Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated UC patients (pts) and nab-paclitaxel (nPtx) has shown one of the highest activities among CT options in UC. Their combination may overcome resistance to immunotherapy (IT) and result in longer delay in the time to disease progression (PD). We will explore dynamic biomarkers of response to CT+IT.
In an open-label, single-arm, single-center, phase 2 trial, pts receive pembro 200 mg intravenously (IV) on D1 and nPtx 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 ≤ 2 platinum-based CT 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 assessed at the study conclusion on both immune cells (IC) and tumor cells at a centralized laboratory (Qualtek, Goleta, CA, USA). 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 pts 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 PD-L1+ pts, there is the option to expand this cohort up to a maximum of 50 pts. As such, we estimate 85.1% 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 (EudraCT number 2017-000579-10).
Clinical trial identification
EudraCT number 2017-000579-10
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale dei Tumori
All authors have declared no conflicts of interest.