TY - JOUR
T1 - Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer
AU - Kates, Max
AU - Mansour, Ahmed M.
AU - Lamm, Donald L.
AU - Shore, Neal
AU - Maulhardt, Holly
AU - Wendt, Alison
AU - Verco, James
AU - Marin, Alyson
AU - Dewnani, Karan
AU - Verco, Shelagh
AU - Dizerega, Gere S.
N1 - Funding Information:
Support: This work was supported by NanOlogy, LLC.
Publisher Copyright:
© 2022 The Author(s). Published on behalf of the American Urological Association Education and Research, Inc.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Purpose:We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer.Materials and Methods:The trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses. Tumor recurrence was evaluated by cytology, cystoscopy, or biopsy. Pharmacokinetic analysis of blood and multiplex immunofluorescence of tumor microenvironment occurred pre- and post-LSAM-DTX.Results:Nineteen subjects were enrolled, 14 with prior bacillus Calmette-Guérin exposure and 16 with ≥1 prior TURBT. Direct injection and intravesical LSAM-DTX were well tolerated. 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.Conclusions:Post-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk nonmuscle-invasive bladder cancer. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrants investigation alone as well as in combination with immune checkpoint inhibitor therapy.
AB - Purpose:We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer.Materials and Methods:The trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses. Tumor recurrence was evaluated by cytology, cystoscopy, or biopsy. Pharmacokinetic analysis of blood and multiplex immunofluorescence of tumor microenvironment occurred pre- and post-LSAM-DTX.Results:Nineteen subjects were enrolled, 14 with prior bacillus Calmette-Guérin exposure and 16 with ≥1 prior TURBT. Direct injection and intravesical LSAM-DTX were well tolerated. 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.Conclusions:Post-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk nonmuscle-invasive bladder cancer. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrants investigation alone as well as in combination with immune checkpoint inhibitor therapy.
KW - docetaxel
KW - tumor microenvironment
KW - urinary bladder neoplasms
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U2 - 10.1097/JU.0000000000002778
DO - 10.1097/JU.0000000000002778
M3 - Article
C2 - 35574612
AN - SCOPUS:85137459369
SN - 0022-5347
VL - 208
SP - 821
EP - 829
JO - Investigative Urology
JF - Investigative Urology
IS - 4
ER -