Efficacy and safety of the combination of Cisplatin plus Nab-paclitaxel and Nivolumab with radiotherapy after maximal tumor resection in non-metastatic muscle invasive Bladder Cancer. (CA209-6E8, CNN-BC trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Feb 2023 → ongoing

Decision date (initial)

2024-11-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bristol Myers Squibbs s.r.l

External identifiers

EU CT number

2024-518937-26-00

EudraCT number

2021-001443-27

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To investigate the efficacy of medical treatment with cisplatin plus nab-paclitaxel and nivolumab with concomitant radiotherapy after maximal tumor resection in improving the disease-free survival
in patients with non-metastatic muscle invasive bladder cancer

Secondary objectives 8

1. To investigate the patients rate of who required salvage surgery after trimodal therapy
2. To investigate the response rate of the bladder tumor
3. To investigate the incidence of locoregional progression
4. To investigate the time without evidence of disease
5. To investigate the time without evidence of metastatic disease
6. To investigate the survival of patients treated with the trimodal therapy
7. To investigate the safety of the combination of cisplatin, nivolumab nabplaclitaxel with the radiotherapy in bladder cancer patients
8. To investigate the quality of life in patients reciving trimodale therapy for bladder cancer

Conditions and MedDRA coding

Patients with non-metastatic muscle invasive bladder cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 18 years old or older
2. Histologic diagnosis of predominantly urothelial carcinoma of the bladder. Focal differentiation allowed other than small cell histology
3. 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)
4. FDG-PET within 6 weeks from the start of treatments, showing no evidence of lymph nodes or metastatic disease
5. 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
6. Life expectancy greater than 6 months
7. ECOG performance status of 1 or better
8. 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)
9. 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.
10. Able and willing to give written informed consent
11. 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
12. 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.

Exclusion criteria 23

1. Prior systemic therapy for other urothelial tumours
2. Prior RT to the pelvis
3. 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.
4. 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
5. Pre-existing medical conditions precluding treatment (e.g., previous history of immunerelated adverse reactions, pneumonitis, colitis, etc.)
6. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
7. 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.
8. Active tuberculosis
9. 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.
10. 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).
11. 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
12. Active autoimmune disease that has required systemic treatment in past 2 years
13. 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.
14. 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.
15. Active infection requiring IV systemic therapy
16. 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
17. 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.
18. 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
19. Prior allogeneic stem cell or solid organ transplant
20. 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
21. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
22. Patients with active Hepatitis B virus (HBV) or Hepatitis C virus (HCV)
23. Not willing or unable to sign a consent form.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary end point is one –year disease–free survival, which will be defined as the rate of survival free of recurrence in pelvic nodes or bladder (cis excluded), or appearance of distant metastasis with data censored at the first sign of disease or second primary tumor, or death

Secondary endpoints 8

1. To describe the rate of patients who require salvage cystectomy
2. To describe the rate of locoregional complete response
3. To describe the rate of locoregional disease-free survival
4. To describe the median disease-free survival
5. To describe the median metastasis-free survival
6. To describe the safety of the combination of nivolumab plus cisplatin and nab-paclitaxel with concomitant RT
7. To describe the safety of nivolumab after RT
8. Quality of life

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Sponsor organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Address

Largo Francesco Vito 1

City

Rome

Postcode

00168

Country

Italy

Scientific contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Roberto Iacovelli

Public contact point

Organisation

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Contact name

Roberto Iacovelli

Locations

1 EU/EEA country · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications