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

Prior treatment

• 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).
• 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.
• Has received prior radiotherapy on the bladder tumor.
• 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).
• 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.
• Has received a partial cystectomy.
• 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.

Other illness

• 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.
• Active allergy requiring systemic treatment (with the exception of histamine H1 receptor blocker treatment) or active infections requiring systemic anti-infectious therapy.
• 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
• 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.

Lab values

• QT interval corrected for heart rate using Fridericia’s formula interval ≥ 470 ms regardless of sex.
• 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.
• 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.

Other

• Pregnant or breastfeeding.
• Primary refusal to undergo RC.

• 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.
• 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)
• 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.