Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer

Abstract

BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for X4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of X50% was noted in two patients. The median time to PSA progression (425%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

The quinoline-3-carboxamide paquinimod (ABR-215757) reduces leukocyte recruitment during sterile inflammation: Leukocyte- and context-specific effects

“…These compounds have shown efficacy in several mouse models of inflammatory autoimmune disease [29][30][31][32][33] and they are currently in clinical development for multiple sclerosis [34][35][36][37], systemic sclerosis and prostate cancer [38,39]. Recently, the S100A9 protein was identified as one molecular target of the Q-compound paquinimod (ABR-215757) [40].…”

The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration

“…These patients could also be enrolled in clinical trials with drugs that target HIF1a function (e.g. tasquinimod and other agents that target HIF1a or its downstream products) [34][35][36][37]. Present findings should be further extended and replicated by future studies focusing on genetic polymorphisms as predictors of treatment response to allow tailored therapy in PCa patients.…”

Potential antitumour and pro-oxidative effects of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (QNACR)

“…Potential antitumour and pro-oxidative effects of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (QNACR) Juan R. Rodrigues 1 , Rosa Ferrer 2 , Neira Gamboa 2 , Jaime Charris 2 , and Fernando Antunes 1 abietyl-Isothiocyanate (ABITC) to treat endometrial cancer is related to its actions on cell-cycle progression and apoptosis as well as on the ROS generation 5 . Pro-oxidative compounds are being considered as potential novel antitumour therapies.…”

“…Over the last years, there has been a strong interest in the development of new heteroaromatic compounds derived from quinolines due to their wide range of pharmacological properties. Indeed, quinoline derivatives have shown effects as antineoplastics such as tasquinimod (ABR-215050) which is one of the main quinoline compounds that is currently in clinical research whose effects are related to the inhibition of angiogenesis in patients with tumour metastasis 1 . On the other hand, substitutions with an acrylate group on organic structures such as benzofuranes improves the antitumour activity in vitro 2 , being proposed as potential DNA-intercalating compounds, inhibitors of angiogenesis and apoptosis inducers 3,4 confirming the multi-target effects of these structures.…”