JU INSIGHT Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer

By: Ahmed M. Mansour, MD; Donald L. Lamm, MD; Neal Shore, MD; Holly Maulhardt, BS; Alison Wendt, BS; James Verco, BS; Alyson Marin, MS; Karan Dewnani, BS; Shelagh Verco, PhD; Gere S. diZerega, MD | Posted on: 01 Oct 2022

Kates M, Mansour AM, Lamm DL, et al. Phase 1/2 trial results of a large surface area microparticle docetaxel for the treatment of high-risk nonmuscle-invasive bladder cancer. J Urol. 2022;208(4)821-829.

Study Need and Importance

Most patients with high-risk nonmuscle-invasive bladder cancer (NMIBC) are treated with transurethral resection of bladder tumor (TURBT) followed by bacillus Calmette-Guérin (BCG) intravesical therapy. Despite moderate efficacy with intravesical chemotherapy for BCG-exposed NMIBC, there remains a need to enhance therapeutic options to improve the efficacy of these treatments. We discuss our experience with large surface area microparticle docetaxel (LSAM-DTX) administered via direct injection at the site of TURBT followed by intravesical instillation for the treatment of high-risk NMIBC.

Figure. Fold-change in immune cell densities (cells/mm2) from bladder biopsies collected before and after LSAM-DTX therapy as determined by multiplex immunofluorescence. Boxplots show minimum to maximum fold-changes (extremes), per subject data (dots), mean (+), and median (line) for 5 subjects analyzed. Cell types are identified using marker (CD11b, CD14, CD15, CD3, CD4, CD8, CD20, CD33, CD45RO, CD56, CD68, HLA-DR, FOXP3, CTLA4, PD-1, PD-L1, and pan-cytokeratin) co-expression over an average of 24 regions of interest (ROIs; range 7 to 37) within the tumor microenvironment per slide. ROI was selected by a pathologist blinded to treatment status on a hematoxylin and eosin-stained slide. Cell type density is the total number of cells counted divided by the total area (sum of all ROI areas) per slide. In cases where the pre-LSAM-DTX cell density was 0 cells/mm², no data are reported and number of patients is less than 5.

What We Found

Nineteen subjects were enrolled, 14 with prior BCG exposure and 16 with ≥1 prior TURBT. Post-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk NMIBC. In the 3 lowest dose escalation cohorts the median recurrence-free survival was 5.4 months (10 patients, median followup 8.6 months). In the high-dose and expansion cohorts median recurrence-free survival was significantly increased (p <0.05; hazard ratio 0.29) to 12.2 months (9 patients, median followup 12.4 months). Systemic docetaxel exposure was negligible, and increases in antitumor immune cells were found in the tumor microenvironment along with elevations in the PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitor targets (see Figure).

Limitations

Although 14/19 subjects in this study were BCG-exposed, the type of BCG failure was not defined. Other limitations included small sample size, heterogeneous tumor stage, wide range of number of prior TURBT procedures, limited immune analysis, short maintenance period, and short study followup period.

Interpretations for Patient Care

The unique route of administration, direct injection immediately after TURBT followed by intravesical administration, was shown to be safe and well tolerated. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrant investigation alone as well as in combination with immune checkpoint inhibitor therapy.