AUA 2021: Initial Results from a Phase 1/2 Trial of Large Surface Area Microparticle Docetaxel for High-Risk Non-Muscle Invasive Bladder Cancer

( 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 ( 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:

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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.

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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:

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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:

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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:

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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.

Presented by: Max Kates, MD, Assistant Professor of Urology, Johns Hopkins University

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.

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