Enfortumab Vedotin in Patients With Advanced Small Bowel Adenocarcinoma Refractory or Intolerant to Platinum-based Combination Therapy

NCT07347314 | Recruiting Phase 2 DMC

• 1 other identifier: NCCH2412/MK015
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 3

Brief Summary

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. Recent retrospective research from our group has shown that the majority of the small bowel adenocarcinomas strongly express a protein called Nectin-4 on the surface of cancer cells. High Nectin-4 expression was also associated with poorer survival, suggesting that Nectin-4 could be a crucial treatment target in this disease. Enfortumab vedotin is a targeted anticancer drug called an antibody-drug conjugate. It combines an antibody that recognizes Nectin-4 with vedotin, a cytotoxic anticancer agent (payload). After enfortumab vedotin binds to Nectin-4 on the tumor cell surface, it is taken up into the cell and releases the anticancer payload, which damages the cell's internal structure and leads to cell death and apoptosis. Enfortumab vedotin has already shown meaningful antitumor activity and an acceptable safety profile in patients with advanced urothelial carcinoma and is approved over the world. However, its efficacy has never been formally evaluated in patients with small bowel adenocarcinoma. ENVELOPE is a multicenter, single-arm, phase II investigator-initiated trial designed to evaluate the efficacy and safety of enfortumab vedotin 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. Testing positive for Nectin-4 is not required to take part in this study. Participants will receive enfortumab vedotin as an intravenous infusion at a dose of 1.25 mg/kg on days 1, 8, and 15 of each 28-day treatment cycle. Treatment will continue as long as the cancer does not grow and side effects remain manageable. 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 enfortumab vedotin. The primary objective is to determine the proportion of patients achieving a tumor response to enfortumab vedotin, 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 Nectin-4 expression using immunohistochemistry, and researchers will investigate the relationship between Nectin-4 levels and the effects of enfortumab vedotin. 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 ENVELOPE 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. The study is funded by the Japan Agency for Medical Research and Development (AMED), and enfortumab vedotin is supplied by Astellas Pharma. Enrollment began in October 2025 and is planned to continue through October 2027, with patients followed for at least 12 months after the last participant is enrolled.

Conditions

Advanced Small Bowel Adenocarcinoma

Keywords

enfortumab vedotin; small bowel adenocarcinoma; advanced

Outcome Measures

Primary Outcomes (1)

• 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.

  Overall response will be assessed every 8 weeks through 24 weeks, then every 12 weeks thereafter, from baseline up to 3 years or until disease progression or post-study treatment, whichever occurs first.

Secondary Outcomes (9)

• Objective response rate by institutional review

  Overall response will be assessed every 8 weeks through 24 weeks, then every 12 weeks thereafter, from baseline up to 3 years or until disease progression or post-study treatment, whichever occurs first.

• Progression-free survival

  From baseline up to 3 years

• Overall survival

  From baseline up to 3 years

• Disease control rate

  From baseline up to 3 years

• Incidence of adverse events

  From baseline up to 3 years

Other Outcomes (1)

• Objective response rate according to Nectin-4 expression status

  Overall response will be assessed every 8 weeks through 24 weeks, then every 12 weeks thereafter, from baseline up to 3 years or until disease progression or post-study treatment, whichever occurs first.

Study Arms (1)

Enfortumab vedotin

EXPERIMENTAL

Drug: Enfortumab vedotin

Interventions

Enfortumab vedotin DRUG

Enfortumab vedotin 1.25 mg/kg administered intravenously over at least 30 minutes on Days 1, 8, and 15 of each 28-day cycle, continued until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation.

Enfortumab vedotin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed small bowel adenocarcinoma (duodenum excluding the ampulla of Vater, jejunum, or ileum). If pathology was performed at another institution, slides/blocks must be reviewed by a pathologist at the study site before enrollment.
• One of the following:
• unresectable locally advanced small bowel adenocarcinoma in which R0 resection would require combined resection of invaded organs and is judged infeasible
• UICC-TNM stage IV small bowel adenocarcinoma with distant metastasis
• postoperative recurrence of small bowel adenocarcinoma.
• No symptomatic brain metastases, carcinomatous meningitis, or spinal metastases requiring radiation or surgical intervention.
• No clinically significant pericardial effusion, pleural effusion, or ascites requiring treatment.
• Age ≥18 years at registration.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1.
• ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, on contrast-enhanced CT (slice thickness ≤5 mm) obtained within 14 days before registration.
• Prior platinum-based chemotherapy for unresectable locally advanced or metastatic small bowel adenocarcinoma (FOLFOX or CapeOX) with documented progression, recurrence or treatment discontinuation due to toxicity.
• If prior testing (e.g., microsatellite instability, mismatch repair, or comprehensive genomic profiling) has identified alterations that qualify for tumor-agnostic approved therapies, the patient must be refractory, intolerant, or ineligible to such therapies. These tests are not mandatory; lack of testing does not preclude enrollment.
• Archival tumor tissue is available; if unavailable, the patient agrees to a pre-treatment biopsy to obtain tumor tissue.
• No anticancer chemotherapy or radiotherapy within 14 days before registration.
• No surgery under general anesthesia within 28 days before registration.

You may not qualify if:

• Active second primary malignancy.
• Active infection requiring systemic therapy.
• Interstitial lung disease/pneumonitis, diagnosed by imaging or clinical findings, current or prior, irrespective of steroid use.
• Poorly controlled diabetes mellitus: HbA1c ≥8%, or HbA1c 7.0-\<8.0% with otherwise unexplained hyperglycemic symptoms (polyuria and/or polydipsia).
• Known hypersensitivity to enfortumab vedotin, its excipients (e.g., histidine, trehalose dihydrate, polysorbate 20).
• Ongoing grade ≥2 sensory or motor peripheral neuropathy.
• Cerebrovascular event, unstable angina, myocardial infarction, or severe heart failure within 6 months before registration.
• Ongoing grade ≥2 unresolved clinically significant toxicities from prior therapy, excluding alopecia.
• Ongoing grade ≥2 dermatologic disorders regardless of prior-treatment causality.
• Ongoing use of chronic systemic corticosteroids or other immunosuppressants.
• Active keratitis or corneal ulcer.
• Positive for HIV antibodies, HBs antigen, or HCV RNA
• Negative for HBs antigen, positive for HBs or HBc antibodies, and positive HBV DNA quantification (patients are not excluded if HBV DNA is detected but below the limit of quantification).
• Pregnant or possibly pregnant women.
• Psychiatric illness or psychiatric symptoms that interfere with activities of daily living and, in the investigator's judgment, preclude study participation.

Sponsors & Collaborators

• National Cancer Center, Japan: lead
• Astellas Pharma Inc: collaborator

Study Sites (3)

Kyushu University Hospital

Fukuoka, Japan

RECRUITING

Osaka International Cancer Institute

Osaka, Japan

RECRUITING

National Cancer Center Hospital

Tokyo, Japan

RECRUITING

Related Publications (1)

• Fujii H, Shoji H, Hirano H, Hirose T, Okita N, Takashima A, Kato K. Exploring novel therapeutic targets in small bowel adenocarcinoma: insights from claudin 18.2, nectin-4, and HER3 expression analysis. ESMO Open. 2025 Jan;10(1):104098. doi: 10.1016/j.esmoop.2024.104098. Epub 2025 Jan 3.

  PMID: 39754977 RESULT

MeSH Terms

Interventions

enfortumab vedotin

Central Study Contacts

Ken Kato, M.D., Ph.D.

CONTACT

+81.3.3542.2511; kenkato@ncc.go.jp

Hiroyuki Fujii, M.D., Ph.D.

CONTACT

+81.3.3542.2511; hifuj2@ncc.go.jp

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2025
• First Posted: January 16, 2026
• Study Start: November 4, 2025
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2028
• Last Updated: March 11, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

JP (3)