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

This is a Phase 2 study for nuzefatide pevedotin (BT5528) in adults with a specific type of pancreatic cancer called metastatic pancreatic ductal adenocarcinoma (PDAC) that has spread and worsened after one previous treatment. The drug, nuzefatide pevedotin (nuzefatide), is designed to find a specific protein called EphA2. The main aims of the study are to see how well the drug works against the tumor (efficacy), what side effects it may have (safety), and how the body processes it (pharmacokinetics). All participants in this study will receive nuzefatide, and both they and their doctors will know what is being administered (single-arm, open-label). The trial will take place at several different medical centers.

More details:

This is a Phase 2, open-label, multicenter, single-arm study to evaluate the efficacy, safety, and pharmacokinetics (PK) of nuzefatide in adult participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who have progressed on or after one prior line of systemic therapy. Nuzefatide is a novel Bicycle® drug conjugate (BDC®) that targets EphA2, a protein often found on cancer cells, and delivers a potent anti-cancer agent (MMAE).

Overview

Nuzefatide pevedotin (BT5528) is an investigational, intravenously administered Bicycle drug conjugate being developed for EphA2-expressing solid tumors. It has been evaluated as monotherapy and with nivolumab in a Phase 1/2 trial (NCT04180371); a Phase 2 study in metastatic pancreatic ductal adenocarcinoma is also underway. Clinical evidence remains preliminary and comes from nonrandomized early-phase cohorts. (clinicaltrials.gov)

Mechanism of action

The drug consists of a small, structurally constrained bicyclic peptide that selectively binds EphA2, joined through a cleavable linker to monomethyl auristatin E (MMAE). After tumor targeting and payload release, MMAE disrupts microtubule dynamics, inhibiting cell division and producing tumor-cell and bystander killing. Its small size and rapid renal clearance are intended to improve tumor penetration while limiting prolonged systemic exposure compared with antibody–drug conjugates. (aacrjournals.org)

Efficacy

In 2024 monotherapy data, the objective response rate (ORR; confirmed and unconfirmed responses) was 12% among 113 evaluable patients across tumor types and 34% among 29 patients with urothelial cancer. In urothelial cancer, ORR was 31% with 6.5 mg/m² every two weeks and 27% with 5 mg/m² weekly. Among patients with evaluable EphA2 expression, ORR was 43% in EphA2-positive versus 20% in EphA2-negative urothelial tumors. (bicycletherapeutics.com)

A 2026 conference abstract evaluating 6.5 mg/m² every two weeks plus nivolumab reported confirmed partial responses in 3/10 EphA2-positive metastatic urothelial cancers; two of three EphA2-positive patients without prior MMAE exposure responded. A subsequent sponsor update, using a later February 9, 2026 cutoff, reported a confirmed ORR of 40% (4/10) in EphA2-positive tumors and 100% (3/3) in the small MMAE-naïve subgroup. (aacrjournals.org)

Safety

Among 128 monotherapy recipients, 88% experienced a treatment-related adverse event and 27% had a grade 3 or higher event. Common treatment-related events included nausea (45%), fatigue (34%), diarrhea (27%), vomiting (21%) and anemia (20%). Peripheral neuropathy occurred in 20%, with no grade 3 or higher cases; treatment-related hemorrhage was not reported. (bicycletherapeutics.com)

In the 21-patient nivolumab-combination dataset, common treatment-related events were fatigue (29%), nausea (24%), diarrhea (19%) and vomiting (14%). Grade 3 or higher events included fatigue (10%) and elevated ALT or AST (5% each); skin reactions and peripheral neuropathy were grade 1–2, and no treatment-related hemorrhage occurred. (aacrjournals.org)

Further reading

• First-in-human Phase 1 results — Journal of Clinical Oncology
• 2026 BT5528 plus nivolumab clinical abstract — Cancer Research
• Preclinical mechanism and pharmacology — Molecular Cancer Therapeutics
• 2024 monotherapy clinical poster
• Phase 1/2 trial record — ClinicalTrials.gov

Last updated: Sep 2026

Inclusion Criteria

* At least 18 years of age at the time of signature of the informed consent form

* Measurable disease as defined by RECIST v1.1

* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

* Life expectancy of at least 12 weeks

* Histologically confirmed metastatic pancreatic ductal adenocarcinoma (PDAC)

* Participants must have failed only 1 prior line of therapy with evidence of radiographic progression. Neoadjuvant or adjuvant systemic therapy may count as the first line if the participant progressed less than 6 months from the end of systemic therapy. Prior treatment with KRAS inhibitors is permitted

* Participants must have sufficient tumor tissue (fresh or archived) available for analysis of EphA2 tumor expression and other biomarkers

* Adequate organ function (hematologic, renal, and hepatic)

* Negative pregnancy test for participants of childbearing potential (POCBP)

* Must be willing and able to comply with the protocol and study procedures

Exclusion Criteria

* Chemotherapy or radiotherapy within 14 days prior to the first dose of study treatment

* Experimental treatments within 28 days or 5 half-lives, whichever is longer, of first dose of nuzefatide study treatment

* Prior treatment with taxane therapy (e.g., paclitaxel) for pancreatic cancer or prior treatment with any MMAE-containing agent

* Known microsatellite instability-high (MSI-H) status and are eligible for immune checkpoint inhibitor therapy

* Prior toxicities must have resolved to Grade 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v6.0

* Untreated central nervous system (CNS) metastases

Note: Additional protocol defined Inclusion/Exclusion criteria apply