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This is a multi-center, stratified and single-blinded Phase 2 trial of neoadjuvant immunotherapy in combination with the anti-GDF15 antibody visugromab (CTL-002) for the treatment of participants with MIBC set to undergo radical Cystectomy (RC)/Re-TURBT who cannot receive or refuse to receive cisplatin-based chemotherapy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Combination with Placebo | Active Comparator | Placebo + Checkpoint Inhibitor nivolumab |
|
| Combination with Visugromab/Verum | Experimental | visugromab (CTL-002) + Checkpoint Inhibitor nivolumab |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nivolumab | Drug | Biological, monoclonal antibody |
|
| Measure | Description | Time Frame |
|---|---|---|
| Pathological complete response rate | Rate of participants with complete pathological responses after IMP treatment as determined by local pathologist review | min. 4 months |
| Radiological response rate according RECIST | Rate of participants with radiological responses according to RECIST 1.1 prior Radical Cystectomy/Re-TURBT as assessed by the Investigator/Radiologist | min. 4 months |
| Measure | Description | Time Frame |
|---|---|---|
| Adverse Events | Incidence of adverse events (related or unrelated to IMPs) | min. 6 months |
| Treatment related delay of surgery | Treatment related delay of Radical Cystectomy/Re-TURBT > 8 weeks after last dose of IMP |
| Measure | Description | Time Frame |
|---|---|---|
| Tumor biopsy analysis | min. 3 months | |
| Evaluation of selected cytokine and chemokine concentration in peripheral blood | min. 3 months |
Main Inclusion Criteria:
Main Exclusion Criteria:
Pregnant or breastfeeding.
Received prior radiotherapy on the bladder tumor.
Received a partial cystectomy.
Any prior systemic anti-cancer therapy including investigational agents and immunotherapy.
Following cardio-vascular risk factors:
Left ventricular ejection fraction (LVEF) < 50% measured by echocardiogram or MUGA.
QTcF ≥ 470 ms regardless of sex.
Any active autoimmune requiring systemic immunosuppressive treatments.
Any history of non-infectious pneumonitis < 6 months prior to Screening.
Any active inflammatory bowel disease such as Crohn's disease or ulcerative colitis which are generally excluded or active autoimmunthyroiditis present < 6 months prior to Screening.
History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening).
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| Name | Affiliation | Role |
|---|---|---|
| Felix Lichtenegger, MD | CatalYm GmbH | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IRCCS Ospedale San Raffaele Hospital Vita-Salute San Raffaele University | Milan | 20132 | Italy | |||
| Fondazione IRCCS Istituto Nazionale dei Tumori |
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| ID | Term |
|---|---|
| D001749 | Urinary Bladder Neoplasms |
| ID | Term |
|---|---|
| D014571 | Urologic Neoplasms |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000077594 | Nivolumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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Participants will be stratified into four cohorts based on disease stage and PD-L1 expression. Within each cohort, participants are centrally and sequentially assigned to one of two treatment arms in a non-randomized, parallel assignment model.
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| Visugromab (CTL-002) | Drug | Biological, monoclonal antibody |
|
| Placebo | Drug | Placebo (NaCl) for Visugromab (CTL-002) |
|
| min. 6 months |
| Cmax following the first dose of Visugromab (CTL-002) | PK parameter from serum Visugromab (CTL-002) levels | 1 day |
| AUC following the first dose of Visugromab (CTL-002) | PK parameter from serum Visugromab (CTL-002) levels | 28 days |
| Half-life of Visugromab (CTL-002) | PK parameter from serum Visugromab (CTL-002) levels | min. 3 months |
| GDF-15 serum levels | Measurement of concentration in peripheral blood | 1 day |
| Pathological complete response rate | Rate of participants with complete pathological responses after IMP treatment as determined by central independent pathological review | min. 4 months |
| Radiological response rate according RECIST | Rate of participants with radiological responses according to RECIST 1.1 prior Radical Cystectomy/Re-TURBT as assessed by the central independent review | Min. 4 months |
| Major pathological response rate | Rate of participants with major pathological responses after IMP treatment as determined by local pathologist review or central independent pathological review | Min. 4 months |
| Evaluation of EFS (Event-free Survival) | Event-free survival will be defined as the time from first IMP administration to one of the following: Radiographic disease progression precluding a curative intent surgery per RECIST v1.1 prior to RC/Re-TURBT. Initiation of neoadjuvant chemotherapy preceding RC/Re-TURBT as per Investigator decision. Inability to undergo RC/Re-TURBT due to the onset of treatment-related side effects. Inability to complete a curative intent surgery determined by the urologist at the time of RC/Re-TURBT (e.g., unresectable tumor, metastases discovered at RC). Local or distant recurrence assessed by cross-sectional imaging and/or biopsy after RC/Re-TURBT. Death from any cause. In this trial, participant refusal to undergo RC due to the evidence of complete or near-complete clinical response (assessed on cross-sectional imaging as previously described) will not be considered an event. | 12 months after Radical Cystectomy/Re-TURBT |
| OS (Overall Survival) | Overall survival is defined as the time from the first IMP administration to the date of death, regardless of the cause of death. Participants who were alive at the time of the analysis will be censored at the date the participant was last known to be alive. | 15 months |
| Evaluation of TTR (Time to Relapse) | Time to relapse will be measured from the time of RC/Re-TURBT until the day of documented relapse. | 12 months after Radical Cystectomy/Re-TURBT |
| Visugromab-induced anti-drug antibodies (ADA) development. | The number and percentage of participants with any detectable ADA after first IMP administration | min. 5 months |
| Milan |
| 20133 |
| Italy |
| Fondazione Policlinico Universitario Agostino Gemelli IRCCS, UOC Oncologia Medica | Roma | 00168 | Italy |
| A.O.U. Città della Salute e della Scienza di Torino | Torino | 10126 | Italy |
| D052776 |
| Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D001745 | Urinary Bladder Diseases |
| D014570 | Urologic Diseases |
| D052801 | Male Urogenital Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |