Introduction:

Based on level 1 clinical trial evidence, taxane chemotherapies are guideline recommended first-line treatment for a variety of significant cancers.   Paclitaxel is also active against metastatic urothelial cancer.  A novel proliposomal third-generation formulation of paclitaxel specifically designed for intra-cavitary administration has been developed (TSD-001), which enables targeted tissue penetration and persistence, while minimizing systemic exposure and toxicity.  The complete 2-year clinical results (NCT03081858) of the first in human TSD-001 exposure in Non-Muscle Invasive Bladder Cancer (NMIBC) patients are presented.

Methods:

Fifteen patients with recurrent Ta, low grade (intermediate risk) NMIBC were enrolled in this prospective, single-arm, open label clinical trial.  Six of these patients were dose escalated (10-540 mg) every other week to establish the maximum deliverable dose (MDD).  Nine patients received the intravesical MDD (i.e. 360 mg) immediately post-operatively and then weekly up to 8 total doses to establish the marker lesion response rate (MLRR).  Urinary Health Related Quality of Life (HR-QOL) was measured using the Overactive Bladder Syndrome-questionnaire (OAB-q) and the International Prostate Symptom score (IPSS).

Results:

The 2-year RFS was 83% in patients after TURBT who received induction intravesical instillation of TSD-001 bi-weekly for 6 doses (figure).  In recurrent, Ta, LG NMIBC patients the per protocol MLRR was 63%.  Persistence of paclitaxel in the voided urine was observed up to 48 hours after intravesical instillation (Table).  Despite high and dose-proportional levels in the urinary bladder, paclitaxel was not detectable in the peripheral venous blood.  No Dose limiting toxicity (DLT) was observed in the 15 patients exposed to TSD-001.  Urinary HR-QOL was maintained during and after intravesical exposure to TSD-001. 

Conclusion:

In patients with recurrent, Ta, LG NMIBC, intravesical administration of TSD-001 demonstrated no DLT, and it was found to be well tolerated with no significant reduction in urinary HR-QOL.  Persistence of paclitaxel in the voided urine was observed up to 48 hours post instillation.  The MLRR in pretreated and recurrent NMIBC patients was 63%.  The 2-year RFS is 83%.  Our results support the conclusion that formulation enhanced urothelial penetration and persistence of paclitaxel translate into favorable MLRR and RFS in patients with LG, recurrent NMIBC.

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Funding: Lipac Oncology