ENVELOPE trial (NCCH2412): Enfortumab vedotin in patients with locally advanced or metastatic small bowel adenocarcinoma refractory or intolerant to platinum-based combination therapy—A multicenter, phase II trial (trial in progress).

TPS4269 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy with limited systemic options beyond first-line platinum-based combination therapy (FOLFOX/CapeOX) and no established second-line treatment. We recently reported that Nectin-4 is frequently highly expressed in SBA, providing a biological rationale for enfortumab vedotin, a Nectin-4–directed antibody-drug conjugate (ADC). We designed a multicenter phase II trial to evaluate the antitumor activity and safety of enfortumab vedotin in unresectable locally advanced or metastatic SBA refractory or intolerant to platinum-based combination therapy. To our knowledge, this is the first trial to evaluate the efficacy of ADC in this rare cancer. Methods: Key eligibility criteria include age ≥18 years, histologically/cytologically confirmed SBA, ECOG PS 0–1, prior FOLFOX or CapeOX with progression or intolerance, ≥1 measurable lesion (RECIST v1.1) and adequate organ function. If prior testing has identified alterations qualifying for approved tumor-agnostic therapies, patients must be refractory or intolerant to such therapies. Nectin-4 positivity is not required for enrollment. Exclusion criteria include a history of interstitial lung disease and poorly controlled diabetes. Enfortumab vedotin is administered at 1.25 mg/kg intravenously on days 1, 8, and 15 of each 28-day cycle until progression or unacceptable toxicity. Tumor assessments are performed by enhanced CT every 8 weeks up to week 24 and every 12 weeks thereafter. The primary endpoint is the objective response rate (ORR), as determined by blinded independent central review. Representative secondary endpoints include disease control rate, progression-free survival, overall survival, and safety outcomes, as assessed by the Common Terminology Criteria for Adverse Events v5.0. The null ORR is 5%, and the expected ORR is 25%. An exact binomial design (one-sided α = 0.05; 90% power) requires 25 evaluable patients, with the planned sample size of 27 to account for non-evaluable cases. In a prespecified translational study, tumor Nectin-4 expression will be assessed by immunohistochemistry, and its association with the efficacy of enfortumab vedotin will be explored. Biological specimens will be collected at baseline, during treatment, and at progression for multi-omics analysis to investigate mechanisms of response and resistance. The ENVELOPE trial has been approved by the Institutional Review Board of the National Cancer Center Japan. Enrollment opened on October 2025 and will continue through October 2027; follow-up will extend 12 months after the last patient is enrolled. As of December 31, 2025, 5 patients had been enrolled. Clinical trial information: NCT07347314 /jRCT2031250424.