(UroToday.com) In this abstract by Max Kates and colleagues, they report on the safety and preliminary efficacy of a large surface area microparticle docetaxel (LSAM-DTX) for the treatment of patients with AUA high-risk non-muscle-invasive bladder cancer (NMIBC).
This was a phase 1/2 clinical trial (clinicaltrials.org NCT03636256) investigating the safety, preliminary efficacy, and immune effect of large surface area microparticle docetaxel (LSAM-DTX) given via direct intramural injection and intravesical instillations in subjects with AUA high-risk non-muscle-invasive bladder cancer (hrNMIBC per 2016 AUA Guidelines).
Inclusion and exclusion criteria are summarized below:
Per their report, LSAM-DTX is a unique mechanism of delivery of docetaxel. It is manufactured by supercritical precipitation that produces microparticles formulated for sustained, high concentration drug release in tumors.
The drug depot effect has been demonstrated in preclinical models and in mouse xenograft models.
This open-label trial followed a 3+3 dose-escalating design of four LSAM-DTX concentrations (3-15 mg) injected cystoscopically into and around the resection bed after transurethral resection of bladder tumor (TURBT) followed by intravesical LSAM-DTX (50-75 mg/ml). This was followed in 4 weeks by a 6-week intravesical induction, a 6-week interval (break), and then 3-week maintenance course. This diagram depicts the dosing protocol:
Tumor recurrence was evaluated by cystoscopy and cytology with biopsies conducted as needed, prior to initiating induction therapy and at 3- and 6-months post-induction initiation. Tissue multiplex immunofluorescence (mIF) and blood pharmacokinetic profiles were analyzed.
They enrolled 19 subjects with hrNMIBC, of whom 12 were unresponsive to BCG – the rest had de novo diagnosis of hrNMIBC. Demographics summarized below:
First, in terms of safety, both direct injection and intravesical instillations of LSAM-DTX were well-tolerated without drug-related systemic toxicities, SAEs or AEs Grade 3-5.
Looking at efficacy, in the lower dose cohorts (total drug: 513-717 mg), 2 of 11 subjects (n=13, 2 withdrew) were free of recurrence (RFS) at the 6-month study endpoint. In contrast, in subjects that received the highest doses (total drug: 740-765 mg), 6 of 6 subjects were free of recurrence at 6 months, and 4 were free of disease at 12 months.
Overall outcomes summarized below:
3-month CR for the entire cohort was 68%, but dropped to 62% at 6 months and 31% at 12 months.
mIF analysis of biopsies from 3 of 4 subjects showed an increase in concentrations of PD-L1+ tumor cells, PD-L1+ Tregs, PD-L1+ macrophages, and NK cells as well as increases in the density of immune effector T cells. Plasma docetaxel concentrations were below lower limit of quantification (LLOQ=10 ng/mL) except for two subjects at one early timepoint (11.6 ng/mL and 10.3 ng/mL) suggesting minimal systemic toxicity or exposure.
Based on these results, the authors conclude that
- LSAM-DTX treatment was safe by both intramural injection and intravesical instillations, at all doses.
- Preliminary efficacy data suggest post-TURBT intramural injection and intravesical instillation of high dose LSAM-DTX may prevent recurrence in patients with hrNMIBC for 6-months
- PK analysis demonstrated negligible systemic exposure
- Data shows infiltration of favorable immune cells and suggests a potential for enhanced tumor cell sensitivity to immune checkpoint blockade.
This is a promising new agent that warrants larger-scale studies.
Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.