subjects in untreated (1st line)* and platinum-based pretreated (2nd and 3rd line) subjects with metastatic or surgically unresectable TCC *First-line has been finally stopped since 06.01.2020 MedDRA version: 21.0 Level: LLT Classification code 10038514 Term: Renal pelvis and ureteric cancer transitional cell metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10071664 Term: Bladder t
Conditions
Interventions
Trade Name: OPDIVO
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: nivolumab
CAS Number: 946414-94-4
Current Sponsor code: BMS-936558
Other descriptive name: NIVOLUMAB
Sponsors
AIO-Studien-gGmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Signed Written Informed Consent a) Subjects or legally acceptable representatives must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care. b) Subjects or legally acceptable representatives must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study. • Target population: c) Histological evidence of metastatic or surgically unresectable transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis. Minor histologic variants of transitional cell carcinoma (e.g. squamous cell, comprising 12 months from last therapy [for chemoradiation and adjuvant treatment] or >12 months from last surgery [for neoadjuvant treatment]; in all other patients who received cisplatin based neoadjuvant and/or adjuvant chemotherapy and progression within 12 months this will be considered one line of therapy. *First-line has been finally stopped since 06.01.2020 e) KPS of at least 70% f) Measurable disease as per RECIST v1.1 g) Formalin-fixed paraffin embedded tumor tissue obtained within 2 years prior to screening must be available and received by the central pathology (tumor block is preferred, alternatively 15 unstained slides). Note that: i. Fine Needle Aspiration [FNA] and bone metastases samples (without soft tissue component) are not acceptable for submission). ii. Tumor lesions used for newly acquired biopsies should not be target lesions, unless there are no other lesions. • Age and Reproductive Status h) Males and Females, ? 18 years of age i) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug. j) Women must not be breastfeeding k) Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug. l) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Males who receive nivolumab combined with ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time require
Exclusion criteria
Exclusion criteria: • Target Disease Exceptions a) Any history of or current CNS metastases. Baseline imaging of the brain by MRI (preferred) or CT scan is required within 28 days prior to registration in 2nd/3rd line patients only. • Medical History and Concurrent Diseases b) Prior systemic treatment with more than two different chemotherapy regimen (Sequential chemotherapy as a planned sequence to optimize response will count as 1 regimen) c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA 4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. d) Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll. e) Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. f) Prior malignancy active within the previous 3 years except for i. locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. ii. Patients in active surveillance for prostate cancer g) Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS). h) Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection. i) Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results. j) Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug. k) Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug. l) Presence of any toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia and fatigue, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug. • Physical and Laboratory Test Findings m) Any of the following laboratory test findings: i. WBC 3 x ULN (> 5 x ULN if liver metastases are present) v. Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula): • Allergies and Adverse Drug Reaction n) History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the products. • Other Exclusion Criteria o) Prisoners or subjects who are involuntarily incarcerated p) Subjects who are compu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective will be measured by the primary endpoint of ORR (based on investigator assessments). The ORR is based on investigator assessment using RECIST 1.1 of the TITAN-TCC regimen in untreated (1st line) and platinum-based pretreated (2nd and 3rd line) subjects with metastatic or surgically unresectable TCC;Secondary Objective: • PFS, DOR, Time to Immunotherapy Resistance (TIR) and OS in untreated (1st line) and pretreated (2nd/3rd line) patients, and the overall cohort • RR, TTR and DOR after nivolumab/ipilimumab combination “boost” for initial SD and PD, respectively • RR, TTR and DOR after nivolumab/ipilimumab combination “boost” for PD during nivolumab maintenance (including re-treatment) • Treatment emergent adverse events according to NCI-CTCAE version 4 • To assess the overall safety and tolerability of the TITAN-TCC regimen with ipilimumab dose escalation • To evaluate Health Related Quality of Life (HRQoL) as assessed by the European Organization for Research and Treatment of Care (EORTC) QLQ-C30 • To assess changes in reported global health outcomes based on the EQ-5D index score • To monitor immunogenicity of nivolumab and nivolumab/ipilimumab “boosts” with regard to prediction of response as well as immune related adverse events;Primary end point(s): best ORR based on investigator assessment using RECIST 1.1 of the TITAN-TCC regimen in untreated (1st line) and platinum-based pretreated (2nd and 3rd line) subjects with metastatic or surgically unresectable TCC 30 weeks after last patient first treatment;Timepoint(s) of evaluation of this end point: 30 weeks after last patient first treatment | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • PFS, DOR, Time to Immunotherapy Resistance (TIR) and OS in untreated (1st line) and pretreated (2nd/3rd line) patients, and the overall cohort • RR, TTR and DOR after nivolumab/ipilimumab combination “boost” for initial SD and PD, respectively • RR, TTR and DOR after nivolumab/ipilimumab combination “boost” for PD during nivolumab maintenance (including re-treatment) • Treatment emergent adverse events according to NCI-CTCAE version 4 • To assess the overall safety and tolerability of the TITAN-TCC regimen with ipilimumab dose escalation • To evaluate Health Related Quality of Life (HRQoL) as assessed by the European Organization for Research and Treatment of Care (EORTC) QLQ-C30 • To assess changes in reported global health outcomes based on the EQ-5D index score • To monitor immunogenicity of nivolumab and nivolumab/ipilimumab “boosts” with regard to prediction of response as well as immune related adverse events;Timepoint(s) of evaluation of this end point: after 68 months | — |
Countries
Austria, Germany
Contacts
Public ContactClinical trial desk of the sponsor
AIO-Studien-gGmbH
Outcome results
None listed