Phase II trial of neoadjuvant nivolumab with cisplatin and gemcitabine in muscle-invasive bladder cancer patients undergoing radical cystectomy.

Abstract

TPS528 Background: Cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) improves survival outcomes. The survival benefit correlates with pathologic response (PaR) and strategies to improve pathologic response at cystectomy are urgently needed to improve outcomes in these pts. while limiting toxicity. We are exploring the efficacy and safety of N with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC. Methods: This is a single-arm, multi-center phase II study for pts with MIBC eligible for neoadjuvant GC and planned for radical cystectomy. Pts will be treated with N+ GC every 21 days for 4 treatment cycles over 12 weeks followed by radical cystectomy. The primary endpoint of PaR will be evaluated in a single stage design; 41 adult pts will be enrolled and the treatment will be worthy of further study (and the null hypothesis rejected) if paR is seen at the time of cystectomy in more than 19 pts. Key inclusion criteria are presence of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring < 2 cm) and M0 and deemed eligible for radical cystectomy, ECOG PS of 0 or 1, Cr Cl ≥ 50 ml/min, adequate organ function, eligible to receive GC and no contraindications to receiving N. Patients will receive C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by radical cystectomy within 6-8 weeks. Secondary Objectives are to determine safety of N+GC in pts with MIBC prior to radical cystectomy and PFS. The correlative objectives include: 1)Whole Exome Sequencing (WES) of the pre-treatment bladder cancer biopsy tissues will be correlated with response.2) Molecular subtypes of bladder cancer will be performed using Genomedx to evaluate whether addition of N alters the response to neoadjuvant GC. 3)PD-L1 expression in tumor tissue at baseline will be correlated with response to N+GC therapy and 4) Nanostring pancan immune panel gene expression will be studied at baseline and at cystectomy.The extensive exploratory analyses are aimed at understanding correlation between genomic and immunologic changes in tumor tissues with clinical outcomes. (NCT03294304) Clinical trial information: NCT03294304.