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Sonidegib

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https://www.readbyqxmd.com/read/28317088/phase-i-trial-of-the-oral-smoothened-inhibitor-sonidegib-in-combination-with-paclitaxel-in-patients-with-advanced-solid-tumors
#1
A Stathis, D Hess, R von Moos, K Homicsko, G Griguolo, M Joerger, M Mark, C J Ackermann, S Allegrini, C V Catapano, A Xyrafas, M Enoiu, S Berardi, P Gargiulo, C Sessa
Purpose To establish a recommended phase II dose (RP2D) for the oral smoothened inhibitor sonidegib in combination with paclitaxel; secondary objectives include evaluation of safety, tolerability, markers of Hedgehog (Hh) signaling and preliminary antitumor activity. Methods Patients with advanced solid tumors were enrolled in cohorts of escalating sonidegib dose levels (400mg, 600mg and 800mg orally, once daily on days 1-28) in combination with paclitaxel 80 mg/m(2) on days 1, 8 and 15 in 4-weekly cycles. Dose-limiting toxicities (DLTs) were assessed using CTCAE v4...
March 20, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28182134/differential-pharmacology-and-clinical-utility-of-sonidegib-in-advanced-basal-cell-carcinoma
#2
REVIEW
Mohd Wahid, Arshad Jawed, Sajad Ahmad Dar, Raju K Mandal, Shafiul Haque
Patients suffering from advanced basal cell carcinoma (BCC) have very limited treatment options. Sonidegib selectively inhibits the growth of Hedgehog pathway-dependent tumors and can treat locally advanced BCC patients who are not candidates for surgery or radiation therapy. The BOLT clinical trials were conducted to evaluate the efficacy/potency of sonidegib in the treatment of advanced BCC or metastatic BCC. The patients were randomized in 1:2 ratios to receive 200 or 800 mg oral sonidegib daily, stratified by disease, histological subtype and geographical region...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28122787/a-physiologically-based-pharmacokinetic-modeling-approach-to-predict-drug-drug-interactions-of-sonidegib-lde225-with-perpetrators-of-cyp3a-in-cancer-patients
#3
Heidi J Einolf, Jocelyn Zhou, Christina Won, Lai Wang, Sam Rebello
Sonidegib (Odomzo®) is an orally available Smoothened inhibitor for the treatment of advanced basal cell carcinoma. Sonidegib was found to be metabolized primarily by cytochrome P450 (CYP)3A in vitro The effect of multiple doses of the strong CYP3A perpetrators, ketoconazole (KTZ) and rifampin (RIF), on sonidegib pharmacokinetics (PK) after a single 800 mg dose in healthy subjects was therefore assessed. This data was used to verify a physiologically-based pharmacokinetic (PBPK) model developed to: 1) bridge the clinical drug-drug interaction (DDI) study of sonidegib with KTZ and RIF in healthy subjects to the marketed dose (200 mg) in patients, 2) predict acute (14 days) versus long-term dosing of the perpetrators with sonidegib at steady-state, and 3) predict the effect of moderate CYP3A perpetrators on sonidegib exposure in patients...
January 25, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28073840/fda-approval-summary-sonidegib-for-locally-advanced-basal-cell-carcinoma
#4
Denise Casey, Suzanne Demko, Stacy Shord, Hong Zhao, Huanyu Chen, Kun He, Alexander Putman, Whitney S Helms, Patricia Keegan, Richard Pazdur
On July 24, 2015, the U. S. Food and Drug Administration (FDA) approved sonidegib (ODOMZO®, Novartis) for treatment of patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiation therapy. The approval was based on data from one randomized, double-blind, non-comparative trial of two doses of sonidegib administered to 230 hedgehog inhibitor-naïve patients with metastatic basal cell carcinoma (mBCC, n=36) or laBCC (n=194). Patients were randomized 2:1 to receive sonidegib 800 mg (n=151) or 200 mg (n=79) daily...
January 10, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27972507/cost-efffectivenes-of-sonidegib-versus-vismodegib-for-the-treatment-of-patients-with-locally-advanced-basal-cell-carcinoma-not-amenable-to-surgery-or-radiotherapy
#5
M Purser, D Mladsi, J A Kaye
No abstract text is available yet for this article.
November 2016: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/27942391/metastatic-basal-cell-carcinoma-with-amplification-of-pd-l1-exceptional-response-to-anti-pd1-therapy
#6
Sadakatsu Ikeda, Aaron M Goodman, Philip R Cohen, Taylor J Jensen, Christopher K Ellison, Garrett Frampton, Vincent Miller, Sandip P Patel, Razelle Kurzrock
Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA)...
2016: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/27928965/targeting-the-hedgehog-pathway-for-locally-advanced-and-metastatic-basal-cell-carcinoma
#7
Vivian T Yin, Bita Esmaeli
Basal cell caricnoma (BCC), the most common periocular magliancy, is treated with complete surgical excision. However, in patients not amenable to surgery or when surgical resection means loss of vital organs or disfiguring procedures due to locally advanced or metastatic disease, targeting the hedgehog pathway offers a novel treatment approach for such patients. Mutation in PTCH1 and SMO has been identified in patients with basal cell nevoid syndrome as well as in patients with sporadic BCC. Inhibition of SMO by vismodegib or sonidegib, the two sonic hedgehog inhibitor drugs approved by the Food and Drug Administration in the United States, has shown overall response rate for locally advanced and metastatic BCC around 50%...
2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/27875522/hedgehog-inhibition-enhances-efficacy-of-radiation-and-cisplatin-in-orthotopic-cervical-cancer-xenografts
#8
Naz Chaudary, Melania Pintilie, David Hedley, Richard P Hill, Michael Milosevic, Helen Mackay
BACKGROUND: The Hedgehog (Hh) pathway is upregulated in cervical cancer and associated with poor outcome. We explored the effects of Hh pathway inhibition in combination with RTCT in a patient derived orthotopic cervical cancer xenograft model (OCICx). METHODS: 5E1, a monoclonal antibody for SHH, or Sonidegib (LDE225), a clinical SMO inhibitor (Novartis) were added to RTCT. We investigated tumour growth delay, metastasis and GI toxicity using orthotopic cervical cancer xenografts models...
January 3, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/27810591/design-synthesis-and-biological-evaluation-of-structurally-modified-isoindolinone-and-quinazolinone-derivatives-as-hedgehog-pathway-inhibitors
#9
Deepak Bhattarai, Joo Hyun Jung, Seunghyeon Han, Hankyu Lee, Soo Jin Oh, Hyuk Wan Ko, Kyeong Lee
The Hedgehog (Hh) signaling pathway is associated with diverse aspects of cellular events, such as cell migration, proliferation, and differentiation throughout embryonic development and tissue patterning. An abnormal Hh signaling pathway is linked to numerous human cancers, including basal cell carcinoma (BCC), medulloblastoma (MB), lung cancer, prostate cancer, and ovarian cancer, and it is therefore a promising target in cancer therapy. Using a structure-hopping approach, we designed new Hh signaling pathway inhibitors with isoindolinone or quinazolinone moieties, which were synthesized and biologically evaluated using an 8xGli-luciferase (Gli-Luc) reporter assay in NIH3T3 cells...
January 5, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27729673/gefitinib-and-sonidegib
#10
EDITORIAL
Corey J Medler, J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
November 2015: Hospital Pharmacy
https://www.readbyqxmd.com/read/27695345/sonidegib-a-novel-smoothened-inhibitor-for-the-treatment-of-advanced-basal-cell-carcinoma
#11
REVIEW
Hung Q Doan, Sirunya Silapunt, Michael R Migden
Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. If left untreated, BCCs can become locally aggressive or even metastasize. Currently available treatments include local destruction, surgery, and radiation. Systemic options for advanced disease are limited. The Hedgehog (Hh) pathway is aberrantly activated in a majority of BCCs and in other cancers. Hh pathway inhibitors are targeted agents that inhibit the aberrant activation of the Hh pathway, with smoothened being a targeted component...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27663457/exposure-qt-analysis-for-sonidegib-lde225-an-oral-inhibitor-of-the-hedgehog-signaling-pathway-for-measures-of-the-qt-prolongation-potential-in-healthy-subjects-and-in-patients-with-advanced-solid-tumors
#12
Michelle Quinlan, Jocelyn Zhou, Eunju Hurh, Dalila Sellami
PURPOSE: Sonidegib prevents activation of the Hedgehog signal transduction pathway. This PK-QT analysis has been performed to test for potential prolongation of the QT/QTc interval during extended use, and to understand the exposure-QT relationship for sonidegib in patients and in healthy volunteers (HV). METHODS: A pooled analysis of the change in QT interval corrected for heart rate according to Fridericia's formula was conducted across four patient studies from a total of 341 patients (n = 211, 102, 21, and 7 from the phase II pivotal study A2201, study X2101, study X1101, and study B2209, respectively), and across four healthy volunteer studies from a total of 204 healthy volunteers (n = 146, 36, 16, and 6 from study A2114, study A1102, study A2108, and study A2110, respectively)...
December 2016: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27636236/the-safety-and-efficacy-of-sonidegib-for-the-treatment-of-locally-advanced-basal-cell-carcinoma
#13
Nicholas J Collier, Faisal R Ali, John T Lear
INTRODUCTION: Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs. AREAS COVERED: Sonidegib is an oral hedgehog pathway inhibitor with a novel structure...
October 2016: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/27565909/a-phase-i-trial-of-the-hedgehog-inhibitor-sonidegib-lde225-in-combination-with-etoposide-and-cisplatin-for-the-initial-treatment-of-extensive-stage-small-cell-lung-cancer
#14
M Catherine Pietanza, Anya M Litvak, Anna M Varghese, Lee M Krug, Martin Fleisher, Jerrold B Teitcher, Andrei I Holodny, Cami S Sima, Kaitlin M Woo, Kenneth K Ng, Helen H Won, Michael F Berger, Mark G Kris, Charles M Rudin
OBJECTIVES: The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC. MATERIALS AND METHODS: Patients received 4-6 21-day cycles of etoposide/cisplatin with daily sonidegib...
September 2016: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/27538055/sonidegib-for-the-treatment-of-advanced-basal-cell-carcinoma
#15
REVIEW
Egle Ramelyte, Valerie C Amann, Reinhard Dummer
INTRODUCTION: Advanced and metastatic basal cell carcinomas (BCCs) are rare but still present a severe medical problem. These tumors are often disfiguring and impact the quality of life by pain or bleeding. Based on discovery of the hedgehog (Hh) signaling pathway and its role in the pathogenesis of BCCs, smoothened (SMO) inhibitors have been developed with Sonidegib being the 2nd in class. It is the only Hh pathway inhibitor investigated in a randomized trial accompanied by pharmacodynamic investigations...
October 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27511905/characterization-and-management-of-hedgehog-pathway-inhibitor-related-adverse-events-in-patients-with-advanced-basal-cell-carcinoma
#16
REVIEW
Mario E Lacouture, Brigitte Dréno, Paolo Antonio Ascierto, Reinhard Dummer, Nicole Basset-Seguin, Kate Fife, Scott Ernst, Lisa Licitra, Rogerio I Neves, Ketty Peris, Susana Puig, Jonas Sokolof, Aleksandar Sekulic, Axel Hauschild, Rainer Kunstfeld
: Abnormal activation of hedgehog pathway signaling is a key driver in the pathogenesis of basal cell carcinoma (BCC). Vismodegib, a first-in-class small-molecule inhibitor of hedgehog pathway signaling, is approved by regulatory authorities for the treatment of adults who have metastatic BCC or locally advanced BCC that has recurred after surgery, or who are not candidates for surgery and who are not candidates for radiation. A second inhibitor, sonidegib, was also recently approved for the same patient group with locally advanced BCC...
October 2016: Oncologist
https://www.readbyqxmd.com/read/27467121/phase-i-multicenter-open-label-dose-escalation-study-of-sonidegib-in-asian-patients-with-advanced-solid-tumors
#17
MULTICENTER STUDY
Hironobu Minami, Yuichi Ando, Brigette Buig Yue Ma, Jih- Hsiang Lee, Hiroyuki Momota, Yutaka Fujiwara, Leung Li, Koichi Fukino, Koji Ito, Takeshi Tajima, Asuka Mori, Chia-Chi Lin
Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan...
October 2016: Cancer Science
https://www.readbyqxmd.com/read/27376162/sonidegib-phosphate-new-approval-for-basal-cell-carcinoma
#18
R Tibes
Basal cell carcinoma (BCC), although mostly locally confined, is the most common cancer. Most BCCs harbor inactivating mutations in the membrane receptor/gene Ptch, thereby activating the Hedgehog signaling pathway (Hh) via the essential signaling molecule Smoothened (SMO). Novel small-molecule inhibitors or antagonists of SMO have shown excellent response rates in patients with locally advanced, unresectable and metastatic BCC in roughly 35-60% of patients, with disease control rates and clinical benefit being even higher...
May 2016: Drugs of Today
https://www.readbyqxmd.com/read/27277189/effect-of-esomeprazole-a-proton-pump-inhibitor-on-the-pharmacokinetics-of-sonidegib-in-healthy-volunteers
#19
Jocelyn Zhou, Michelle Quinlan, Kelli Glenn, Hildegard Boss, Franck Picard, Henry Castro, Dalila Sellami
AIMS: This study aimed to evaluate the impact of esomeprazole on the pharmacokinetics of sonidegib. METHODS: This Phase I study evaluated the impact of the proton pump inhibitor (PPI) esomeprazole on the oral absorption and pharmacokinetics (PKs) of a single dose of sonidegib under fasted conditions. A total of 42 healthy subjects were enrolled to receive either sonidegib alone (200 mg single dose) or sonidegib in combination with esomeprazole (40 mg pre-treatment 5 days and combination were given on day 6)...
October 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27189494/sonidegib-for-the-treatment-of-advanced-basal-cell-carcinoma-a-comprehensive-review-of-sonidegib-and-the-bolt-trial-with-12-month-update
#20
Leon Chen, Sirunya Silapunt, Michael R Migden
The Hedgehog inhibitors are promising alternative for patients with advanced basal cell carcinoma that are not amenable to radiotherapy or surgery. Sonidegib, also known as LDE225, is an orally available SMO antagonist that was recently approved by the US FDA for the treatment of patients with locally advanced basal cell carcinoma. This article will provide an overview of the pharmacology and pharmacokinetics of sonidegib and in-depth analysis of the BOLT trial with additional data from the 12-month update...
September 2016: Future Oncology
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