzumab tirumotecan is a humanized anti-TROP2 antibody-drug conjugate 
(ADC) linked to a topoisomerase I inhibitor payload. TROP2 is overexpressed 

in multiple epithelial malignancies, including aggressive thyroid cancers. 
Preclinical studies have demonstrated significant antitumor activity of 
sacituzumab tirumotecan in ATC xenograft models. Combination with PD-1 
blockade may further enhance anti-tumor immunity by promoting immunogenic 
cell death and tumor antigen release. 
Given the unmet clinical need and strong biological rationale, this study aims to 
explore the efficacy and safety of sacituzumab tirumotecan with or without 
tislelizumab in patients with advanced thyroid cancer. 
 
Study Objectives 
Primary Objectives 
• 
To evaluate overall survival (OS) in patients with unresectable or 
metastatic ATC treated with sacituzumab tirumotecan in combination 
with tislelizumab. 
• 
To evaluate progression-free survival (PFS) in patients with 
unresectable or metastatic PDTC and RAIR-DTC treated with 
sacituzumab tirumotecan monotherapy. 
Secondary Objectives 

• 
To evaluate PFS in the ATC cohort. 
• 
To evaluate OS in the PDTC and RAIR-DTC cohorts. 
• 
To evaluate objective response rate (ORR), disease control rate (DCR), 
and duration of response (DoR) according to RECIST v1.1. 
• 
To evaluate R0/R1 resection rate in PDTC patients who become 
surgically resectable during treatment. 
• 
To evaluate safety and tolerability according to NCI CTCAE v5.0. 
Exploratory Objectives 
• 
To assess correlations between TROP2 expression and clinical 
outcomes. 
• 
To evaluate tumor genomic and immune profiling, including next-
generation sequencing (NGS), circulating tumor DNA (cfDNA), and 
immune-related biomarkers. 
• 
To evaluate longitudinal changes in tumor microenvironment and 
systemic immune parameters. 
 
Study Design 
This is a multicenter, open-label, multi-cohort, Phase II exploratory study. 
Approximately 94 patients will be enrolled across three parallel cohorts: 

• 
ATC cohort (n=40) 
• 
PDTC cohort (n=30) 
• 
RAIR-DTC cohort (n=24) 
 
Study Population 
Inclusion Criteria 
Participants must meet all of the following criteria: 
1. Age ≥ 18 years at the time of informed consent. 
2. Histologically confirmed unresectable, locally advanced, or metastatic: 
o Anaplastic thyroid carcinoma (ATC), or 
o Poorly differentiated thyroid carcinoma (PDTC), or 
o Radioactive iodine-refractory differentiated thyroid carcinoma 
(RAIR-DTC), including papillary thyroid carcinoma or follicular 
thyroid carcinoma and variants. 
3. For ATC or PDTC: 
o No BRAF V600E mutation, RET fusion, NTRK fusion, or ALK 
fusion; 
o Or harboring such alterations but have failed prior standard first-
line targeted therapy. 

4. For RAIR-DTC: 
Disease must be refractory to radioactive iodine (RAI), defined as at 
least one of the following: 
o No RAI uptake in measurable lesions; 
o Radiographic progression within 12 months after RAI therapy; 
o Cumulative RAI dose >600 mCi (or iodine-equivalent); 
o Fluorodeoxyglucose (FDG)-avid measurable disease; 
o Failure of prior multi-target tyrosine kinase inhibitor (TKI) therapy. 
5. At least one measurable lesion per RECIST version 1.1. 
6. ECOG performance status 0–2. 
7. Life expectancy ≥ 12 weeks. 
8. Adequate hematologic function: 
o Absolute neutrophil count ≥ 1.2 × 10⁹/L 
o Platelet count ≥ 100 × 10⁹/L 
o Hemoglobin ≥ 90 g/L 
9. Adequate hepatic function: 
o AST and ALT ≤ 2.5 × upper limit of normal (ULN) 
o ≤ 5 × ULN if liver metastases present 
o Total bilirubin ≤ 1.5 × ULN 
10. Adequate renal function: 
• 
Creatinine clearance ≥ 60 mL/min (Cockcroft–Gault formula) 

11. No active autoimmune disease requiring systemic therapy. 
12. No concurrent active malignancy requiring treatment. 
13. Willing and able to provide written informed consent. 
Exclusion Criteria 
Participants meeting any of the following criteria will be excluded: 
1. Prior therapy targeting TROP2. 
2. Prior treatment with any topoisomerase I inhibitor antibody-drug 
conjugate. 
3. Prior immune checkpoint agonists (e.g., ICOS, CD40, CD137, GITR, 
OX40) or immune cell therapy. 
4. Another malignancy within 3 years prior to first dose, except adequately 
treated localized cancers (e.g., basal cell carcinoma, squamous cell 
carcinoma of the skin, carcinoma in situ of the cervix). 
5. Uncontrolled or symptomatic central nervous system metastases. 
o Patients with treated and stable CNS disease for ≥4 weeks and 
off corticosteroids for ≥2 weeks may be eligible. 
6. Significant uncontrolled comorbidities including, but not limited to: 
o Uncontrolled hypertension 
o Severe diabetes mellitus 
o Active infection 

7. History of interstitial lung disease (ILD) or non-infectious pneumonitis 
requiring steroids, or current suspected ILD. 
8. Unresolved toxicities from prior anti-cancer therapy greater than Grade 
1 (CTCAE v5.0), except alopecia or other clinically insignificant toxicities. 
9. Active autoimmune disease requiring systemic treatment within the past 
2 years (excluding hormone replacement therapy such as levothyroxine 
or physiologic corticosteroids). 
10. Systemic corticosteroid use >10 mg/day prednisone equivalent within 10 
days prior to first dose (except inhaled, topical, or physiologic 
replacement doses). 
11. Known HIV infection or AIDS. 
Active syphilis infection. 
12. History of allogeneic organ transplantation or hematopoietic stem cell 
transplantation. 
13. Known severe hypersensitivity to study drugs or components. 
14. Chemotherapy, radiotherapy, immunotherapy, biologic therapy, TKI, or 
systemic immune stimulation within protocol-defined washout period 
prior to first dose. 
15. Pregnant or breastfeeding women. 
16. Severe ocular disorders that may interfere with corneal healing (e.g., 
severe dry eye syndrome, severe meibomian gland disease). 
 

Treatment Regimens 
ATC cohort: 
Sacituzumab tirumotecan 5 mg/kg intravenously plus tislelizumab 200 mg 
intravenously on Day 1, Day 15, and Day 29 of each 6-week cycle. 
PDTC and RAIR-DTC cohorts: 
Sacituzumab tirumotecan 5 mg/kg intravenously on Day 1, Day 15, and Day 29 
of each 6-week cycle. 
Treatment will continue until radiographic disease progression, unacceptable 
toxicity, withdrawal of consent, death, or investigator decision. 
 
Tumor Assessments 
Radiographic tumor assessments will be performed: 
• 
Every 6 weeks (±7 days) during the first year 
• 
Every 12 weeks (±7 days) thereafter 
Tumor response will be evaluated by investigators according to RECIST 
version 1.1. 
For patients who achieve resectability (R0 or R1 resection) during treatment: 

• 
Surgery will not be considered a PFS event. 
• 
PFS will be calculated from the date of first dose. 
• 
ORR and DCR will be based on the best preoperative imaging response. 
Patients who discontinue treatment for reasons other than disease progression 
will continue radiographic assessments until documented progression or 
initiation of new anticancer therapy. 
 
Statistical Considerations 
This is an exploratory Phase II study with fixed sample sizes per cohort. 
Time-to-event endpoints (OS and PFS) will be estimated using the Kaplan-
Meier method with corresponding 95% confidence intervals. ORR and DCR will 
be summarized with exact (Clopper–Pearson) confidence intervals. Safety 
analyses will include incidence and severity of adverse events. 
The study is designed to generate preliminary efficacy signals and biomarker 
hypotheses to support future confirmatory trials.