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Anne Lynn S Chang - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of Vismodegib in patients aged 65 years with advanced basal cell carcinoma
Oncotarget, 2016Co-Authors: Anne Lynn S Chang, Sarah T Arron, James A Solomon, Edward Mckenna, Bann Mo Day, Karl D Lewis, Michael R Migden, Simon Yoo, Aleksandar SekulicAbstract:Because many patients with unresectable basal cell carcinoma (BCC) are aged ≥65 years, this study explores the efficacy and safety of Vismodegib in these patients with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC) in the ERIVANCE BCC trial and the expanded access study (EAS).We compared patients aged ≥65 years to patients aged <65 years taking Vismodegib 150 mg/day, using descriptive statistics for response and safety. Patients aged ≥65 years (laBCC/mBCC) were enrolled in ERIVANCE BCC (33/14) and EAS (27/26). Investigator-assessed best overall response rate in patients ≥65 and <65 years was 46.7%/35.7% and 72.7%/52.6% (laBCC/mBCC), respectively, in ERIVANCE BCC and 45.8%/33.3% and 46.9%/28.6%, respectively, in EAS. These differences were not clinically meaningful. Safety was similar in both groups, although those aged ≥65 years had a higher percentage of grade 3-5 adverse events than those aged <65 years. Vismodegib demonstrated similar clinical activity and adverse events regardless of age.
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safety and efficacy of Vismodegib in patients with basal cell carcinoma nevus syndrome pooled analysis of two trials
Orphanet Journal of Rare Diseases, 2016Co-Authors: Anne Lynn S Chang, Sarah T Arron, James A Solomon, Edward Mckenna, Bann Mo Day, Michael R Migden, Simon S Yoo, Aleksandar SekulicAbstract:Background Aberrant activation of the Hedgehog (Hh) pathway is a key driver in the pathogenesis of basal cell carcinomas (BCCs), including patients with BCC nevus syndrome (BCCNS). It is unclear whether BCCs arising in patients with BCCNS respond differently to Vismodegib than in patients without BCCNS. We examined the best overall response rate (BORR) and adverse events (AEs) of Vismodegib in patients with advanced BCC (aBCC) with and without BCCNS.
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increased risk of cutaneous squamous cell carcinoma after Vismodegib therapy for basal cell carcinoma
JAMA Dermatology, 2016Co-Authors: Julia Chang, Shalini V Mohan, Solomon Henry, Douglas J Wood, Anne Lynn S ChangAbstract:Importance Smoothened inhibitors (SIs) are a new type of targeted therapy for advanced basal cell carcinoma (BCC), and their long-term effects, such as increased risk of subsequent malignancy, are still being explored. Objective To evaluate the risk of developing a non-BCC malignancy after SI exposure in patients with BCC. Design, Setting, and Participants A case-control study at Stanford Medical Center, an academic hospital. Participants were higher-risk patients with BCC diagnosed from January 1, 1998, to December 31, 2014. The dates of the analysis were January 1 to November 1, 2015. Exposures The exposed participants (cases) comprised patients who had confirmed prior Vismodegib treatment, and the nonexposed participants (controls) comprised patients who had never received any SI. Because Vismodegib was the first approved SI, only patients exposed to this SI were included. Main Outcomes and Measures Hazard ratio for non-BCC malignancies after Vismodegib exposure, adjusting for covariates. Results The study cohort comprised 180 participants. Their mean (SD) age at BCC diagnosis was 56 (16) years, and 68.9% (n = 124) were male. Fifty-five cases were compared with 125 controls, accounting for age, sex, prior radiation therapy or cisplatin treatment, Charlson Comorbidity Index, clinical follow-up time, immunosuppression, and basal cell nevus syndrome status. Patients exposed to Vismodegib had a hazard ratio of 6.37 (95% CI, 3.39-11.96; P P Conclusions and Relevance Increased risk for cutaneous squamous cell carcinomas after Vismodegib therapy highlights the importance of continued skin surveillance after initiation of this therapy.
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concurrent Vismodegib and radiotherapy for recurrent advanced basal cell carcinoma
JAMA Dermatology, 2015Co-Authors: Erqi L Pollom, Anne Lynn S Chang, Timothy T Bui, Dimitrios A Colevas, Wendy HaraAbstract:Importance Vismodegib is a targeted agent recently approved for treating patients who develop recurrent or locally advanced basal cell carcinoma (BCC), and will inevitably be integrated into existing therapy for advanced BCC as it becomes increasingly used. Improved understanding of how Vismodegib interacts with other treatment modalities, including radiotherapy, would help optimize multidisciplinary therapy and clinical outcomes. Observations We report 2 cases of recurrent, advanced BCC treated from April 1, 2012, through October 31, 2014, with concurrent radiotherapy and Vismodegib. Concurrent treatment appeared to be well tolerated and efficacious, with both patients having no evidence of progressive disease at last follow-up. Conclusions and Relevance We found that the combination of Vismodegib and radiotherapy is feasible for patients with recurrent or locally advanced BCC and that combined use of currently available therapies for advanced BCC warrants further prospective study.
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an investigator initiated open label clinical trial of Vismodegib as a neoadjuvant to surgery for high risk basal cell carcinoma
Journal of The American Academy of Dermatology, 2014Co-Authors: Mina S Ally, Anthony E Oro, Sumaira Z Aasi, Ashley Wysong, C Teng, Eric M Anderson, I Baileyhealy, Jinah Kim, Anne Lynn S ChangAbstract:Background Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis. Objective We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant Vismodegib. Methods This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-Vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability. Results Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4 ± 2 months of Vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of Vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, Vismodegib reduced the surgical defect area by 27% (95% confidence interval –45.7% to –7.9%; P = .006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery. Limitations Short follow-up time and no placebo control are limitations. Conclusion Neoadjuvant Vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.
Brigitte Dréno - One of the best experts on this subject based on the ideXlab platform.
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key clinical adverse events in patients with advanced basal cell carcinoma treated with sonidegib or Vismodegib a post hoc analysis
Dermatologic Therapy, 2021Co-Authors: Ralf Gutzmer, Brigitte Dréno, Carmen Loquai, Caroline Robert, Alexander Guminski, Karl D Lewis, Ramon Arntz, Serena Martelli, Nicholas SquittieriAbstract:Introduction Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the sonidegib phase 2 BOLT study and the expanded-access, open-label Vismodegib study. Methods This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received sonidegib 200 mg once daily (QD) and patients from the Vismodegib study who received Vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for sonidegib and 28-day cycles for Vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Results Over 18 treatment cycles, the most common all-grade AEs for sonidegib and Vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than Vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. Conclusion This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with sonidegib compared with Vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.
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sonidegib and Vismodegib in the treatment of patients with locally advanced basal cell carcinoma a joint expert opinion
Journal of The European Academy of Dermatology and Venereology, 2020Co-Authors: R Dummer, Brigitte Dréno, N Bassetseguin, Ralf Gutzmer, Axel Hauschild, P A Ascierto, Claus Garbe, R Krattinger, John T Lear, J MalvehyAbstract:Sonidegib and Vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, Vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head-to-head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (Vismodegib), and these differences complicate evidence-based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and Vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single-arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double-blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST-like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for Vismodegib was 47.6% (95% CI: 35.5-60.6) at 21-month follow-up using RECIST. After adjusting with RECIST-like criteria, the ORR for sonidegib according to central review at 18-month follow-up was 60.6% (95% CI: 47.8-72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and Vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half-life. Further studies are needed to understand how these differences may impact clinical practice.
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two intermittent Vismodegib dosing regimens in patients with multiple basal cell carcinomas mikie a randomised regimen controlled double blind phase 2 trial
Lancet Oncology, 2017Co-Authors: Brigitte Dréno, Axel Hauschild, Scott W Fosko, Rainer Kunstfeld, David Zloty, Bruno Labeille, Jean Jacques Grob, Susana Puig, Frank GilbergAbstract:Summary Background Vismodegib, a first-in-class Hedgehog-pathway inhibitor, is approved for use in adults with advanced basal-cell carcinoma. Patients with multiple basal-cell carcinomas, including those with basal-cell nevus (Gorlin) syndrome, need extended treatment. We assessed the safety and activity of two long-term intermittent Vismodegib dosing regimens in patients with multiple basal-cell carcinomas. Methods In this randomised, regimen-controlled, double-blind, phase 2 trial, we enrolled adult patients with multiple basal-cell carcinomas, including those with basal-cell nevus syndrome, who had one or more histopathologically confirmed and at least six clinically evident basal-cell carcinomas. From a centralised randomisation schedule accessed via an interactive voice or web-based response system, patients were randomly assigned (1:1) to treatment group A (150 mg oral Vismodegib per day for 12 weeks, then three rounds of 8 weeks of placebo daily followed by 12 weeks of 150 mg Vismodegib daily) or treatment group B (150 mg oral Vismodegib per day for 24 weeks, then three rounds of 8 weeks of placebo daily followed by 8 weeks of 150 mg Vismodegib daily). Treatment assignment was stratified by diagnosis of basal-cell nevus syndrome, geographical region, and immunosuppression status. The primary endpoint was percentage reduction from baseline in the number of clinically evident basal-cell carcinomas at week 73. The primary analysis was by intention to treat. The safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01815840, and the study is ongoing. Findings Between April 30, 2013, and April 9, 2014, 229 patients were randomly assigned treatment, 116 in treatment group A and 113 in treatment group B. The mean number of basal-cell carcinoma lesions at week 73 was reduced from baseline by 62·7% (95% CI 53·0–72·3) in treatment group A and 54·0% (43·6–64·4) in treatment group B. 216 (95%) of 227 patients included in the safety analysis had at least one treatment-emergent adverse event deemed to be related to study treatment (107 [94%] of 114 in treatment group A and 109 [97%] of 113 in treatment group B). The most common grade 3 or worse treatment-related adverse events were muscle spasms (four [4%] patients in treatment group A vs 12 [11%] in treatment group B), increased blood creatine phosphokinase (one [1%] vs four [4%]), and hypophosphataemia (zero vs three [3%]). Serious treatment-emergent events were noted in 22 (19%) patients in treatment group A and 19 (17%) patients in treatment group B. Four (2%) patients died from adverse events; one (pulmonary embolism in treatment group A) was possibly related to treatment. Interpretation Both intermittent dosing schedules of Vismodegib seemed to show good activity in long-term regimens in patients with multiple basal-cell carcinomas. Further study is warranted. Funding F Hoffmann-La Roche.
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dysgeusia and weight loss under treatment with Vismodegib benefit of nutritional management
Supportive Care in Cancer, 2016Co-Authors: Marie Le Moigne, M Saintjean, A Jirka, L Peuvrel, A Brocard, Abdolali Khammari, Aurélie Gaultier, Gaëlle Quéreux, Dominique Darmaun, Brigitte DrénoAbstract:Purpose Whereas Vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of Vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management.
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dysgeusia and weight loss under treatment with Vismodegib benefit of nutritional management
Supportive Care in Cancer, 2016Co-Authors: Marie Le Moigne, M Saintjean, A Jirka, L Peuvrel, A Brocard, Abdolali Khammari, Aurélie Gaultier, Gaëlle Quéreux, Dominique Darmaun, Brigitte DrénoAbstract:Whereas Vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of Vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management. This prospective study included all patients who started Vismodegib between October 2011 and May 2013 at Nantes University Hospital. Prior to July 2012, patients treated with Vismodegib had not received any specific nutritional management (Historical cohort). Body weight and presence of dysgeusia were recorded monthly. Patients treated after July 2012 (Nutrition cohort) were evaluated by a physician of the Nutrition Support Unit and received dietary counseling at Vismodegib initiation. A standardized nutritional management protocol was initiated in case of significant weight loss. Forty-five patients (21 and 24 in the Nutrition and Historical cohort, respectively) were enrolled. In the Nutrition cohort, five patients (24 %) were undernourished at Vismodegib initiation, and the 6-month cumulative incidence of dysgeusia was 71 %. Eight patients (38 %) and 13 patients (54 %) had a weight loss greater than 5 % in the Nutrition and Historical cohort, respectively (p = 0.3727). The results of this pilot study suggest the benefit of early nutritional screening. The potential benefit of nutritional support in this setting warrants further investigation.
Jean Y Tang - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the hedgehog pathway in patients with basal cell nevus syndrome final results from the multicentre randomised double blind placebo controlled phase 2 trial
Lancet Oncology, 2016Co-Authors: Mina S Ally, Jean Y Tang, Julian Mackaywiggan, Michelle Aszterbaum, Joselyn Lindgren, Anita M Chanana, Grace Ulerio, Melika RezaeeAbstract:Summary Background Aberrant hedgehog signalling underlies the development of basal-cell carcinomas. We previously reported the interim analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial in patients with the basal-cell nevus (Gorlin) syndrome indicating that the smoothened inhibitor Vismodegib reduces basal-cell carcinoma tumour burden and prevents new basal-cell carcinoma growth in patients with basal-cell nevus syndrome. We report the final results of this 36 month trial. Methods In our multicentre, randomised, double-blind, placebo-controlled, phase 2 trial we enrolled patients aged 35–75 years with basal-cell nevus syndrome with at least ten surgically eligible basal-cell carcinomas at the Children's Hospital Oakland, Columbia University outpatient dermatology clinic (NY, USA) and a private practice outpatient dermatology office in Newport Beach (CA, USA). Patients were assigned to Vismodegib or placebo (2:1) according to a randomisation sequence generated by computer code. The primary endpoint of the trial of 41 patients was to compare the effect of oral Vismodegib (150 mg/day) versus placebo on the incidence of new surgically eligible basal-cell carcinomas after 3 months of treatment. In the subsequent, open-label phase (n=37) patients continued Vismodegib at two sites for as long as month 36 (n=25) and at the third site were monitored up to month 36 (n=12). Additional endpoints for this phase were: whether continuous versus interrupted dosing differentially affected tumour burden; time to reach various levels of reduction in tumour burden; reduction in tumour size in patients who took less than 50% of the expected number of Vismodegib tablets; reduction in the number of surgical excisions required per year before, during, and after treatment; and the effect of Vismodegib on hedgehog target gene expression. We monitored patients at visits every 3 months for up to 36 months. The primary endpoint was analysed on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00957229. Findings Between Sept 22, 2009, and Jan 24, 2011, 41 patients were monitored for a median of 36 months (IQR 36–36). Patients treated with Vismodegib (n=26) had a mean reduced rate of new surgically eligible basal-cell carcinomas compared with patients randomly assigned to placebo (n=15; two [SD 0·12] new surgically eligible basal-cell carcinomas per patient per year vs 34 [1·32] new surgically eligible basal-cell carcinomas per patient per year, p vs 30·0 [7·8] new surgically eligible basal-cell carcinomas per patient per year, p vs 1·7 [1·8] new surgically eligible basal-cell carcinomas per patient per year, p Interpretation Vismodegib reduces basal-cell carcinoma tumour burden in patients with basal-cell nevus syndrome. Adverse events associated with Vismodegib frequently led to interruption of treatment, which is followed by basal-cell carcinoma recurrence. Funding Genentech investigator-initiated trial funding, Clinical and Translational Science Award from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, Damon Runyon Cancer Research Foundation Clinical Investigator Award, Swim across America Foundation, and Michael J Rainen Family Foundation.
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the use of Vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome
JAMA Dermatology, 2014Co-Authors: Mina S Ally, Jean Y Tang, Julian Mackaywiggan, Joselyn Lindgren, Anita M Chanana, Timmy Joseph, Bobbye J Thompson, Maria Acosta Raphael, Grace Ulerio, David R BickersAbstract:Importance Keratocystic odontogenic tumors (KCOTs) of the jaw affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog signaling pathway. Observations We examined the effect of Vismodegib (an oral Hedgehog pathway inhibitor) on KCOT size in patients with BCNS enrolled in a clinical trial testing Vismodegib for basal cell carcinoma prevention (NCT00957229), using pretreatment and posttreatment magnetic resonance imaging. Four men and 2 women had pretreatment KCOTs (mean longest diameter, 2.0 cm; range, 0.7-3.3 cm), occurring primarily in the mandible. Patients were treated with Vismodegib, 150 mg/d, for a mean (SD) of 18.0 (4.8) months (range, 11-24 months). Four patients experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all patients by 1.0 cm (95% CI, 0.03-1.94;P = .02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development. Conclusions and Relevance Vismodegib shrinks some KCOTs in patients with BCNS and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.
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abstract 5644 itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to Vismodegib
Cancer Research, 2013Co-Authors: Blake T Aftab, Jean Y Tang, James Kim, Emily M King, Daniel H Kim, Jynho Kim, Ervin H Epstein, Philip A Beachy, Charles M RudinAbstract:Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors, most recently culminating in the FDA-approval of Vismodegib (Genentech/Roche) for the treatment of locally advanced or metastatic basal cell carcinoma. Vismodegib and other hedgehog pathway antagonists currently being evaluated in the clinical setting are small molecules that act by binding to a common site within Smoothened (SMO), a critical pathway component. Acquired mutations in SMO that map to these overlapping binding pockets compromise the potency and clinical efficacy of Vismodegib and other clinically relevant agents in this space through an apparent class effect. As a consequence there are currently no visible therapeutic options for maintaining profound on-target efficacies in patients that present with recurrent disease harboring these point mutations. We report here that itraconazole and arsenic trioxide, two FDA-approved agents recently reported to inhibit Hedgehog signaling through mechanisms distinct from that of current SMO antagonists, maintain potent inhibition of hedgehog signaling in the face of acquired SMO mutations, both as single agents and when used in combination. Using a preclinical mouse model of medulloblastoma that mimics clinical mechanisms of Vismodegib-associated acquired resistance, we demonstrate that itraconazole and arsenic trioxide inhibit pathway activation, proliferation, and tumor growth of medulloblastoma harboring SMO-D477G mutation, both in vitro and in vivo. These drugs act as effectively in syngeneic models of medulloblastoma demonstrating constitutive signaling through wild-type SMO. Combination of itraconazole and arsenic trioxide further suppress tumor growth and improves survival in an orthotopic model of Vismodegib-resistant medulloblastoma compared to either single agent alone. Furthermore, itraconazole and arsenic trioxide retain activity in all reported drug-resistant SMO mutants, including those reported in relation to NVP-LDE225 (Novartis). Taken together, these results support clinical evaluation of itraconazole and arsenic trioxide for the treatment of Hh-dependent tumors, most notably those with acquired resistance to cyclopamine-mimics. These readily available FDA-approved agents have well defined pharmacokinetic and toxicity profiles. Our data support the rapid entry of itraconazole and arsenic trioxide into clinical testing to address patient populations for which Vismodegib may not be available or is no longer efficacious. Citation Format: Blake T. Aftab, James Kim, Jean Y. Tang, Emily M. King, Daniel Kim, Jynho Kim, Ervin H. Epstein, Philip A. Beachy, Charles M. Rudin. Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to Vismodegib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5644. doi:10.1158/1538-7445.AM2013-5644
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inhibiting the hedgehog pathway in patients with the basal cell nevus syndrome
The New England Journal of Medicine, 2012Co-Authors: Jean Y Tang, Robert L Yauch, Julian Mackaywiggan, Michelle Aszterbaum, Joselyn Lindgren, Kris S Chang, Carol Coppola, Anita M Chanana, Jackleen Marji, David R BickersAbstract:Background Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. Methods We tested the anti–basal-cell carcinoma efficacy of Vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with Vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. Results In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with Vismodegib than with placebo (2 vs. 29 cases per g...
James A Solomon - One of the best experts on this subject based on the ideXlab platform.
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safety and efficacy of Vismodegib in patients aged 65 years with advanced basal cell carcinoma
Oncotarget, 2016Co-Authors: Anne Lynn S Chang, Sarah T Arron, James A Solomon, Edward Mckenna, Bann Mo Day, Karl D Lewis, Michael R Migden, Simon Yoo, Aleksandar SekulicAbstract:Because many patients with unresectable basal cell carcinoma (BCC) are aged ≥65 years, this study explores the efficacy and safety of Vismodegib in these patients with locally advanced (la) or metastatic (m) basal cell carcinoma (BCC) in the ERIVANCE BCC trial and the expanded access study (EAS).We compared patients aged ≥65 years to patients aged <65 years taking Vismodegib 150 mg/day, using descriptive statistics for response and safety. Patients aged ≥65 years (laBCC/mBCC) were enrolled in ERIVANCE BCC (33/14) and EAS (27/26). Investigator-assessed best overall response rate in patients ≥65 and <65 years was 46.7%/35.7% and 72.7%/52.6% (laBCC/mBCC), respectively, in ERIVANCE BCC and 45.8%/33.3% and 46.9%/28.6%, respectively, in EAS. These differences were not clinically meaningful. Safety was similar in both groups, although those aged ≥65 years had a higher percentage of grade 3-5 adverse events than those aged <65 years. Vismodegib demonstrated similar clinical activity and adverse events regardless of age.
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safety and efficacy of Vismodegib in patients with basal cell carcinoma nevus syndrome pooled analysis of two trials
Orphanet Journal of Rare Diseases, 2016Co-Authors: Anne Lynn S Chang, Sarah T Arron, James A Solomon, Edward Mckenna, Bann Mo Day, Michael R Migden, Simon S Yoo, Aleksandar SekulicAbstract:Background Aberrant activation of the Hedgehog (Hh) pathway is a key driver in the pathogenesis of basal cell carcinomas (BCCs), including patients with BCC nevus syndrome (BCCNS). It is unclear whether BCCs arising in patients with BCCNS respond differently to Vismodegib than in patients without BCCNS. We examined the best overall response rate (BORR) and adverse events (AEs) of Vismodegib in patients with advanced BCC (aBCC) with and without BCCNS.
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pivotal erivance basal cell carcinoma bcc study 12 month update of efficacy and safety of Vismodegib in advanced bcc
Journal of The American Academy of Dermatology, 2015Co-Authors: Aleksandar Sekulic, Sarah T Arron, James A Solomon, John D Hainsworth, Karl D Lewis, Michael R Migden, Simon Yoo, Philip FriedlanderAbstract:Background Primary analysis from the pivotal ERIVANCE BCC study resulted in approval of Vismodegib, a Hedgehog pathway inhibitor indicated for treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC) that has recurred after surgery or for patients who are not candidates for surgery or radiation. Objective An efficacy and safety analysis was conducted 12 months after primary analysis. Methods This was a multinational, multicenter, nonrandomized, 2-cohort study in patients with measurable and histologically confirmed locally advanced or metastatic BCC taking oral Vismodegib (150 mg/d). Primary outcome measure was objective response rate (complete and partial responses) assessed by independent review facility. Results After 12 months of additional follow-up, median duration of exposure to Vismodegib was 12.9 months. Objective response rate increased from 30.3% to 33.3% in patients with metastatic disease, and from 42.9% to 47.6% in patients with the locally advanced form. Median duration of response in patients with locally advanced BCC increased from 7.6 to 9.5 months. No new safety signals emerged with extended treatment duration. Limitations Limitations include low prevalence of advanced BCC and challenges of designing a study with heterogenous manifestations. Conclusion The 12-month update of the study confirms the efficacy and safety of Vismodegib in management of advanced BCC.
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expanded access study of patients with advanced basal cell carcinoma treated with the hedgehog pathway inhibitor Vismodegib
Journal of The American Academy of Dermatology, 2014Co-Authors: Anne Lynn S Chang, Leonard Harry Goldberg, James A Solomon, John D Hainsworth, Edward Mckenna, Bann Mo Day, D M Chen, Glen J WeissAbstract:Background Vismodegib, a first-in-class Hedgehog pathway inhibitor, was US Food and Drug Administration (FDA) approved for advanced basal cell carcinomas (BCCs) based on a single, nonrandomized, phase-II trial. Consequently, additional clinical data are critical to confirm the efficacy and safety of Vismodegib. Objective We sought to assess efficacy and safety of Vismodegib, while providing early drug access to patients with advanced BCC and limited treatment options. Methods This was an open-label, multicenter study in patients with advanced BCC inappropriate for radiotherapy or surgery. Patients received 150 mg Vismodegib daily until disease progression or intolerable toxicity. Tumor response was assessed via Response Evaluation Criteria in Solid Tumors version 1.0. Results A total of 119 patients with advanced BCC took Vismodegib for a median of 5.5 months. Objective responses occurred in 46.4% of locally advanced BCC and 30.8% of patients with metastatic BCC. Response was negatively associated with prior systemic therapy in patients with locally advanced BCC ( P = .002). Mean follow-up for safety was 6.5 months, with muscle spasms (70.6%), dysgeusia (70.6%), alopecia (58.0%), and diarrhea (25.2%) as the most common adverse events. Limitations Abbreviated follow-up time because of study termination upon FDA approval was a limitation. Conclusion This study provides important clinical data supporting the efficacy and safety of Vismodegib. Larger studies are underway to assess predictors of response and long-term outcomes.
Mina S Ally - One of the best experts on this subject based on the ideXlab platform.
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inhibition of the hedgehog pathway in patients with basal cell nevus syndrome final results from the multicentre randomised double blind placebo controlled phase 2 trial
Lancet Oncology, 2016Co-Authors: Mina S Ally, Jean Y Tang, Julian Mackaywiggan, Michelle Aszterbaum, Joselyn Lindgren, Anita M Chanana, Grace Ulerio, Melika RezaeeAbstract:Summary Background Aberrant hedgehog signalling underlies the development of basal-cell carcinomas. We previously reported the interim analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial in patients with the basal-cell nevus (Gorlin) syndrome indicating that the smoothened inhibitor Vismodegib reduces basal-cell carcinoma tumour burden and prevents new basal-cell carcinoma growth in patients with basal-cell nevus syndrome. We report the final results of this 36 month trial. Methods In our multicentre, randomised, double-blind, placebo-controlled, phase 2 trial we enrolled patients aged 35–75 years with basal-cell nevus syndrome with at least ten surgically eligible basal-cell carcinomas at the Children's Hospital Oakland, Columbia University outpatient dermatology clinic (NY, USA) and a private practice outpatient dermatology office in Newport Beach (CA, USA). Patients were assigned to Vismodegib or placebo (2:1) according to a randomisation sequence generated by computer code. The primary endpoint of the trial of 41 patients was to compare the effect of oral Vismodegib (150 mg/day) versus placebo on the incidence of new surgically eligible basal-cell carcinomas after 3 months of treatment. In the subsequent, open-label phase (n=37) patients continued Vismodegib at two sites for as long as month 36 (n=25) and at the third site were monitored up to month 36 (n=12). Additional endpoints for this phase were: whether continuous versus interrupted dosing differentially affected tumour burden; time to reach various levels of reduction in tumour burden; reduction in tumour size in patients who took less than 50% of the expected number of Vismodegib tablets; reduction in the number of surgical excisions required per year before, during, and after treatment; and the effect of Vismodegib on hedgehog target gene expression. We monitored patients at visits every 3 months for up to 36 months. The primary endpoint was analysed on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00957229. Findings Between Sept 22, 2009, and Jan 24, 2011, 41 patients were monitored for a median of 36 months (IQR 36–36). Patients treated with Vismodegib (n=26) had a mean reduced rate of new surgically eligible basal-cell carcinomas compared with patients randomly assigned to placebo (n=15; two [SD 0·12] new surgically eligible basal-cell carcinomas per patient per year vs 34 [1·32] new surgically eligible basal-cell carcinomas per patient per year, p vs 30·0 [7·8] new surgically eligible basal-cell carcinomas per patient per year, p vs 1·7 [1·8] new surgically eligible basal-cell carcinomas per patient per year, p Interpretation Vismodegib reduces basal-cell carcinoma tumour burden in patients with basal-cell nevus syndrome. Adverse events associated with Vismodegib frequently led to interruption of treatment, which is followed by basal-cell carcinoma recurrence. Funding Genentech investigator-initiated trial funding, Clinical and Translational Science Award from the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Cancer Institute, Damon Runyon Cancer Research Foundation Clinical Investigator Award, Swim across America Foundation, and Michael J Rainen Family Foundation.
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an investigator initiated open label clinical trial of Vismodegib as a neoadjuvant to surgery for high risk basal cell carcinoma
Journal of The American Academy of Dermatology, 2014Co-Authors: Mina S Ally, Anthony E Oro, Sumaira Z Aasi, Ashley Wysong, C Teng, Eric M Anderson, I Baileyhealy, Jinah Kim, Anne Lynn S ChangAbstract:Background Vismodegib is an oral hedgehog-pathway inhibitor approved for advanced basal cell carcinoma (BCC). Although most BCCs are amenable to surgery, excision of large tumors in aesthetically sensitive sites may compromise function or cosmesis. Objective We sought to evaluate the reduction in BCC surgical defect area after 3 to 6 months of neoadjuvant Vismodegib. Methods This was an open-label, single-arm intervention trial with a primary outcome of change in target-tumor surgical defect area pre- and post-Vismodegib (150 mg/d). Secondary outcomes were change in tumor area and tolerability. Results Eleven of 15 enrolled patients, aged 39 to 100 years, completed the trial. Thirteen target tumors were excised after a mean of 4 ± 2 months of Vismodegib. In all, 29% (4 of 14 patients) could not complete more than 3 months because of Vismodegib-related side effects. The mean baseline target-tumor diameter was 3.2 cm, and 10 of 13 tumors occurred on the face. Overall, Vismodegib reduced the surgical defect area by 27% (95% confidence interval –45.7% to –7.9%; P = .006) from baseline. Vismodegib was not effective in patients who received less than 3 months. Over a mean follow-up of 11.5 (range 4-21) months for all tumors, only 1 tumor recurred at 17 months post-Mohs micrographic surgery. Limitations Short follow-up time and no placebo control are limitations. Conclusion Neoadjuvant Vismodegib appears to reduce surgical defect area when taken for 3 months or longer for nonrecurrent BCCs in functionally sensitive locations. Further studies with larger sample sizes and long-term follow-up are warranted.
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the use of Vismodegib to shrink keratocystic odontogenic tumors in patients with basal cell nevus syndrome
JAMA Dermatology, 2014Co-Authors: Mina S Ally, Jean Y Tang, Julian Mackaywiggan, Joselyn Lindgren, Anita M Chanana, Timmy Joseph, Bobbye J Thompson, Maria Acosta Raphael, Grace Ulerio, David R BickersAbstract:Importance Keratocystic odontogenic tumors (KCOTs) of the jaw affect more than 65% of patients with basal cell nevus syndrome (BCNS). Surgery frequently causes facial disfigurement and is not always curative. Most BCNS-related and some sporadic KCOTs have malignant activation of the Hedgehog signaling pathway. Observations We examined the effect of Vismodegib (an oral Hedgehog pathway inhibitor) on KCOT size in patients with BCNS enrolled in a clinical trial testing Vismodegib for basal cell carcinoma prevention (NCT00957229), using pretreatment and posttreatment magnetic resonance imaging. Four men and 2 women had pretreatment KCOTs (mean longest diameter, 2.0 cm; range, 0.7-3.3 cm), occurring primarily in the mandible. Patients were treated with Vismodegib, 150 mg/d, for a mean (SD) of 18.0 (4.8) months (range, 11-24 months). Four patients experienced a size reduction and 2 had no change. Vismodegib reduced the mean longest diameter of KCOTs in all patients by 1.0 cm (95% CI, 0.03-1.94;P = .02) or 50% from baseline. We observed no enlargement of existing KCOTs or new KCOT development. Conclusions and Relevance Vismodegib shrinks some KCOTs in patients with BCNS and may offer an alternative to surgical therapy. These effects were maintained for at least 9 months after drug cessation in 1 patient. Further studies assessing long-term efficacy and optimal maintenance regimens should be performed.
