GDFATHER-NEO Trial Design: Neoadjuvant PD-1 Blockade With or Without Visugromab in Muscle-Invasive Bladder Cancer
Researchers are evaluating a neoadjuvant combination of nivolumab and visugromab for patients with muscle-invasive bladder cancer who cannot or choose not to receive cisplatin-based chemotherapy, as detailed in data published by nature.com.
Key Clinical Takeaways:
- The GDFATHER-NEO trial tests nivolumab alongside visugromab in patients with muscle-invasive bladder cancer ineligible for or declining cisplatin.
- Patients were allocated across four strata based on clinical tumor stage and PD-L1 expression scores using a sequential participant-blinded design.
- CatalYm GmbH sponsors the trial, which holds regulatory and ethics approvals under identifiers including NCT06059547.
Trial Design and Patient Allocation in the GDFATHER-NEO Study
The GDFATHER-NEO trial, registered under NCT06059547, is an exploratory, stratified, participant-blinded, parallel-group phase 2a study. It investigates neoadjuvant programmed cell death protein 1 (PD-1) blockade with nivolumab, administered with or without growth differentiation factor-15 (GDF-15) neutralization via visugromab. Eligible participants include adults with newly diagnosed clinical stage cT2–T4a N0 M0 muscle-invasive bladder cancer. These individuals are either ineligible for cisplatin-based chemotherapy under modified Galsky criteria or have declined such treatment, yet remain fit to undergo radical cystectomy following 12 weeks of neoadjuvant therapy.
Before allocation, investigators stratified patients by clinical tumor stage (T2 versus T3–T4a) and by PD-L1 expression on tumor and immune cells. Local pathology determined PD-L1 status using a combined positive score, dividing participants into categories of CPS under 10 versus CPS of 10 or greater. This process established four distinct strata: T2 with CPS under 10, T2 with CPS of 10 or greater, T3–T4a with CPS under 10, and T3–T4a with CPS of 10 or greater. Within each stratum, patients were allocated in a 1:1 ratio to receive nivolumab plus visugromab in group B or nivolumab plus placebo in group A.
Blinded Sequential Allocation Prevents Imbalances Between Treatment Arms
Sequential allocation with participant blinding, rather than standard randomization, was chosen due to the small size of the individual strata. This method prevents imbalances between treatment arms during this initial evaluation of combined GDF-15 and PD-1 blockade in early-stage disease treated with curative intent. While investigators and sponsor staff remained aware of treatment allocations, patients stayed blinded. Local pathologists, along with independent central pathology and imaging reviewers, assessed responses without knowledge of treatment assignments.
CatalYm GmbH, based in Munich, Germany, sponsors the trial. The protocol and its amendments received approval from the competent ethics committee of the coordinating center, Comitato Etico Territoriale Lombardia 1, and the Italian regulatory authority, Agencia Italiana del Farmaco. The trial operates in accordance with the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. A clinical cutoff date of July 15, 2026, governed the analyses, supplemented by central review, bioanalytical, and translational data.
Visugromab and Nivolumab Follow a 19 Week Treatment Phase
Visugromab, designated as CTL-002, is an investigational humanized hinge-stabilized immunoglobulin G4 monoclonal antibody binding GDF-15 with high affinity. It was administered intravenously at 20 milligrams per kilogram every four weeks. Nivolumab, a fully human IgG4 monoclonal antibody targeting PD-1, was administered at 480 milligrams every four weeks. In group B, visugromab preceded nivolumab with a 30-minute observation window. Group A received identical placebo infusion bags prior to nivolumab.
The core treatment phase spans 19 weeks, covering three four-week immunotherapy cycles followed by a four- to eight-week window for surgery. Depending on European Association of Urology guidelines and patient discretion, procedures included radical cystectomy with pelvic lymph node dissection or maximal transurethral resection of the bladder tumor. The trial’s two primary endpoints are the pathological complete response rate determined by blinded local pathologists and the radiographic response rate assessed by investigators according to RECIST version 1.1.
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