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 cancer
- Conditions
- Muscle invasive bladder cancer set to undergo radical cystectomy who cannot receive or refuse to receive cisplatin-based chemotherapy
- Interventions
- Registration Number
- 2024-513957-55-00
- Lead Sponsor
- CatalYm GmbH
- Brief Summary
To assess the anti-tumor activity of visugromab (CTL-002) 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 in subjects with muscle-invasive bladder cancer (MIBC).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing, recruitment ended
- Sex
- Not specified
- Target Recruitment
- 30
Able to understand the purpose of the study, provide signed and dated informed consent prior to performing any protocol-related procedures (including Screening evaluations), and comply with the study procedures.
If subject has Type II diabetes and receives metformin, metformin has to be replaced with other antidiabetic(s) prior to start of study treatment (at minimum 7 days prior to study baseline GDF-15 measurement) and for the whole study treatment duration.
Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to study 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 subjects, male and female, who are not surgically sterilized or postmenopausal as defined below, and subjects’ partners of childbearing potential must agree to use “highly effective methods of contraception” during the study and for at least 5 months (5 times the predicted halflife of visugromab [CTL-002] in humans) after the last dose of study drug. “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)
Age ≥ 18 years
Histopathologically confirmed urothelial carcinoma. Subjects 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 subjects are excluded): a. Subjects with CTCAE v4 grade ≥ 2 audiometric hearing loss (Galsky Criteria). b. Subjects 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 study 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 study 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.
Pregnant or breastfeeding.
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 subject 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 – subjects with suspected brain metastases at Screening should undergo a CT/MRI of the brain prior to study 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.
Has received prior radiotherapy on the bladder tumor.
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 study.
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 study is prohibited. Administration of inactivated vaccines like inactivated influenza vaccines or RNAvaccines is allowed, including COVID-19
Known active drug or alcohol abuse.
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: Subjects 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. Subjects 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 study 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Combination with Visugromab/Verum Visugromab (CTL-002) visugromab (CTL-002) + Checkpoint Inhibitor nivolumab Combination with Placebo Placebo Placebo + Checkpoint Inhibitor nivolumab Combination with Placebo Nivolumab Placebo + Checkpoint Inhibitor nivolumab Combination with Visugromab/Verum Nivolumab visugromab (CTL-002) + Checkpoint Inhibitor nivolumab
- Primary Outcome Measures
Name Time Method Pathologic complete response (pCR) rate of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone Pathologic complete response (pCR) rate of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone
Radiologic response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone Radiologic response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone
- Secondary Outcome Measures
Name Time Method Evaluation of visugromab-induced anti-drug antibodies (ADA) development. Evaluation of visugromab-induced anti-drug antibodies (ADA) development.
Evaluation of pathologic response of visugromab (CTL-002) in combination with an antiPD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone Evaluation of pathologic response of visugromab (CTL-002) in combination with an antiPD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone
Positron emission tomography (PET)-computed tomography (CT) and/or multiparametric (mp) magnetic resonance imaging (MRI) assessed response of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone Positron emission tomography (PET)-computed tomography (CT) and/or multiparametric (mp) magnetic resonance imaging (MRI) assessed response of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone
Evaluation of the number of subjects with adverse events (AEs) including serious adverse events (SAEs), abnormal clinical laboratory data, and physical findings of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone Evaluation of the number of subjects with adverse events (AEs) including serious adverse events (SAEs), abnormal clinical laboratory data, and physical findings of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone
Evaluation of number of subjects with treatment-related delay of surgery Evaluation of number of subjects with treatment-related delay of surgery
Evaluation of PK parameters of visugromab (CTL-002; e.g., maximum concentration [Cmax], area under the curve [AUC], and half-life [t1/2]) Evaluation of PK parameters of visugromab (CTL-002; e.g., maximum concentration [Cmax], area under the curve [AUC], and half-life [t1/2])
Evaluation of GDF-15 baseline serum levels and their correlation with pharmacodynamics and clinical activity Evaluation of GDF-15 baseline serum levels and their correlation with pharmacodynamics and clinical activity
Evaluation of radiologic response according to RECIST v1.1 of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone Evaluation of radiologic response according to RECIST v1.1 of visugromab (CTL-002) in combination with an anti-PD-1 checkpoint inhibitor or an anti-PD-1 checkpoint inhibitor alone
Evaluation of tumor stage downgrading from baseline assessment to assessment prior to radical cystectomy (RC)/ repeated transurethral resection of the bladder tumor (re-TURBT) Evaluation of tumor stage downgrading from baseline assessment to assessment prior to radical cystectomy (RC)/ repeated transurethral resection of the bladder tumor (re-TURBT)
Evaluation of event-free survival (EFS), time to relapse (TTR), and overall survival (OS) Evaluation of event-free survival (EFS), time to relapse (TTR), and overall survival (OS)
Trial Locations
- Locations (8)
Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino
🇮🇹Turin, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Rome, Italy
Azienda Ospedaliera Ordine Mauriziano Di Torino
🇮🇹Turin, Italy
Fondazione IRCCS Istituto Nazionale Dei Tumori
🇮🇹Milan, Italy
Azienda Sanitaria Locale Di Salerno
🇮🇹Salerno, Italy
Istituto San Raffaele
🇮🇹Milan, Italy
Istituto Oncologico Veneto
🇮🇹Padova, Italy
IRCCS Istituto Nazionale Tumori Fondazione Pascale
🇮🇹Naples, Italy
Azienda Ospedaliera Universitaria Citta Della Salute E Della Scienza Di Torino🇮🇹Turin, ItalyPaolo GonteroSite contact+390116335416paolo.gontero@unito.it