This report describes local administration of submicron particle paclitaxel (SPP) (NanoPac®: ~ 800-nm-sized particles with high relative surface area with each particle containing ~ 2 billion molecules of paclitaxel) in preclinical models and clinical trials evaluating treatment of carcinomas. Paclitaxel is active in the treatment of epithelial solid tumors including ovarian, peritoneal, pancreatic, breast, esophageal, prostate, and non-small cell lung cancer. SPP has been delivered directly to solid tumors, where the particles are retained and continuously release the drug, exposing primary tumors to high, therapeutic levels of paclitaxel for several weeks. As a result, tumor cell death shifts from primarily apoptosis to both apoptosis and necroptosis. Direct local tumoricidal effects of paclitaxel, as well as stimulation of innate and adaptive immune responses, contribute to antineoplastic effects. Local administration of SPP may facilitate tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Results of preclinical and clinical investigations described here suggest that local administration of SPP achieves clinical benefit with negligible toxicity and may complement standard treatments for metastatic disease. Graphical abstract
Purpose This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. Methods Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50–275 mg/m2) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). Results Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration–time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450–2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. Conclusions Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.
Intratumoral (IT) administration of submicron particle docetaxel (NanoDoce®, NanOlogy LLC, Fort Worth, TX, USA) and its efficacy against genitourinary-oncologic xenografts in rats and mice, xenograft-site docetaxel concentrations and immune-cell infiltration were studied. IT-NanoDoce®, IV-docetaxel and IT-vehicle were administered to clear cell renal carcinoma (786-O: rats), transitional cell bladder carcinoma (UM-UC-3: mice) and prostate carcinoma (PC-3: mice). Treatments were given every 7 days with 1, 2, or 3 doses administered. Animals were followed for tumor growth and clinical signs. At necropsy, 786-O and UM-UC-3 tumor-site tissues were evaluated by H&E and IHC and analyzed by LC-MS/MS for docetaxel concentration. Two and 3 cycles of IT-NanoDoce® significantly reduced UM-UC-3 tumor volume (p < 0.01) and eliminated most UM-UC-3 and 786-O tumors. In both models, NanoDoce® treatment was associated with (peri)tumor-infiltrating immune cells. Lymphoid structures were observed in IT-NanoDoce®-treated UM-UC-3 animals adjacent to tumor sites. IT-vehicle and IV-docetaxel exhibited limited immune-cell infiltration. In both studies, high levels of docetaxel were detected in NanoDoce®-treated animals up to 50 days post-treatment. In the PC-3 study, IT-NanoDoce® and IV-docetaxel resulted in similar tumor reduction. NanoDoce® significantly reduced tumor volume compared to IT-vehicle in all xenografts (p < 0.0001). We hypothesize that local, persistent, therapeutic levels of docetaxel from IT-NanoDoce® reduces tumor burden while increasing immune-cell infiltration. IT NanoDoce® treatment of prostate, renal and bladder cancer may result in enhanced tumoricidal effects.
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.
This report describes local administration of large surface area microparticle docetaxel (LSAM-DTX: ~ 3.5- to 7.5-µm-sized particles with high relative surface area) in preclinical oncology models and in a clinical trial in urothelial carcinoma. Reductions in tumor volumes were found following intratumoral (IT) injection of LSAM-DTX into human urologic carcinoma cell lines and syngeneic murine renal and breast cancer cell lines. Compared to IT injections of docetaxel solution typically administered intravenously, IT LSAM-DTX results in 40-fold more docetaxel retained within the tumor. The long residence time of LSAM-DTX within the tumor acts as a drug depot, allowing for continuous release of docetaxel, exposing tumor cells to high, therapeutic levels of chemotherapeutic for several weeks. Local LSAM-DTX results in tumoricidal effects at the site of deposition as well as in distant tumors, and IT LSAM-DTX in combination with immune checkpoint inhibitor therapy reduces or eliminates metastatic spread. Tumoricidal effects of local LSAM-DTX are accompanied by immunomodulation including increases in innate and adaptive immune cells in the tumor microenvironment and peripheral blood. Encouraging clinical results indicate that local administration of LSAM-DTX may provide therapeutic benefits for non-muscle invasive bladder cancer and muscle invasive bladder cancer patients; treatments were well-tolerated with few local and systemic adverse events and negligible systemic docetaxel exposure. Results of preclinical and clinical investigations summarized here indicate that local administration of LSAM-DTX may augment tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Graphical abstract
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