Evaluation of Cisplatin, Nab-Paclitaxel, and Nivolumab with Radiotherapy Post-Maximal Tumor Resection in Non-Metastatic Muscle-Invasive Bladder Cancer

Trial ID: 2024-518937-26-00
Protocol: CA209-6E8, CNN-BC
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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Diseases & Conditions

Bladder cancer

Objectives

The primary objective of this study is to evaluate the **efficacy** of a combination treatment regimen consisting of cisplatin, nab-paclitaxel, and nivolumab, administered with concomitant radiotherapy, in enhancing disease-free survival in patients with non-metastatic muscle-invasive bladder cancer. This objective is clinically significant as it aims to improve patient outcomes by potentially extending the period during which patients remain free from disease recurrence following maximal tumor resection.

Secondary objectives include: - Investigating the rate of patients requiring salvage surgery after trimodal therapy. - Assessing the response rate of the bladder tumor. - Evaluating the incidence of locoregional progression. - Determining the time without evidence of disease. - Measuring the time without evidence of metastatic disease. - Analyzing the survival of patients treated with the trimodal therapy. - Evaluating the safety of the combination of cisplatin, nivolumab, and nab-paclitaxel with radiotherapy in bladder cancer patients. - Assessing the quality of life in patients receiving trimodal therapy for bladder cancer.

Participants

The clinical trial involves participants diagnosed with **non-metastatic muscle invasive bladder cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologic diagnosis of predominantly urothelial carcinoma of the bladder, with specific staging criteria of T2-T3 N0M0 according to the AJCC TNM Staging System, 8th edition. The trial does not include a vulnerable population. Participants must demonstrate adequate bone marrow, liver, and renal function, and have a life expectancy greater than six months. The selection criteria emphasize the ability to tolerate systemic chemosensitizer combined with pelvic IMRT, as determined by both a radiation oncologist and a medical oncologist. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of a combination therapy involving **nivolumab**, **cisplatin**, and **paclitaxel albumin-bound** with concomitant radiotherapy in patients with non-metastatic muscle invasive bladder cancer. This is a randomized, double-blind, controlled trial with an estimated duration from September 2021 to November 2026. The trial aims to improve disease-free survival following maximal tumor resection. Participants will be randomly assigned to receive the investigational treatment or a control, with neither the participants nor the investigators aware of the group assignments, ensuring a double-blind methodology.

The trial will include several study visits, beginning with a screening visit to assess eligibility based on specific inclusion criteria, such as age, performance status, and adequate organ function. Following successful screening, participants will undergo baseline assessments before starting the treatment regimen. The treatment phase will involve regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will include clinical evaluations, laboratory tests, and imaging studies as necessary. The end-of-study visit will occur after the completion of the treatment period or upon early termination, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last up to 12 months, with the possibility of early termination if significant adverse events occur, if the participant withdraws consent, or if the investigator deems it in the participant's best interest. The primary endpoint is the one-year disease-free survival rate, defined as survival without recurrence in pelvic nodes or bladder, or the appearance of distant metastasis. Secondary endpoints include the rate of salvage cystectomy, locoregional complete response, and safety of the treatment combination. The trial will also assess quality of life throughout the study duration.

Treatment

The clinical trial involves the administration of **Nivolumab**, a monoclonal antibody classified under antineoplastic agents. It is provided as a **solution for infusion** and is administered **intravenously**. The maximum daily dose is 480 mg, with a total dose not exceeding 480 mg over a treatment period of up to 12 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

**Cisplatin** is another experimental medication used in this trial. It is categorized as a platinum compound within the group of other antineoplastic agents. Cisplatin is also provided as a **solution for infusion** and administered **intravenously**. The dosing is calculated based on body surface area, with a maximum daily dose of 20 mg/m² and a total dose of 20 mg/m² over a treatment period of up to 5 days. Compliance with the dosing schedule is closely monitored throughout the trial.

The trial also includes **Paclitaxel Albumin-Bound**, which is classified under antineoplastics, specifically taxanes derived from alkaloids and other natural products. This medication is provided as a **powder for suspension for solution** and is administered **intravenously**. The dosing is based on body surface area, with a maximum daily dose of 60 mg/m² and a total dose of 60 mg/m² over a treatment period of up to 5 days. Participant adherence to the dosing schedule is monitored to ensure compliance.

In addition to the experimental medications, the study protocol includes the use of standard-of-care therapy, which may involve radiotherapy as part of the treatment regimen. The combination of these treatments aims to improve disease-free survival in patients with non-metastatic muscle invasive bladder cancer. The trial design ensures that all treatments are administered according to the specified dosing schedules, with rigorous monitoring of participant compliance to maintain the integrity of the study outcomes.

Efficacy

The efficacy of the clinical trial investigating the combination of **Nivolumab**, Cisplatin, and Paclitaxel Albumin-Bound with radiotherapy in non-metastatic muscle invasive bladder cancer will be assessed through several parameters. The primary endpoint is the one-year disease-free survival rate, defined as the rate of survival free of recurrence in pelvic nodes or bladder, excluding the cis, or the appearance of distant metastasis. Data will be censored at the first sign of disease, second primary tumor, or death.

Secondary endpoints include the rate of patients requiring salvage cystectomy, the rate of locoregional complete response, the rate of locoregional disease-free survival, median disease-free survival, and median metastasis-free survival. Additionally, the safety of the combination therapy and the quality of life of participants will be evaluated. These parameters will be measured and collected at specified intervals throughout the trial, with data analysis conducted to determine the efficacy of the treatment regimen.

Inclusion and Exclusion Criteria

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Inclusion Criteria

18 years old or older
Histologic diagnosis of predominantly urothelial carcinoma of the bladder. Focal differentiation allowed other than small cell histology
Stage T2-T3 N0M0 (AJCC TNM Staging System 8th ed. 2017) based on trans-urethral resection of bladder tumor (TURBT), CT or MRI imaging, +/- bimanual examination under anaesthesia (EUA)
FDG-PET within 6 weeks from the start of treatments, showing no evidence of lymph nodes or metastatic disease
Attempt of complete TURBT within 56 days (8 weeks) prior to the start of chemoradiation. If TURBT was performed > 8 weeks ago but a recent cystoscopy shows no residual disease, then a repeat TURBT is not necessary
Life expectancy greater than 6 months
ECOG performance status of 1 or better
Another primary cancer is allowed only if treated with curative intent at least 3 years prior to enrolment without evidence of recurrence or if the untreated cancer is clinical indolent (e.g., lower risk prostate cancer)
Patients must be considered able to tolerate systemic chemosensitizer combined with pelvic IMRT by the joint agreement of the participating radiation oncologist and medical oncologist.
Able and willing to give written informed consent
For women of childbearing potential (WOCBP), study participants must use a contraceptive method that is highly effective (with a failure rate of < 1% per year) for at least 5 months after the last dose of study intervention. Men receiving any study drurg and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 6 months after the last dose of chemotherapy with cisplatin or nab-paclitaxel. The investigator or a designated associate is requested to advise the subject how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care. Acceptable methods are oral contraceptives, hormonal implants, hormonal patches, IDU, Diaphragm with spermicides, cervical cape with spermicide, and condom with spermicide
Adequate bone-marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting to study treatment: a) Total bilirubin ≤1∙5 × the upper limit of normal (ULN). b) Alanine aminotransferase and aspartate aminotransferase ≤2 × ULN (≤5 × ULN for patients with liver involvement of their cancer). c) International normalized ratio (INR) and partial thromboplastin time (PTT) ≤1∙5 × ULN. Subjects who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate if no prior evidence of an underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standard of care.Platelet count ≥100 000/mm3, haemoglobin >9 g/dl, absolute neutrophil count >1,500/mm3. e) Alkaline phosphatase limit ≤2∙5 × ULN (≤5 × ULN for patients with liver involvement of their cancer). f) Creatinine clearance greater than 40 as evaluated by Cockcroft-Gault formula.

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Exclusion Criteria

Prior systemic therapy for other urothelial tumours
Prior RT to the pelvis
Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days or five half-lives of the drug, whichever is longer, prior to enrolment.
Malignancies other than urothelial cancer within 3 years prior to Cycle 1, Day 1: a) Patients with localized lower risk prostate cancer (defined as Stage ≤T2b, Gleason score ≤ 7, and PSA at prostate cancer diagnosis ≤ 20 ng/mL [if measured]) treated with radical prostatectomy and without prostate-specific antigen (PSA) recurrence are eligible. b) Patients with lower risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 7 and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible. c) Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death <5% at 5 years) are eligible provided they meet all the following criteria: d) Malignancy treated with expected curative intent (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated surgically with curative intent) No evidence of recurrence or metastasis by follow-up imaging and any diseasespecific tumor markers
Pre-existing medical conditions precluding treatment (e.g., previous history of immunerelated adverse reactions, pneumonitis, colitis, etc.)
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. Patients with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study.
Active tuberculosis
For women of childbearing potential (WOCBP), study participants must use a contraceptive method that is highly effective (with a failure rate of < 1% per year) for at least 5 months after the last dose of study intervention. Men receiving any study drurg and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 6 months after the last dose of chemotehrapy with cisplatin or nab-paclitaxel. Acceptable methods are oral contraceptives, hormonal implants, hormonal patches, IDU, Diaphragm with spermicides, cervical cape with spermicide, and condom with spermicide.
Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti- PD-L1, anti-programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor [TNFR] family), or anti-Cytotoxic Tlymphocyte- associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial
Active autoimmune disease that has required systemic treatment in past 2 years
Received or will receive a live vaccine within 4 weeks prior to first dose of study drug except for vaccine against SARS-CoViD2. Influenza vaccination should be given during influenza season only (approximately October through May in the Northern Hemisphere and approximately April through September in the Southern Hemisphere). Patients must agree not to receive live, attenuated influenza vaccine (e.g., FluMist®) within 28 days prior to randomization, during treatment or within 5 months following the last dose of nivolumab.
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Active infection requiring IV systemic therapy
Receipt of therapeutic oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible
Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
Major surgical procedure other than for diagnosis within 28 days prior to Cycle 1, Day 1, or anticipation of need for a major surgical procedure during the course of the study
Prior allogeneic stem cell or solid organ transplant
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
Patients with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
Not willing or unable to sign a consent form.