Trial: A Study of Nuzefatide Pevedotin (BT5528…

Trial Details

Sponsor: BicycleTx Limited (industry)

Phase: 2

Start date: March 5, 2026

Planned enrollment: 39

Trial ID: NCT07450859

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: nuzefatide pevedotin (BT5528, Bicycle Toxin Conjugate, CIT3DOS0DW)

Overview

BT5528 (a “Bicycle Toxin Conjugate,” BTC) is a small, chemically synthesized bicyclic peptide that targets the EphA2 receptor and delivers the cytotoxic payload monomethyl auristatin E (MMAE). A first‑in‑human, phase I dose‑escalation study identified a recommended phase II monotherapy dose of 6.5 mg/m² every 2 weeks (Q2W). An updated phase I/II dataset presented in 2024 also explored 5 mg/m² weekly (QW) as a potential RP2D. (ascopubs.org)

Mechanism of action

Target: EphA2, a receptor tyrosine kinase overexpressed in multiple solid tumors and implicated in tumor growth, metastasis, and angiogenesis. (ascopubs.org)
Construct: A high‑affinity EphA2‑binding bicyclic peptide linked to MMAE via a tumor‑microenvironment–cleavable linker; the small (~4.5 kDa) BTC rapidly penetrates tumors and clears quickly from plasma, limiting off‑target exposure. Preclinical work supports a bystander effect from released MMAE and activity proportional to EphA2 expression. (aacrjournals.org)

Efficacy

First‑in‑human (dose escalation, data cutoff August 1, 2022): At the expansion dose of 6.5 mg/m² Q2W, overall response rate (ORR) was 6.7% and disease control rate (DCR) was 20% across heavily pretreated solid tumors. (ascopubs.org)
Updated phase I/II monotherapy (ESMO 2024; as of March 14, 2024): Among 110 efficacy‑evaluable patients, 12 objective responses were observed (8 urothelial, 3 ovarian, 1 head and neck). The highest activity was in urothelial cancer, with ORR 45% in the 6.5 mg/m² Q2W expansion cohort and 27% in the 5 mg/m² QW cohort (confirmed + unconfirmed). Responses were also seen in ovarian cancer and HNSCC. (oncologypro.esmo.org)

Notes: BT5528 is also being evaluated in combination with nivolumab within the same phase I/II study (NCT04180371); publicly available summaries to date emphasize monotherapy results. (clinicaltrials.ucsd.edu)

Safety

Dose‑escalation (JCO 2023): Most common treatment‑related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%); the most frequent grade ≥3 AE was neutropenia/neutrophil count decrease (22.2%). Bleeding events were rare and not attributed to study drug, contrasting with prior EphA2‑targeting ADC experience. (ascopubs.org)
ESMO 2024 update (monotherapy, N=128): Any‑grade treatment‑related AEs in 88%; grade ≥3 in 27%. Gastrointestinal AEs were most common (any grade 64%; grade 3, 5%). Treatment‑related peripheral neuropathy occurred in 19% (6.5 mg/m² Q2W) and 29% (5 mg/m² QW), with no grade ≥3 neuropathy reported. (oncologypro.esmo.org)

Clinical development

Ongoing phase I/II study (BT5528‑100; NCT04180371) is assessing BT5528 as monotherapy and with nivolumab across multiple EphA2‑expressing solid tumors, including urothelial, ovarian, NSCLC, TNBC, HNSCC, and gastric/upper GI cancers. (clinicaltrials.ucsd.edu)

TrialFetch AI Analysis

Goal: This study is evaluating whether nuzefatide pevedotin (BT5528) has clinically meaningful antitumor activity in metastatic pancreatic ductal adenocarcinoma after progression on one prior systemic therapy. It will also characterize safety, tolerability, pharmacokinetics, and treatment effects on disease control and survival outcomes.

Patients: The trial is enrolling adults with histologically confirmed metastatic pancreatic ductal adenocarcinoma, measurable disease by RECIST v1.1, ECOG performance status 0 or 1, life expectancy of at least 12 weeks, and radiographic progression after exactly one prior line of systemic therapy. Prior KRAS inhibitor therapy is allowed. Patients must have adequate organ function and sufficient fresh or archival tumor tissue for EphA2 and biomarker analyses. Key exclusions include prior taxane therapy for pancreatic cancer, prior MMAE-containing therapy, untreated CNS metastases, recent chemotherapy or radiotherapy, unresolved clinically significant toxicities, and known MSI-H disease if eligible for checkpoint inhibitor therapy.

Design: This is an open-label, multicenter, single-arm Phase 2 treatment study. All participants receive nuzefatide pevedotin, with no randomization or comparator arm. Response assessments are investigator-assessed using RECIST v1.1, and patients may be followed for outcomes for up to approximately 3 years.

Treatments: The study treatment is nuzefatide pevedotin (BT5528) monotherapy. Nuzefatide is a Bicycle drug conjugate targeting EphA2, a tumor-associated antigen implicated in oncogenesis, angiogenesis, and metastasis, and is linked to the cytotoxic payload monomethyl auristatin E (MMAE) via a cleavable linker. Its small bicyclic peptide format is substantially smaller than conventional antibody-drug conjugates and may improve tumor penetration. In prior Phase 1/2 testing in advanced solid tumors, the recommended Phase 2 dose was established at 6.5 mg/m2 every 2 weeks, with the strongest activity reported in urothelial cancer; common treatment-related toxicities included gastrointestinal events and peripheral neuropathy, without prominent severe neuropathy or the bleeding and hematologic toxicity signals seen with some earlier EphA2-targeted conjugates.

Outcomes: The primary endpoint is objective response rate, defined as confirmed complete or partial response by RECIST v1.1 as assessed by the investigator. Secondary efficacy endpoints include duration of response, disease control rate, clinical benefit rate, progression-free survival, time to progression, and overall survival. Safety endpoints include treatment-emergent adverse events, serious adverse events, laboratory abnormalities, ECG abnormalities, vital sign abnormalities, and treatment modifications due to adverse events. Pharmacokinetic assessment is also part of the study objectives.

Burden on patient: The expected patient burden is moderate. Participants receive an investigational intravenous anticancer therapy at a study site and will need regular visits for dosing, safety monitoring, laboratory testing, ECGs, vital signs, pharmacokinetic blood sampling, and serial imaging for RECIST assessments. Tumor tissue is required for EphA2 and biomarker analyses, but archived tissue may be sufficient, reducing the need for a mandatory new biopsy in some patients. The burden is higher than standard second-line therapy because of trial-specific pharmacokinetic and biomarker procedures, but lower than many early-phase dose-escalation studies because this is a Phase 2 single-arm study at an established dose.

Last updated: May 2026

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Thomas Jefferson University, Sidney Kimmel Comprensive Cancer Center, Clinical Trials Office

Philadelphia, Pennsylvania, 19107, United States

No email / No phone

Status: Recruiting

A Phase 2 Study of BT5528 in Patients With Metastatic Pancreatic Ductal Adenocarcinoma