Small bowel adenocarcinoma is a rare cancer with a poor prognosis. For patients with locally advanced or metastatic disease, the usual first treatment is chemotherapy with platinum-based combinations such as FOLFOX or CapeOX. However, once the cancer grows after this treatment or the side effects become too severe, there is no widely accepted standard second-line therapy, and outcomes are generally poor. New treatment options are therefore urgently needed. In a recent translational research study conducted by Fujii, Shoji, et al., immunohistochemical staining for TROP2 was performed in 51 patients with pathologically diagnosed small bowel adenocarcinoma, and TROP2 positivity was confirmed in 43 cases (84.3%). Furthermore, patient-derived organoids were established using tumor tissues obtained from patients with small bowel adenocarcinoma, and the in vitro efficacy of sacituzumab tirumotecan was evaluated. A concentration-dependent growth-inhibitory effect was observed, with significant sensitivity observed in the nanomolar concentration range. Therefore, treatment with sacituzumab tirumotecan targeting TROP2 is expected to improve the prognosis of patients with small bowel adenocarcinoma. The METROPOLIS trial is a multicenter, single-arm, phase II investigator-initiated trial designed to evaluate the efficacy and safety of sacituzumab tirumotecan in patients with locally advanced or metastatic small bowel adenocarcinoma that has progressed during or after, or is intolerant to, platinum-based combination chemotherapy (FOLFOX or CapeOX). Eligible patients are adults (aged 18 years or older) with histologically or cytologically confirmed small bowel adenocarcinoma, a good performance status, adequate organ function, and at least one measurable lesion on a CT scan. Patients who have genomic alterations that make them candidates for previously approved "tumor-agnostic" targeted drugs (for example, high microsatellite instability or high tumor mutational burden) must already have tried and not benefited from, or not tolerated, those treatments. TROP2 positivity is not required for study participation; however, assessment of TROP2 expression is mandatory for exploratory biomarker analyses. Sacituzumab tirumotecan at 4 mg/kg is administered intravenously on Days 1 and 15 of each 28-day cycle and continued until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria are met. Tumor scans with contrast-enhanced CT will be performed every 8 weeks up to week 24 and every 12 weeks thereafter to monitor the response of the sacituzumab tirumotecan. The primary objective is to determine the proportion of patients achieving a tumor response to sacituzumab tirumotecan, as assessed by independent radiologic review. Key secondary objectives include progression-free survival, overall survival, duration of response, and safety profiling. In addition, this study includes a prespecified translational research program. Tumor samples will be examined for TROP2 using immunohistochemistry, and researchers will investigate the relationship between TROP2 and the effects of sacituzumab tirumotecan. Blood and tissue samples will also be collected before treatment, during treatment, and at the time of cancer progression, when possible, for detailed "multi-omics" analyses. These translational studies aim to elucidate why some patients respond whereas others do not, and to identify biomarkers that could inform future treatment strategies for small bowel adenocarcinoma. The METROPOLIS trial has been approved by the Institutional Review Board of the National Cancer Center, Japan, as well as by the ethics committees at participating sites. This trial is conducted with funding and sacituzumab tirumotecan supplied by MERCK SHARP \& DOHME LLC. Enrollment began in January 2027 and is planned to continue through December 2028, with patients followed for at least 12 months after the last participant is enrolled.
\<Background and Rationale\> Small bowel adenocarcinoma is a rare gastrointestinal malignancy that accounts for fewer than 3% of all gastrointestinal cancers and is associated with poor prognosis. Most patients are diagnosed at an advanced stage because lesions in the distal duodenum, jejunum, and ileum are difficult to detect endoscopically, and symptoms such as anemia, obstruction, or bleeding often appear only after the disease has progressed. For patients with locally advanced or metastatic small bowel adenocarcinoma, fluoropyrimidine plus oxaliplatin regimens such as FOLFOX and CapeOX are widely used as first-line systemic therapy. Prospective studies have reported objective response rates of approximately 40-50% and median overall survival of about 13-20 months with these platinum-based combinations. However, there is no established standard of care beyond first-line treatment, and outcomes after failure of platinum-based chemotherapy are dismal, with small retrospective series suggesting modest activity of regimens such as irinotecan-based chemotherapy or taxanes and very low response rates in routine practice. In the absence of targetable alterations qualifying for tumor-agnostic approved therapies, best supportive care remains the default recommendation for many patients after failure of first-line therapy. Sacituzumab tirumotecan is an antibody-drug conjugate (ADC) consisting of 1) a TROP2-targeting monoclonal antibody (sacituzumab); 2) a cytotoxic payload in the class of topoisomerase 1 inhibitors (tirumotecan); and 3) a novel, irreversible but hydrolyzable linker that joins the monoclonal antibody and the cytotoxic drug payload. Sacituzumab tirumotecan selectively targets TROP2 on the surface of tumor cells. Following the internalization of the complex through the endosomal-lysosomal pathway, the cytotoxic drug payload (tirumotecan) is released inside the tumor cell, leading to cell cycle arrest in the S or G2/M phase and eventually tumor cell apoptosis. In addition, sacituzumab tirumotecan triggers antibody-dependent cell-mediated cytotoxicity and bystander activity to kill tumor cells but shows no complement-dependent cytotoxicity. Normal tissues express relatively low levels of TROP2 compared with some cancers; therefore, sacituzumab tirumotecan may provide a targeted therapy that could possibly improve efficacy and tolerability. Immunohistochemical staining for TROP2 was performed on 51 patients with small bowel adenocarcinoma diagnosed pathologically at the National Cancer Center Hospital, Japan, from July 2010 to July 2023, and TROP2 positivity was confirmed in 43 out of 51 cases (84.3%) . Furthermore, patient-derived organoids were established using tumor tissues obtained from patients with small bowel adenocarcinoma, and the in vitro efficacy of sacituzumab tirumotecan was evaluated. A concentration-dependent growth-inhibitory effect was observed, with significant sensitivity observed in the nanomolar concentration range. Therefore, treatment with sacituzumab tirumotecan targeting TROP2 is expected to improve the prognosis of patients with small bowel adenocarcinoma. \<Study Objectives\> This investigator-initiated phase II clinical trial aims to evaluate the efficacy and safety of sacituzumab tirumotecan monotherapy in patients with locally advanced or metastatic small bowel adenocarcinoma refractory to or intolerant of platinum-based combination therapy (FOLFOX or CapeOX). The primary endpoint of this study is the objective response rate (ORR) as assessed by the independent imaging review committee. Secondary endpoints include objective response rate ORR as assessed by the investigator (site assessment), progression-free survival, overall survival, disease control rate, the incidence of adverse events, adverse reactions, and serious adverse events/adverse reactions, as well as measures of treatment feasibility, including dose intensity and relative dose intensity, and efficacy outcomes such as duration of response and time to response. \<Study Design\> The METROPOLIS trial is a multicenter, single-arm, phase II investigator-initiated trial. \<Study Treatment\> All participants receive sacituzumab tirumotecan 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 7 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 scans with contrast-enhanced CT (brain,neck, chest, abdomen, and pelvis) will be performed every 8 weeks up to week 24 and every 12 weeks thereafter to evaluate the response of the sacituzumab tirumotecan. Tumor response and disease progression are evaluated according to RECIST version 1.1. \<Endpoints\> Primary Endpoint: Objective Response Rate (ORR) as assessed by the Independent Imaging Review Committee. Secondary Endpoints: Objective Response Rate (ORR) as assessed by the investigator (site assessment). 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) Duration of Response(DoR), Time to Response \<Study Oversight and Funding\> National Cancer Center Hospital, Japan, is the coordinating sponsor and is responsible for overall trial coordination, data management, monitoring, and analysis. Merck Sharp \& Dohme LLC provides the investigational product and research funding for the study. \<Prespecified translational research program\> A prespecified translational research program is embedded in the trial. Archival tumor tissue or a pretreatment biopsy is required for enrollment whenever feasible. Tumor TROP2 expression will be evaluated centrally by immunohistochemistry, and exploratory analyses will investigate the association between TROP2 expression levels and clinical outcomes with sacituzumab tirumotecan. Additionally, blood and tissue biospecimens will be collected at baseline, during treatment, and at disease progression, where possible, for multi-omics analyses. These studies aim to elucidate the mechanisms of sensitivity and resistance, identify predictive and prognostic biomarkers, and generate hypotheses for subsequent biomarker-driven trials in small bowel adenocarcinoma.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
27
Sacituzumab tirumotecan at 4 mg/kg is administered intravenously on Days 1 and 15 of each 28-day cycle and continued until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria are met.
Kyushu University Hospital
Fukuoka, Japan
Hiroshima University Hospital
Hiroshima, Japan
Aichi Cancer Center Hospital
Nagoya, Japan
Osaka Medical and Pharmaceutical University Hospital
Takatsuki, Japan
National Cancer Center Hospital
Tokyo, Japan
Objective response rate by central review
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). Best overall response is defined as the best response recorded among CR, PR, stable disease (SD), progressive disease (PD), and not evaluable (NE) using RECIST version 1.1.
Time frame: Baseline up to 3 years. Overall Response is assessed every 8 weeks until 24 weeks after initiation of protocol treatment, and every 12 weeks after 25 weeks and after termination. It continues until PD confirmation or post-study treatment initiation.
Objective response rate by institutional review
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). Best overall response is defined as the best response recorded among CR, PR, stable disease (SD), progressive disease (PD), and not evaluable (NE) using RECIST version 1.1.
Time frame: Baseline up to 3 years. Overall Response is assessed every 8 weeks until 24 weeks after initiation of protocol treatment, and every 12 weeks after 25 weeks and after termination. It continues until PD confirmation or post-study treatment initiation.
Progression-free survival
Progression-free survival for each participant in the full analysis set is defined as the period from the date of enrollment to the date on which PD is confirmed by institutional review or the date of death from any cause, whichever comes first.
Time frame: From baseline up to 3 years
Overall survival
Overall survival for each participant in the full analysis set is defined as the period from the date of enrollment to the date of death from any cause.
Time frame: From baseline up to 3 years
Disease control rate
Disease control rate is defined as the percentage of participants in the full analysis set with the best overall response of CR, PR, and SD. The disease control rate is calculated based on both institutional review and central review.
Time frame: From baseline up to 3 years
Incidence of adverse events
Incidence of adverse events is defined as the percentage of participants in the safety analysis set who experienced each adverse event. In addition, the frequency of the worst grade by CTCAE v5.0-JCOG will be calculated for each adverse event.
Time frame: From baseline up to 3 years
Dose Intensity
Dose Intensity is calculated for each participant as the actual total dose of the study drug administered from the start of treatment to the last dose, normalized by the participant's body weight at enrollment, divided by the treatment duration in weeks.
Time frame: From baseline up to 3 years
Relative dose intensity
Relative dose intensity is calculated for each participant as the actual total dose of the study drug administered from the start of treatment to the last dose, normalized by the participant's body weight at enrollment, divided by the treatment duration in weeks.
Time frame: From baseline up to 3 years
Duration of response
Duration of response for each participant in the full analysis set is defined as the period from the date on which CR or PR is first confirmed to the date on which PD is confirmed by institutional review or the date of death from any cause, whichever comes first.
Time frame: From baseline up to 3 years
Time to response
Time to response for each participant in the full analysis set is defined as the period from the date of enrollment to the date on which CR or PR is first confirmed based on both institutional review and central review.
Time frame: From baseline up to 3 years
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