Direct and Multifaceted LSAM-DTX Treatment May Be Safe and Effective in NMIBC

Max Kates, MD

Administration of direct intramural injection and intravesical instillations of large surface area microparticle docetaxel (LSAM-DTX; NanoDoce) to patients with high-risk non-muscle invasive bladder cancer (NMIBC) was found to be safe with preliminary efficacy signals, according to phase 1/2 study findings presented by Max Kates, MD, during the American Urological Association 2021 Annual Meeting.

Among the 19 patients who received LSAM-DTX at any dose level, the 3-month complete response (CR) rate was 68%. The 6-month durability in 13 evaluable patients who had a CR at 3 months was 62% and the 12-month durability in this group was 31%.

“LSAM-DTXs are large surface area microparticles of pure drug in powder form,” explained Kates, the director of the Bladder Cancer Program and an assistant professor of urology at the Johns Hopkins University School of Medicine in Baltimore, Maryland. “The microparticles are formed using supercritical precipitation technology, then suspended in saline prior to use. The uniqueness of this technology relative to other particle engineering technologies is that it maintains a relatively large particle size of about 3.5 microns. [This size] enhances tumor infiltration and entrapment while at the same time also substantially increasing surface area, allowing for continuous drug release for more than 4 weeks after intratumoral delivery.

“Meanwhile, clearance of drug from the site of administration was shown in preclinical studies to be gradual at subtoxic levels.”

Kates added that, in the dose-escalation group, 54% experienced no recurrence after 3-months and 2 patients had a CR after 6-months. The maximum dose of approximately 15 mg LSAM-DTX via intratumoral injection and approximately 75 mg via intravesical therapy was given to a 6-patient dose-confirmation cohort. All patients in this cohort achieved a CR at 6-months and 4 patients showed durability at 12 months. One patient in this group was lost to follow-up and was not a confirmed failure.

Kates and colleagues evaluated LSAM-DTX in 19 patients with high-risk NMIBC. LSAM-DTX in saline suspension was administered via direct intratumoral injection into resection bed post transurethral resection of a bladder tumor (TURBT) and multiple intravesical instillations. The safety of LSAM-DTX was the primary end point. Preliminary efficacy and immune effects were secondary end points.

Patients included in the trial (NCT0363625) were adults with pathologically- or cytologically-confirmed high-risk NMIBC and urothelial carcinoma. Patients needed to have a life expectancy of at least 6 months and an ECOG performance status of 0-2 at study entry. Eligible patients also needed to have adequate marrow, liver, and renal function and have all visible tumors removed during TURBT.

Ineligible patients included those with metastatic disease and a previous (within 12 months) or concurrent history of a non-bladder malignancy, except for non-melanoma skin cancer. Those undergoing intravesical therapy within 4 weeks prior to consent or with upper tract and urethral disease within 18 months were excluded. Patients with known hypersensitivity to any of the study drug or reconstitution components or those had participated in the treatment phase of another clinical trial within 3 months were also not allowed into the trial.

The median age of the population was 72 (range, 56-82) and consisted mostly of men (n = 14). Most patients were white (n = 18), and 12 reported prior treatment with Bacillus Calmette-Guerin immunotherapy. In terms of staging, most patients had carcinoma in situ (CIS; n = 8). Seven, 3, and 1 patients had Ta, T1, and T1 with CIS disease, respectively.

The trial utilized a 3 + 3 dose-escalating design in 13-patients where 4 concentrations of LSAM-DTX (3 mg to 15 mg) were administered via direct intratumoral injection cytoscopically into and around the resection bed after TURBT. This was followed by an intravesical instillation of LSAM-DTX at 50-75 mg in 25 mL of suspension. One month later, responders received a 6-week induction course and a 3-week maintenance course, for a total of 9 intravesical instillations.

Both LSAM-DTX injections and instillations were well-tolerated, with no attributable local or systemic SAEs, except for a kidney stone in 1 patient. There were 203 treatment-emergent adverse events observed overall. Kates called pharmacokinetic results for systemic LSAM-DT absorption “unremarkable.”

Investigators obtained tissue suitable for immune cell analysis from 5 patients before treatment with LSAM-DTX and at the end of treatment. Samples were analyzed using multiplex immunofluorescence to evaluate potential immune effects from the treatment. Investigators observed increased density of immune effector cells in the tumor microenvironment (TME) compared with pretreatment levels.

“This is really fascinating because it speaks to the hypothesis that direct injection of a cytotoxic chemotherapy into the resection bed, followed by therapeutic instillations leads to a recruitment of immune effector cells to the TME,” remarked Kates.

All 5 of the samples showed an increased density of T cells pre to post LSAM-DTX treatment and all patients also displayed increased density of macrophages, including PD-L1+. Most of the patients (n=3) also had an increase in natural killer (NK) cell density. Variable changes in the density of myeloid and myeloid-derived suppressor cells were reported.

“The increase in PD-L1 expression, increase in NK cells, and decrease in suppressor cells are all very interesting, and may warrant further clinical research in combination with immune checkpoint inhibitors or other immunotherapies aimed at increasing tumor response,” concluded Kates. “Clearly, we have learned that by enhancing chemotherapeutic delivery and efficacy, we also may be getting an enhanced antitumor immune effect. This interplay will need to be studied and expanded on further.”

_Reference

_{Kates M, Mansour A, Lamm D, et al. Initial Results from a phase 1/2 trial of large surface area microparticle docetaxel for high-risk non-muscle invasive bladder cancer.Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-02.}