vt-464 and Prostatic-Neoplasms--Castration-Resistant
vt-464 has been researched along with Prostatic-Neoplasms--Castration-Resistant* in 5 studies
Reviews
1 review(s) available for vt-464 and Prostatic-Neoplasms--Castration-Resistant
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Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide.
The approval of abiraterone and enzalutamide for the treatment of advanced castration-resistant prostate cancer heralded a paradigm shift in the management of this disease. Nevertheless, new and improved treatments are needed since the disease remains incurable for the majority of these patients. In this article, we review the biology of castration-resistant disease as well as emerging therapeutic compounds directed at the androgen receptor, including galeterone, VT-464, ARN-509, and ODM-201. Mechanisms of action, early clinical data, and ongoing clinical studies for these compounds are all reviewed. The need to find optimal sequencing and combination strategies as well as the need for predictive biomarkers of response to these agents is discussed. Topics: Androgen Receptor Antagonists; Androstadienes; Androstenes; Benzamides; Benzimidazoles; Humans; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Receptors, Androgen; Thiohydantoins; Triazoles | 2016 |
Trials
1 trial(s) available for vt-464 and Prostatic-Neoplasms--Castration-Resistant
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Phase 2 Study of Seviteronel (INO-464) in Patients With Metastatic Castration-Resistant Prostate Cancer After Enzalutamide Treatment.
Seviteronel was being developed by Innocrin Pharmaceuticals as a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) inhibitor and androgen receptor antagonist with activity against prostate cancer cells in vitro and in vivo. This open-label phase 2 clinical study evaluated the tolerability and efficacy of seviteronel in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with enzalutamide.. Patients with mCRPC whose disease previously progressed while receiving enzalutamide therapy were divided into 2 cohorts on the basis of prior exposure to docetaxel. Seviteronel was administered without routine oral steroids either twice daily with dose titration (450 mg) or once daily without dose titration (600 or 750 mg). The primary objective was to determine the rate of significant prostate-specific antigen response (ie, decline of ≥ 50%) after 12 weeks of seviteronel therapy.. Seventeen patients, with a median (range) age of 71 (60-92) years, were enrolled, with 8 patients having received prior docetaxel. Patients received a median of 2 cycles of treatment, with most patients discontinuing treatment because of toxicity related to the study drug. The most common adverse events included concentration impairment, fatigue, tremor, and nausea. Despite changes in dosing, the study was closed prematurely because of the high magnitude of toxicity. One (6%) of 17 patients experienced a significant decline in prostate-specific antigen.. Seviteronel was not generally well tolerated nor associated with significant clinical responses in patients with mCRPC who had previously received enzalutamide. Further investigation of single-agent seviteronel in this patient population is not warranted; however, studies investigating seviteronel with low-dose dexamethasone are ongoing in patients with androgen receptor-positive tumors. Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Drug Resistance, Neoplasm; Follow-Up Studies; Humans; Male; Middle Aged; Naphthalenes; Nitriles; Phenylthiohydantoin; Prognosis; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Triazoles | 2020 |
Other Studies
3 other study(ies) available for vt-464 and Prostatic-Neoplasms--Castration-Resistant
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A population pharmacokinetic analysis of the oral CYP17 lyase and androgen receptor inhibitor seviteronel in patients with advanced/metastatic castration-resistant prostate cancer or breast cancer.
Seviteronel is an orally-administered selective cytochrome P450c17a 17,20-lyase and androgen receptor inhibitor with anti-tumor activity in vitro and in vivo, and clinical activity in men with advanced castration-resistant prostate cancer (CRPC) and men and women with advanced breast cancer. The purpose of this study was to assess the pharmacokinetics (PK) of seviteronel across the aforementioned populations.. This report describes the PK of seviteronel (50-750 mg, QD or BID) using noncompartmental and population approaches from 243 patients with advanced breast or prostate cancer pooled across 4 clinical studies. First dose and steady-state PK were examined, as well as covariates including prandial status, sex and concomitant dexamethasone.. Seviteronel PK can be characterized by transit absorption and a bi-phasic first-order elimination while accounting for covariance between random effects. Prandial status did not significantly affect any parameters to a clinically-relevant extent. Both sex and body weight were significant covariates on clearance, explaining 37% of the interindividual variability on that parameter. There were no significant effects from the race or the presence of a corticosteroid (either dexamethasone or prednisone).. Seviteronel demonstrates linear PK over the dose range of 50-750 mg given either BID or QD in men with advanced CRPC or men and women with breast cancer. The disposition of seviteronel following oral administration is well described by this population PK model and can be used for accurate simulations for future studies with body weight and sex affecting clearance, but not to a clinically-meaningful degree requiring a change in the current dosing scheme. Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Biological Availability; Breast Neoplasms; Clinical Trials, Phase II as Topic; Dexamethasone; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Male; Naphthalenes; Neoplasm Staging; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Triazoles | 2019 |
Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer.
Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a validated treatment target for the treatment of metastatic castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) inhibits both 17α-hydroxylase (hydroxylase) and 17,20-lyase (lyase) reactions catalyzed by CYP17A1 and thus depletes androgen biosynthesis. However, coadministration of prednisone is required to suppress the mineralocorticoid excess and cortisol depletion that result from hydroxylase inhibition. VT-464, a nonsteroidal small molecule, selectively inhibits CYP17A1 lyase and therefore does not require prednisone supplementation. Administration of VT-464 in a metastatic CRPC patient presenting with high tumoral expression of both androgen receptor (AR) and CYP17A1, showed significant reduction in the level of both dehydroepiandrosterone (DHEA) and serum PSA. Treatment of a CRPC patient-derived xenograft, MDA-PCa-133 expressing H874Y AR mutant with VT-464, reduced the increase in tumor volume in castrate male mice more than twice as much as the vehicle (P < 0.05). Mass spectrometry analysis of post-treatment xenograft tumor tissues showed that VT-464 significantly decreased intratumoral androgens but not cortisol. VT-464 also reduced AR signaling more effectively than abiraterone in cultured PCa cells expressing T877A AR mutant. Collectively, this study suggests that VT-464 therapy can effectively treat CRPC and be used in precision medicine based on androgen receptor mutation status. Topics: Abiraterone Acetate; Androgens; Animals; Biopsy; Cell Line, Tumor; Dehydroepiandrosterone; Humans; Hydrocortisone; Male; Mass Spectrometry; Mice; Mice, SCID; Naphthalenes; Neoplasm Transplantation; Precision Medicine; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Triazoles | 2016 |
Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer.
VT-464 is a novel, nonsteroidal, small-molecule CYP17A1 inhibitor with 17,20-lyase selectivity. This study evaluates the anticancer activity of VT-464 compared with abiraterone (ABI) in castrate-resistant prostate cancer cell lines and xenograft models that are enzalutamide (ENZ)-responsive (C4-2) or ENZ-resistant (MR49C, MR49F). In vitro, androgen receptor (AR) transactivation was assessed by probasin luciferase reporter, whereas AR and AR-regulated genes and steroidogenic pathway enzymes were assessed by Western blot and/or qRT-PCR. The MR49F xenograft model was used to compare effects of oral VT-464 treatment to vehicle and abiraterone acetate (AA). Steroid concentrations were measured using LC-MS chromatography. VT-464 demonstrated a greater decrease in AR transactivation compared with ABI in C4-2 and both ENZ-resistant cell lines. At the gene and protein level, VT-464 suppressed the AR axis to a greater extent compared with ABI. Gene transcripts StAR, CYP17A1, HSD17B3, and SRD5A1 increased following treatment with ABI and to a greater extent with VT-464. In vivo, intratumoral androgen levels were significantly lower after VT-464 or AA treatment compared with vehicle, with the greatest decrease seen with VT-464. Similarly, tumor growth inhibition and PSA decrease trends were greater with VT-464 than with AA. Finally, an AR-antagonist effect of VT-464 independent of CYP17A1 inhibition was observed using luciferase reporter assays, and a direct interaction was confirmed using an AR ligand binding domain biolayer interferometry. These preclinical results suggest greater suppression of the AR axis with VT-464 than ABI that is likely due to both superior selective suppression of androgen synthesis and AR antagonism. Topics: Androstenes; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Naphthalenes; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Triazoles; Xenograft Model Antitumor Assays | 2015 |