Neoadjuvant Immunotherapy in Combination With the Anti-GDF-15 Antibody Visugromab (CTL-002) for Treatment of Muscle Invasive Bladder Cancer

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, stratified and single-blinded Phase 2 study of neoadjuvant immunotherapy in combination with the antiGDF15 antibody visugromab (CTL-002) for the treatment of subjects with MIBC set to undergo radical Cystectomy (RC) who cannot receive or refuse to receive cisplatin-based chemotherapy.

Official Title
-----------------
A Multi-center Phase 2 Study of Neoadjuvant Immunotherapy in Combination With the Anti-GDF-15 Antibody Visugromab (CTL-002) for the Treatment of Muscle Invasive Bladder

Conditions
-----------------
Bladder Cancer, Adult Solid Tumor

Intervention / Treatment
-----------------
* Drug: Nivolumab
* Drug: Visugromab (CTL-002)
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Signed and dated informed consent, and able to comply with the study procedures and any locally required authorization. Male or female aged ≥ 18 years. Histopathologically confirmed urothelial carcinoma. Clinical Stage T2-T4aN0M0 MIBC. Ineligible for cisplatin therapy per modified Galsky criteria or refuses cisplatin-based chemotherapy. Eligible for radical Cystectomy. Pretreatment tumor material from transurethral resection of the bladder tumor (TURBT) must be available. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Adequate organ function (bone marrow, hepatic, renal function and coagulation). 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 for bladder cancer. Pre-existing arrhythmia, uncontrolled angina pectoris, uncontrolled heart failure (NYHA) Grade IV, any myocardial infarction/coronary event, CNS-ischemic event and any thromboembolic event at any time < 6 months prior to Screening or presence of uncontrolled heart failure NYHA Grade III or higher. Left ventricular ejection fraction (LVEF) < 50% measured by echocardiogram or MUGA. QTcF > 450 ms for men or > 470 ms for women. 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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be assigned to a treatment group based on tumor tissue and tumor size.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination with Placebo<br>Placebo + Checkpoint Inhibitor nivolumab | Drug: Nivolumab<br>* Biological, monoclonal antibody<br>Drug: Placebo<br>* Placebo for Visugromab (CTL-002)<br>|
| Experimental: Combination with Visugromab/Verum<br>visugromab (CTL-002) + Checkpoint Inhibitor nivolumab | Drug: Nivolumab<br>* Biological, monoclonal antibody<br>Drug: Visugromab (CTL-002)<br>* Biological, monoclonal antibody<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response rate | Rate of subjects with no viable tumor cells in Radical Cystectomy Resection | min. 3 months | 
| Radiologic response rate according RECIST | RECIST 1.1 prior Radical Cystectomy | min. 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Incidence of treatment emergent adverse events | min. 4 months | 
| Treatment related delay of surgery | Treatment related delay of Radical Cystectomy > 8 weeks after last dose of study | min. 4 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 | 14 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 | 
| Evaluation of tumor stage downgrading from baseline to Radical Cystectomy |  | min. 3 months | 
| Evaluation of EFS (Event-free Survival) | Event-free survival will be defined as the time from first study drug administration to one of the following: Radiographic disease progression precluding a curative intent surgery per RECIST v1.1 prior to RC Initiation of neoadjuvant chemotherapy preceding RC as per Investigator decision Inability to undergo RC 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 (e.g., unresectable tumor, metastases discovered at RC) Local or distant recurrence assessed by cross-sectional imaging and/or biopsy after RC Death from any cause. In this study, subject 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 | 
| OS (Overall Survival) | Overall survival is defined as the time from the first study drug administration to the date of death, regardless of the cause of death. Subjects who were alive at the time of the analysis will be censored at the date the subject was last known to be alive. | 15 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CTL-002, visugromab, GDF-15