Phase 2 Multicenter Study of Neoadjuvant Immunotherapy with Anti-GDF-15 Antibody Visugromab and Nivolumab in Muscle-Invasive Bladder Cancer
- Trial ID
- 2024-513957-55-00
- Protocol
- CTL-002-002
- Sponsor
- CatalYm GmbH
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **anti-tumor activity** of visugromab (CTL-002) when administered in combination with an anti-programmed death receptor-1 (PD-1) checkpoint inhibitor, compared to an anti-PD-1 checkpoint inhibitor alone, in the neoadjuvant setting for subjects with muscle-invasive bladder cancer (MIBC). This is clinically relevant as it aims to determine the potential enhancement of therapeutic efficacy in patients who are unable or unwilling to receive cisplatin-based chemotherapy, potentially offering an alternative treatment strategy.
Secondary objectives include:
- Assessing the safety and tolerability of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor compared to the checkpoint inhibitor alone.
- Exploring the pharmacokinetics and pharmacodynamics of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor.
- Investigating the development of visugromab-induced anti-drug antibodies (ADA).
- Exploring the clinical outcomes of subjects treated with visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor in the neoadjuvant setting.
Participants
The clinical trial involves participants diagnosed with **muscle-invasive bladder cancer** who are scheduled to undergo radical cystectomy and are either unable to receive or have declined cisplatin-based chemotherapy. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histopathologically confirmed diagnosis of urothelial carcinoma, with a dominant transitional cell pattern if mixed histologies are present. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial population was selected based on specific inclusion criteria, including adequate organ function and eligibility for radical cystectomy according to local guidelines. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information on the total number of participants in the study.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **visugromab** (CTL-002) in combination with an anti-programmed death receptor-1 (PD-1) checkpoint inhibitor for the treatment of muscle-invasive bladder cancer. The trial aims to assess the anti-tumor activity of the combination therapy compared to the anti-PD-1 checkpoint inhibitor alone. The study is expected to last approximately four years, with an estimated end date of January 1, 2027.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on specific criteria, such as age, histopathological confirmation of urothelial carcinoma, and adequate organ function. Following the screening, eligible participants will be randomized to receive either the combination therapy or the anti-PD-1 checkpoint inhibitor alone. The treatment period will last up to 12 weeks, during which participants will receive intravenous infusions of the study drugs. Follow-up visits will be conducted to monitor the participants' response to treatment and any adverse events. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be made to evaluate the primary and secondary endpoints, including pathologic complete response rate and radiologic response rate according to RECIST v1.1.
The expected length of participant involvement in the study is approximately 12 weeks of treatment, with additional time for follow-up assessments. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, withdrawal of consent, or failure to comply with study procedures. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their safety and well-being are prioritized throughout the study.
Treatment
The clinical trial involves the administration of **Nivolumab**, marketed as OPDIVO, which is a **concentrate for solution for infusion**. This experimental medication is provided by Bristol-Myers Squibb Pharma EEIG. Nivolumab is an anti-programmed death receptor-1 (PD-1) checkpoint inhibitor, classified under the ATC code L01FF01. The pharmaceutical form is a solution for infusion, and it is administered intravenously. The maximum daily dose is 480 mg, with a total maximum dose of 1440 mg over a treatment period of up to 12 months. The administration schedule and participant compliance are monitored according to the study protocol.
Another experimental treatment in the study is **Visugromab**, also known as CTL-002, provided by Catalym GmbH. Visugromab is an anti-GDF-15 humanized hinge-stabilized IgG4 monoclonal antibody. It is also administered as a solution for infusion intravenously. The dosing regimen for Visugromab is based on body weight, with a maximum daily dose of 20 mg/kg and a total maximum dose of 60 mg/kg over a 12-month period. The administration schedule is designed to ensure optimal therapeutic outcomes and is closely monitored for compliance.
The study also includes the use of **Sodium Chloride** solution, marketed as SODIO CLORURO BAXTER S.P.A. 0.9% Soluzione per infusione, provided by Baxter S.P.A. This non-experimental treatment serves as a standard-of-care therapy and is used as a placebo or comparator treatment. Sodium Chloride is a chemical substance classified under the ATC code B05BB01, which falls under electrolytes. It is administered intravenously as a solution for infusion, with a maximum daily dose of 250 ml and a total maximum dose of 750 ml over the course of 12 months. The administration of Sodium Chloride is conducted in accordance with the study protocol to ensure consistency and reliability of the trial results.
Efficacy
The efficacy of the investigational treatment in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **pathologic complete response (pCR) rate** and the **radiologic response rate** according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. These endpoints will evaluate the anti-tumor activity of **visugromab (CTL-002)** in combination with an anti-PD-1 checkpoint inhibitor compared to an anti-PD-1 checkpoint inhibitor alone in subjects with muscle-invasive bladder cancer (MIBC).
Secondary endpoints will include the evaluation of the number of subjects with adverse events (AEs) and serious adverse events (SAEs), as well as abnormal clinical laboratory data and physical findings. Additional secondary endpoints will assess the pharmacokinetic (PK) parameters of visugromab, such as maximum concentration (Cmax), area under the curve (AUC), and half-life (t1/2). The development of visugromab-induced anti-drug antibodies (ADA) and the correlation of GDF-15 baseline serum levels with pharmacodynamics and clinical activity will also be evaluated. Furthermore, the study will assess the pathologic response, radiologic response according to RECIST v1.1, tumor stage downgrading, event-free survival (EFS), time to relapse (TTR), and overall survival (OS). Imaging assessments using positron emission tomography (PET)-computed tomography (CT) and/or multiparametric (mp) magnetic resonance imaging (MRI) will be conducted to evaluate the response to the treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand the purpose of the trial, provide signed and dated informed consent prior to performing any protocol-related procedures (including Screening evaluations), and comply with the trial procedures.
- Age ≥ 18 years
- Histopathologically confirmed urothelial carcinoma. Participants with mixed histologies are required to have a dominant (i.e., 50% at least) transitional cell pattern.
- Clinical stage T2-T4aN0M0 MIBC, as assessed by CT (mandatory), PET/CT, or mpMRI (both optional).
- Ineligible for cisplatin therapy per modified Galsky criteria (Eastern Cooperative Oncology Group [ECOG] Performance Status 2 participants are excluded): a. Participants with CTCAE v4 grade ≥ 2 audiometric hearing loss (Galsky Criteria). b. Participants with CTCAE v4 grade ≥ 2 peripheral neuropathy (Galsky Criteria). c. Creatinine clearance of < 60 mL/min but ≥ 30 mL/min (measured by the Cockcroft Gault formula or 24-hour urine). d. New York Heart Association (NYHA) Class III heart failureOr, refuses cisplatin-based chemotherapy.
- Eligible for RC by the following: a. Fit and planned for RC according to local guidelines. b. Able to receive a minimum of 12 weeks of neoadjuvant treatment on trial before date of scheduled RC.
- Pretreatment tumor material from TURBT (stored paraffin block) must be available for planned scientific analyses and stem from biopsy/removal of primary tumor within less than 3 months prior to trial treatment initiation and contain at least 20% of tumor cells.
- ECOG performance status score of 0 or 1.
- Adequate organ function: a. Bone marrow function: hemoglobin ≥ 10.0 g/dL (equal to 5.59 mmol/L); platelet count ≥ 100×109 /L; leukocyte count ≥ 2.5×109 /L. b. Hepatic function: AST and ALT ≤ 2×upper limit of normal (ULN); bilirubin ≤ 1.5×ULN (2×ULN in case of Gilbert’s disease). c. Renal function: serum creatinine < 1.5×ULN and/or creatinine clearance ≥ 50 mL/min (Cockcroft-Gault equation). d. Coagulation: no evidence for clinically relevant hypo- or hypercoagulability or presence of thrombosis/thrombotic event as per D-Dimer, antithrombin III(ATIII), prothrombin time /international normalized ratio, activated partial thromboplastin time analysis, and treating physician’s assessment.
- If participant has Type II diabetes and receives metformin, metformin has to be replaced with other antidiabetic(s) prior to start of trial treatment (at minimum 7 days prior to trial baseline GDF-15 measurement) and for the whole trial treatment duration.
- Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to trial treatment. Women of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had any evidence of menses in the past 12 months. However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, or ovarian suppression.
- All participants, male and female, who are not surgically sterilized or postmenopausal as defined below, and participants’ partners of childbearing potential must agree to use “highly effective methods of contraception” during the trial and for at least 5 months (5 times the predicted halflife of visugromab [CTL-002] in humans) after the last dose of IMP. “Highly effective methods of contraception” are combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogenonly hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence. The double-barrier method (synthetic condoms, diaphragm, or cervical cap with spermicidal foam, cream, or gel), periodic abstinence (such as calendar, symptothermal, or postovulation), withdrawal (coitus interruptus), lactational amenorrhea method and spermicide only are NOT acceptable as “highly effective methods of contraception.” Postmenopausal is defined as at least 12 months after last menstrual bleeding without an alternative medical cause (e.g., amenorrhea due to prior chemotherapy, anti-estrogens, or ovarian suppression)
Exclusion Criteria
- Pregnant or breastfeeding.
- Has received prior radiotherapy on the bladder tumor.
- Has received a partial cystectomy.
- Primary refusal to undergo RC.
- Has received any prior systemic anti-cancer therapy including investigational agents and immunotherapy.
- Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer defined as follows are not excluded; Stage T1c or T2a with a Gleason score ≤ 6 and prostatic-specific antigen < 10 ng/mL either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to trial allocation.
- Any acute or chronic major tissue injury that may require maintained GDF-15 function for tissue protection as per Investigator assessment (diagnosed with liver, kidney, myocardial infarction, or other major organ failure, all within < 3 months prior to Screening and with ongoing organ dysfunction as per clinical assessment).
- Has one of the following cardio-vascular risk factors: a. Myocardial infarction in the past 6 months before planned treatment start. b. Uncontrolled heart failure. c. Uncontrolled ventricular arrhythmia. d. A peri/myocarditis in the past 3 months before planned treatment start. Note: Stable atrial fibrillation is permissive with or without anticoagulation if there was no decompensation in the past 3 months before planned treatment start.
- Left ventricular ejection fraction < 50% as measured by an echocardiogram (ECHO) or multigated acquisition scan if ECHO cannot be performed at site for any reason.
- QT interval corrected for heart rate using Fridericia’s formula interval ≥ 470 ms regardless of sex.
- Any active autoimmune disease that requires systemic immunosuppressive treatments, for which (re-)activation may present a medical threat to the participant as per the Investigator’s assessment.
- Any history of non-infectious pneumonitis < 6 months prior to Screening.
- Any active inflammatory bowel disease such as Crohn’s disease or ulcerative colitis or active autoimmune thyroiditis, all present < 6 months prior to Screening.
- History of CNS disease such as stroke, seizure, encephalitis, or multiple sclerosis (< 6 months prior to Screening).
- Active allergy requiring systemic treatment (with the exception of histamine H1 receptor blocker treatment) or active infections requiring systemic anti-infectious therapy.
- History of or clinical evidence of CNS primary tumors or metastases including leptomeningeal metastases, unless they have been previously treated, demonstrated no progression at least for 3 months before Screening, are asymptomatic and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days before Screening – participants with suspected brain metastases at Screening should undergo a CT/MRI of the brain prior to trial entry.
- Systemic steroids at a daily dose of > 10 mg of prednisolone, > 2 mg of dexamethasone or equivalent, except non-systemic (inhaled, topical, nasal), for the last 28 days and ongoing.
- Major surgery within last 2 weeks prior to Screening (TURBT is not considered major surgery).
- Known/expected hypersensitivity against visugromab (CTL-002) and/or anti-PD-1 agents or their ingredients or previously had a severe hypersensitivity (≥ Grade 3) reaction to treatment with monoclonal antibodies (including pembrolizumab, nivolumab etc.) and/or any of their excipients.
- Evidence for active infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, tuberculosis, or severe acute respiratory syndrome coronavirus 2 as per adequate testing performed.
- Dementia or altered mental status that would prohibit informed consent
- Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory abnormality giving reasonable suspicion of a disease or condition that in the opinion of the Investigator would contraindicate the use of an investigational drug or participation in a clinical trial.
- Receipt of any organ transplantation, including hematopoietic cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
- Has a paraneoplastic syndrome (PNS) of autoimmune nature, requiring systemic treatment (systemic steroids or immunosuppressive agents) or has a clinical symptomatology suggesting worsening of PNS.
- Vaccine administration within 4 weeks of investigational drug administration (exception: coronavirus disease 2019 [COVID-19] vaccination). Vaccination with live vaccines while on trial is prohibited. Administration of inactivated vaccines like inactivated influenza vaccines or RNAvaccines is allowed, including COVID-19
- Known active drug or alcohol abuse.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 06 Sept 2023 | 31 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
SODIO CLORURO BAXTER S.P.A. 0,9% Soluzione per infusione | Placebo | SOLUZIONE PER INFUSIONE | INTRAVENOUS | 250 | 12 | PRD4315562 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION. | INTRAVENOUS | 480 | 12 | PRD9332410 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 480 | 12 | PRD2941375 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 480 | 12 | PRD2941372 |
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 480 | 12 | PRD6183485 |
VisugromabCTL-002 | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 20 | 12 | PRD8524649 |