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This phase II, single-center study will assess the efficacy of pembrolizumab + nab-paclitaxel in patients who have metastatic urothelial tumor and do not respond to chemotherapy. The time between drug administration and progression of the disease will be assessed to determine if the drug will work.
Full description
In an open-label, single-arm, single-center, phase 2 trial, patients will receive pembrolizumab 200 mg intravenously (IV) on D1 and nab paclitaxel at the dose of 125 mg/m2 IV on D1 and D8. Cycles are repeated every 3 weeks until PD or onset of unacceptable toxicity. Key inclusion criteria are: predominant UC, failure of maximum 2 platinum-based CT regimens for metastatic disease (2nd-to-3rd line only). Neoadjuvant/adjuvant CT is counted if relapse occurred 6 months of the last CT cycle. Response is evaluated by RECIST criteria v.1.1 every 2 cycles. PD-L1 expression will be prospectively assessed on both immune cells (IC) and tumor cells at a centralized laboratory (National Cancer Institute Milano). Combined positivity score (CPS) for PD-L1 assessment will be used, as previously reported, and the 10% cutoff will be adopted for the analyses. The primary endpoint of the study is the progression-free survival (PFS). The target is to detect an improvement in the median PFS from 3.0 months (H0) to 5.0 months (H1). To achieve 90% power with a one-sided non-parametric test at the 10% significance level, we estimated that 64 patients must be accrued over 18 months, with follow-up duration of 12 months. PFS will be also analyzed according to the PD-L1 expression. Should the above investigation suggest that the treatment benefit is stronger in patients with CPS 10%, there is the option to expand this cohort up to a maximum of 50 patients. As such, we estimate 85% power to detect the target improvement in PFS. The decision of cohort expansion will rely on predictive power (PP) calculation: a PP 30% will be regarded as promising. Translational analyses will include multiparametric flow cytometry of blood samples, gene expression (RNA-seq, Illumina HiSeq) and mutation profiling of tumor samples (Ion Torrent Personal Genome Machine). These profiles will be matched with response to treatment and PFS/overall survival.
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Inclusion 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 systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
Has a known history of active Bacillus Tuberculosis
Had prior administration of taxane-based chemotherapy
Is taking regular oral steroids, above the allowed limit of 10mg/day methylprednisolone or analogues, for any reason. Patients must not have had steroids for 28 days prior to study entry
Has had a 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
Has had 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
Has a 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
Has 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
Has 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
Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
Has an active infection requiring systemic therapy.
Has a 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
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
Has known active Hepatitis B or Hepatitis C
Has received a live vaccine within 30 days of planned start of study therapy
Primary purpose
Allocation
Interventional model
Masking
70 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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