Advanced or metastatic urothelial carcinoma of the bladder or urinary tract relapsed or refractory to chemotherapy MedDRA version: 20.0 Level: LLT Classification code 10064467 Term: Urothelial carcinoma System Organ Class: 100000004864
Conditions
Interventions
Product Name: Pembrolizumab
Product Code: [MK-3475 ]
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: Pembrulizumab
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Concentration
Sponsors
FONDAZIONE IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Be willing and able to provide written informed consent for the trial • Be =18 years of age on day of signing informed consent • Histologically-confirmed diagnosis of UC of the bladder or the urothelium, with predominant (>50%) UC component if other divergent histologies (e.g. squamous cell carcinoma, adenocarcinoma, small cell carcinoma) are found • Failure of 1 or 2 cisplatin-based conventional chemotherapy regimens for metastatic disease (2nd-to-3rd line only) • Neoadjuvant/adjuvant regimens will be counted provided that a relapse occurred within 6 months of the last cycle of chemotherapy • Measurable disease based on RECIST v1.1 • Adequate organ function • ECOG Performance status = 1 • Subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication • Life expectancy of at least 12 weeks • Willing and be able to comply with study protocol procedures Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 38 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 26
Exclusion criteria
Exclusion criteria: • Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment • Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug • Known history of active TB (Bacillus Tuberculosis) • Hypersensitivity to pembrolizumab or nab paclitaxel or any of their excipients • Prior administration of taxane-based chemotherapy • Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., Grade =1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier • Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to a previously administered agent o Note: Subjects with Grade =2 neuropathy are an exception to this criterion and may qualify for the study o Note: Major surgical procedures (defined by the investigator) should not be performed within 28 days prior to the first dose of the study drug. Local surgery of isolated lesions for palliative intent is acceptable • Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability • Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment • Known history of, or any evidence of active, non-infectious pneumonitis • Active infection requiring systemic therapy • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial • Pregnancy or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment • Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent • Known history of Human Immu
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate in patients with locally advanced or metastatic urothelial carcinoma relapsed or refractory after chemotherapy whether the combination of pembrolizumab and nab-paclitaxel will be active and will result in an increased activity compared to the available results with the use of both single-agents ;Secondary Objective: To evaluate the safety and tolerability of pembrolizumab combined with nab-paclitaxel in a population of chemotherapy pretreated patients with urothelial carcinoma relapsed or refractory after chemotherapy. To study the biomarkers associated with study treatment response and outcome;Primary end point(s): Progression free survival (PFS);Timepoint(s) of evaluation of this end point: Every 6 weeks from the start of treatment until disease progression | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Objective response-rate (ORR) according to RECIST v1.1 criteria; Objective response-rate (ORR) according to the modified RECIST criteria (immune-RECIST); PET response according to the EORTC criteria; Duration of response; Overall survival; Incidence of all-grade and grade 3-4 side effects; PD-L1 expression in tumor samples; Flow cytometry will be used to look at pembrolizumab-induced changes in: a) absolute count, frequency, phenotype, maturation stage, polarization and expression of markers of proliferation, cytotoxicity, activation, exhaustion and anergy of main T-cell subsets, including CD4+, CD8+ and CD4+ FOXP3+ regulatory T cells; b) frequency and phenotype of main monocyte and dendritic cell (DC) subsets, including cells with immunosuppressive functions such as myeloid-derived suppressive cells (MDSC, i.e. Lin- CD11b+ CD33+ CD14+ HLA-DRlo cells or Lin- CD11b+ CD33+ CD14- CD15+ HLA-DRlo/- cells) and plasmacytoid DCs (Lin- HLA-DR+ CD11c- CD123+ DCs). Pre-post-therapy values and changes in any of these immunological parameters will be tested for association with response to treatment; Extensive characterization, by IHC, of pre- and post-therapy neoplastic lesions. The main goals are: a) to correlate the presence and immune profiles of the infiltrating T-lymphocytes, in the pre-therapy lesions, with responsiveness to therapy, b) to test whether mechanisms of immunosuppression (Treg and MDSCs) and of immune escape (loss of HLA molecules by neoplastic cells) in pre-therapy lesions explain lack of responsiveness to treatment, c) to test whether treatment administration can promote a shift in the immune contexture of the neoplastic lesions that correlates with responsiveness to therapy; Assessment of all the markers of interest (frequency of intra-tumoral or peri-tumoral CD8+ CD45RO+ T cells); On pre- post-therapy tumor samples: expression profiling of tumor and/or tumor infiltrating immune cells, identification of immunogenic neo-antigens whic | — |
Countries
Italy
Contacts
Public ContactClinical Trial Center
Fondazione IRCCS Istituto Nazionale Dei Tumori
Outcome results
None listed