An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer

Tammela, Teuvo L.J.; Häggman, Michael; Ladjevardi, Sam; Taari, Kimmo; Isotalo, Taina; Lennernäs, Hans; Weis, Ján; Below, Catrin von; Wassberg, Cecilia; Lennernäs, Bo; Tamburini, Anna; Axén, N.; Gölander, Carl-Gustaf; Åhlström, Håkan

doi:10.1016/j.juro.2017.07.072

Cited by 7 publications

(6 citation statements)

References 20 publications

(18 reference statements)

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“…Testosterone levels in plasma remained unaffected, showing that the low systemic exposure to 2-HOF from Liproca Depot over time did not significantly alter the gonadal-pituitary axis. Similar results were seen in a previous Liproca Depot study [12].…”

Section: Discussionsupporting

confidence: 91%

“…Liproca Depot (LIDDS AB, Uppsala, Sweden) is an intraprostatic injection of the antiandrogen 2-hydroxyflutamide (2-HOF) in a calcium sulfate-based depot produced with the NanoZolid (LIDDS AB) drug delivery platform, for which the antiandrogen is slowly released over a period of up to 6 mo [12,13]. Treatment with Liproca Depot is a focal therapy that can be performed in an outpatient urology clinic with local anesthesia and a transrectal procedure similar to prostate biopsy.…”

Section: Introductionmentioning

confidence: 99%

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Liproca Depot: A New Antiandrogen Treatment for Active Surveillance Patients

Klotz

Grudén

Axén³

et al. 2022

European Urology Focus

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Background: There is increasing interest in nonmorbid treatments for low-and intermediate-risk prostate cancer with fewer side effects than surgery or radiotherapy. Objective: To investigate the tolerability, safety, and antitumor effects of the intraprostatic NanoZolid depot formulation Liproca Depot (LIDDS AB, Uppsala, Sweden) with antiandrogen 2-hydroxyflutamide (2-HOF) in men with low-or intermediate-risk localized prostate cancer managed with active surveillance. Design, setting, and participants: This clinical phase 2b trial, LPC-004, involved 61 patients. The 2-HOF-containing formulation Liproca Depot was injected transrectally into the prostate under ultrasound guidance. A single dose of 35% or 45% of the prostate volume (study part 1) and a fixed dose of 16 or 20 ml (study part 2) of the formulation were evaluated. Outcome measurements and statistical analyses: The primary endpoints were tolerability and the reduction in serum prostate-specific antigen (PSA) 5 mo after injection. Antitumor effects were evaluated with magnetic resonance imaging (MRI) and prostate biopsies. Quality of life was assessed using a validated questionnaire (International Prostate Symptom Score). Results and limitations: All doses were safe and well tolerated, without hormonal side effects. In part 2 of the study, the PSA reduction was greatest for the group receiving 16 ml, with an average decrease of 14%, and 95% of patients had a PSA reduction. Some 78% of patients showed a prostate volume decrease compared to baseline. Prostate MRI and biopsies confirmed stable or reduced lesion size. However, post treatment biopsies were performed at the discretion of the investigator, and not routinely. Most patients were amenable to a second injection. Conclusions: PSA and prostate volume decreased in most patients. Indications of efficacy were shown by post-treatment MRI and biopsies demonstrating stabilization or regression in the majority of cases.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Liproca Depot: A New Antiandrogen Treatment for Active Surveillance Patients

Klotz

Grudén

Axén³

et al. 2022

European Urology Focus

Self Cite

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“…This technology has been used to generate depot-formulations of anti-androgens for use in prostate cancer. 206 NZ-TLR is a TLR9 agonist with an undisclosed TLR9 structure encapsulated within a calcium sulfate excipient (NanoZolid) that permits slow release depot formulation following intra-tumoral dosing obviating the need for frequent dosing. Preclinical data in syngeneic tumor models have been reported but not published with plans for first-in-human clinical trials in 2021.…”

Section: Preclinical and Clinical Studies Of Tlr9 Agonistsmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

102

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Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.

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“…Liproca ® Depot (LIDSS Pharma) utilises a drug-delivery platform known as Nanozolid ® for the locoregional treatment of prostate cancer to deliver 2-hydroxyflutamide for up to six months. Nanozolid ® is made of granules of compressed calcium sulfate mixed with non-compressed calcium sulfate hemihydrate powder and is rehydrated at point of use to form an injectable paste [94,95]. An initial burst release is observed from the drug content contained in the non-compressed powder, with the granule-encapsulated drug demonstrating prolonged release.…”

Section: Liproca ®mentioning

confidence: 99%

“…Combined results published from two Phase I/II single-arm interventional clinical trials (NCT00913263 & NCT02341404) (n=47) demonstrated that treatment was overall well tolerated following intra-prostatic administration of drugloaded paste. However, the clinical response was variable across the patient population, indicating that further optimisation on clinical dosing and distribution of this drug delivery platform is required to demonstrate true clinical benefit [95]. Based on the efficacy results from these clinical trials a third clinical trial is underway to assess the potential application of Liproca ® Depot during active surveillance of individuals at high risk of progression of prostate cancer (NCT03348527).…”

Section: Liproca ®mentioning

confidence: 99%

Loco-regional drug delivery in oncology: current clinical applications and future translational opportunities

Rossi

Murray

McDonough

et al. 2020

Expert Opinion on Drug Delivery

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IntroductionDrug-based treatment regimens for cancer are often associated with off-target toxic side effects and low penetration of the drug at the tumor site leading to patient morbidity and limited efficacy. Locoregional drug delivery has the potential to increase efficacy while concomitantly reducing toxicity. Areas coveredClinical applications using loco-regional delivery include intra-arterial drug delivery in retinoblastoma, direct intra-tumoral (IT) injection of ethanol for ablation in hepatocellular carcinoma (HCC) and the use of HIPEC in peritoneal carcinomas. In recent years, there has been a significant increase in both approved products and clinical trials, with a particular emphasis on drug delivery platforms such as drug eluting beads for HCC and hydrogel platforms for intravesical delivery in bladder cancer. Expert opinionDevelopment of loco-regional drug delivery systems has been slow, limited by weak clinical data for early applications and challenges relating to dosing, delivery and retention of drugs at the site of action. However, there is increasing focus on the potential of loco-regional drug delivery when combined with bespoke drug delivery platforms. With the growth in immunotherapies, the use of IT delivery to drive priming of the anti-tumor response has opened up a new field of opportunity for locoregional drug delivery.

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An Intraprostatic Modified Release Formulation of Antiandrogen 2-Hydroxyflutamide for Localized Prostate Cancer

Abstract: Intraprostatic injections of 2-hydroxyflutamide depot formulations showed antitumor effects, and proved to be safe and tolerable. However, for better anticancer effects higher doses and better dose distribution are suggested.

Cited by 7 publications

References 20 publications

Liproca Depot: A New Antiandrogen Treatment for Active Surveillance Patients

Liproca Depot: A New Antiandrogen Treatment for Active Surveillance Patients

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Loco-regional drug delivery in oncology: current clinical applications and future translational opportunities

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