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In most Wuchereria bancrofti and Brugia malayi infections, the microfilaria are found in the blood in greatest number between 10 p.m. and 2 a.m., indicating that chronotherapy may be beneficial in treating such infections. This study reports the influence of time of administration on the pharmacokinetics of diethylcarbamazine (DEC) in healthy volunteers. The study was conducted in 12 healthy volunteers by administering a 150 mg single oral dose of diethylcarbamazine citrate at 0600 or 1800 h in a balanced crossover design with the approval of an institutional ethics committee. The subjects fasted for about 10 hours before and 3 hours after drug treatment. Blood samples were collected at predetermined time intervals, and the drug content in the serum was estimated using HPLC with an electrochemical detector. Pharmacokinetic analysis was performed using noncompartmental methods employing WinNonlin (version 3.1), and the means of various pharmacokinetic parameters were compared for any dosing time-related changes using a paired t-test at a probability level of 95%. The mean +/- SD values of pharmacokinetic parameters of DEC for the treatments at 0600 versus 1800 h were as follows: Cmax, 500+/-227 versus 637+/-401 ng/ml; tmax, 2.3+/-0.7 versus 2.7+/-1 h; Ka, 2.23+/-0.72 versus 1.96+/-0.97 h(-1); t1/2, 14.6+/-6.7 versus 11.4+/-4.9 h; AUC0-t, 5,334+/-1,853 versus 6,901+/-4,203 ng x h/ml; AUC0-infinity, 5,840+/-1,922 versus 7,220+/-4,205 ng x h/ml; CL/F, 36,058+/-19,011 versus 32,189+/-25,293 ml/h/kg; Vd/F, 570+/-225 versus 533+/-447 L; and MRT 17.7+/-5.9 versus 15.3+/-5.2 h. None of the parameters was significantly changed (p > 0.05) as a function of time of administration. [ABSTRACT FROM AUTHOR]

The landscape of oncology drug development has witnessed remarkable advancements over the last few decades, significantly improving clinical outcomes and quality of life for patients with cancer. Project Optimus, introduced by the U.S. Food and Drug Administration, stands as a groundbreaking endeavor to reform dose selection of oncology drugs, presenting both opportunities and challenges for the field. To address complex dose optimization challenges, an Oncology Dose Optimization IQ Working Group was created to characterize current practices, provide recommendations for improvement, develop a clinical toolkit, and engage Health Authorities. Historically, dose selection for cytotoxic chemotherapeutics has focused on the maximum tolerated dose, a paradigm that is less relevant for targeted therapies and new treatment modalities. A survey conducted by this group gathered insights from member companies regarding industry practices in oncology dose optimization. Given oncology drug development is a complex effort with multidimensional optimization and high failure rates due to lack of clinically relevant efficacy, this Working Group advocates for a case-by-case approach to inform the timing, specific quantitative targets, and strategies for dose optimization, depending on factors such as disease characteristics, patient population, mechanism of action, including associated resistance mechanisms, and therapeutic index. This white paper highlights the evolving nature of oncology dose optimization, the impact of Project Optimus, and the need for a tailored and evidence-based approach to optimize oncology drug dosing regimens effectively., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Enzalutamide is an oral androgen receptor signaling inhibitor utilized in the treatment of men with prostate cancer. It is a moderate inducer of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and a strong inducer of CYP3A4. It was also shown to be a mild inhibitor of the efflux transporter P-glycoprotein in patients with prostate cancer. Enzalutamide is primarily metabolized by CYP3A4 and CYP2C8. The risk of enzalutamide drug interactions arises primarily when it is coadministered with other drugs that interact with these CYPs, including CYP3A4. In this review, we begin by providing an overview of enzalutamide including its dosing, use in special populations, pharmacokinetics, changes to its prescribing information, and potential for interaction with coadministered drugs. Enzalutamide interactions with drugs from a wide range of medication classes commonly prescribed to patients with prostate cancer are described, including oral androgen deprivation therapy, agents used to treat a range of cardiovascular diseases, antidiabetic drugs, antidepressants, anti-seizure medications, common urology medications, analgesics, proton pump inhibitors, immunosuppressants, and antigout drugs. Enzalutamide interactions with common vitamins and supplements are also briefly discussed. This review provides a resource for healthcare practitioners and patients that will help provide a basis for the understanding and management of enzalutamide drug-drug interactions to inform decision making, improve patient safety, and optimize drug efficacy., (© 2024. Pfizer Inc.)

South Asians (SAs) are among the fastest growing populations in the USA. Colorism - the system of inequality that views lighter skin as more advantageous in society - is prevalent in SA culture. This study evaluates motivations of sun protection use, attitudes of colorism, and skin lightening (SL) practices among SA Americans. Two-hundred-four participants recruited from online forums and ResearchMatch completed a questionnaire. Over half (111/204) reported use of sunscreen, of which 39.6% (44/111) reported daily or frequent use. Nearly half of respondents (98/204) believed that they are not at risk for skin cancer, with 37.7% (77/204) reporting minimal knowledge of skin cancers and only 4.9% (10/204) receiving a total body skin exam. One-third (65/204) reported being more concerned about prevention of tanning than skin cancer. In total, 38.2% (78/204) of respondents reported use of SL products, of which 33.3% (26/78) reported hydroquinone-based products and 26.9% (21/78) were unaware of the ingredients in their SL product. Only 16.7% (13/78) consulted a medical professional before using SL products. While many agreed that SA culture places high importance on light skin with regards to beauty standards (82.3%, 168/204), less noted that lighter skin is more beautiful (37.0%, 74/204). SL users more strongly agreed with colorism attitudes than non-users. Limitations include a small sample size with younger participants. Dermatologists must be mindful of the cultural motivations for skin tone preferences, sun protection habits, and SL behaviors and provide culturally relevant education on sunscreen, skin cancer, and risks of SL for the SA community., (© 2024. W. Montague Cobb-NMA Health Institute.)

Vitiligo is characterized by skin depigmentation, which can lead to profound psychological effects and decreased quality of life, especially for those with skin of color. Individuals with vitiligo may utilize complementary and alternative medicine (CAM) due to limited treatment options with varying efficacy.An anonymous, multiple-choice, cross-sectional questionnaire was distributed to participants with vitiligo in the United States through online forums. Data on disease characteristics, use of prescription medications, use of topical therapies, supplements, and diets, and perceptions of CAM were collected.In total, 625 respondents completed the survey. Overall, 32.5% of participants (203/625) have tried CAM. Commonly reported CAM include supplements of vitamin D (57.7%, 116/203), vitamin B12 (46.3%, 93/203), vitamin C (27.4%, 55/203), topical Nigella sativa oil (26.4%, 53/203), oral omega-3 fatty acids (24.9%, 50/203), folic acid (22.9%, 46/203), and vitamin E (22.9%, 46/203). Frequently cited reasons for CAM use include desire to try "new" (40.4%, 82/203) or "more natural" (26.6%, 54/203) therapies, "frustration with conventional medicine" (24.6%, 50/203), and fear of "adverse side effects of conventional medicine" (23.6%, 48/203). Non-White participants were more likely than their White counterparts to report CAM use and have more positive perceptions of CAM therapies. Less than half (43.3%, 88/203) of CAM users reported that they disclosed their use of CAM with their physician.Dermatologists should be mindful of CAM and ask patients about their use. Further investigation of the role of CAM as adjuvant therapy for vitiligo is warranted to better advise patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n = 748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity., (© 2024. The Author(s).)

Background: Smoking cigarettes can have deleterious effects on hidradenitis suppurativa (HS) disease severity, but little is known about the relationship between vaping electronic nicotine delivery systems (ENDS) and HS severity., Objectives: The aim of this study was to determine the rate of ENDS use in those with HS and the perceptions of HS participants and dermatologists on the relationship between vaping and HS., Methods: Two separate cross-sectional, anonymous, multiple-choice questionnaires were administered. One questionnaire was distributed to those with HS recruited via online HS-related forums. Inclusion criteria were diagnosis of HS, age 18 and over, and residence in USA. The other questionnaire was distributed to currently practicing, board-certified dermatologists recruited via an email listserv., Results: Overall, 302 participants with HS completed the questionnaire. Fifty-six participants (18.5%) smoke cigarettes and 41 participants (13.6%) vape ENDS. One-third of ENDS users (14/41) switched from cigarettes to ENDS after learning of their HS diagnosis, of which 78.6% (11/14) believed that the switch decreased the severity and/or frequency of their HS flares. Fifty dermatologists completed the questionnaire, of whom over half (54%, 27/50) were unsure about the relationship between vaping and HS severity., Conclusions: As cigarette smoking and HS are closely linked, the use of ENDS in HS warrants further study., Competing Interests: Julia Riley has served as an advisory board member for Novartis Pharmaceuticals, which is not relevant to this study. Sneha Poondru and Kourtney Scott have no conflicts of interest to declare., (© 2023 S. Karger AG, Basel.)

More than half of the population will belong to a minority group by the year 2044. Further research needs to be done into the perceptions of those with skin of color regarding their dermatologic care. This study assessed the perceptions and preferences of communities of color regarding the care of their skin and hair. An anonymous, cross-sectional, multiple-choice, online survey was administered from August through October 2021. Participants were recruited using ResearchMatch, a national volunteer health registry supported by the US National Institutes of Health. Eligibility criteria included being 18 years or older, identifying with at least one racial/ethnic group within skin of color, and living in the United States. A total of 547 participants completed the survey, 463 women (84.6%) and 84 men (15.4%) with a mean (standard deviation) age of 44.1 (15.4) years. 301 self-identified as Black (55.0%), 84 Latinx (15.4%), 90 Asian (16.5%), and 72 Multiracial (13.2%). Participants did not feel like dermatologists are trained to treat skin of color (69.5%, n = 380) or ethnic hair (75.1%, n = 411). Participants believed that all dermatologists should have training in skin of color (92.3%, n = 505) and would be more likely to see a dermatologist if they had skin of color training (80.1%, n = 438) as they felt dermatologists who have skin of color training are better equipped to treat their conditions (67.1%, n = 367). Participants were more comfortable receiving treatment at clinics that specialize in skin of color (75.1%, n = 411), but overwhelmingly had never heard of skin of color clinics (94.1%, n = 515). Participants were willing to contribute non-identifiable photos (96.3%, n = 527) and stories about skin and hair diseases (94.1%, n = 515) to create skin of color resources to train dermatologists. Overall, perceptions of communities of color on dermatologic care need to be improved. Greater skin of color training including all races/ethnicities and skin tones is imperative, and greater visibility and resources should also be put into skin of color clinics and formal skin of color research., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in C max for apixaban and a 45% decrease in AUC and a 25% decrease in C max for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety., (© 2023. The Author(s).)

Competing Interests: Conflicts of interest None disclosed.

Wound care management and costs in hidradenitis suppurativa (HS) are unmet needs. This study explored patient perspectives of at-home management of acute flares of HS and chronic daily wounds, their satisfaction with current wound care methods, and the financial burden of wound care supplies. An anonymous, multiple choice, cross-sectional questionnaire was distributed among online HS-related forums between August and October 2022. Participants 18 years or older with a diagnosis of HS who live in the United States were included. In total, 302 participants completed the questionnaire: 168 White (55.6%), 76 Black (25.2%), 33 Hispanic (10.9%), 7 Asian (2.3%), 12 multiracial (4.0%), and 6 other (2.0%). Dressings commonly reported included gauze, panty liners or menstrual pads, tissues or toilet paper, antiseptic dressing, abdominal pads, and adhesive bandages. Commonly reported topical remedies for acute flares of HS included warm compresses, Epsom salt baths, Vicks VapoRub, tea tree oil, witch hazel, and bleach baths. One-third of participants (n = 102) reported dissatisfaction with current wound care methods, and 48.8% (n = 103) believed that their dermatologist does not meet their wound care needs. Nearly half (n = 135) reported being unable to afford the type and quantity of dressings and wound care supplies they would ideally want. Black participants were more likely than White participants to report being unable to afford their dressings and find the cost as very burdensome. Overall, dermatologists must improve patient education of wound care methods in HS and address the financial burden of wound care supplies by exploring insurance-funded options., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: J.M.R. has served on the advisory board for Novartis Pharmaceuticals, which is unrelated to this study. The remaining authors have no conflicts of interest to disclose.

Skin lightening (SL) is a practice involving the use of chemicals to lighten the skin that is more common among skin of color (SOC) individuals, particularly women, and can lead to adverse health consequences., Objective: In this study, we examine SL habits, including both general lightening and lightening for the treatment of a skin condition, among SOC individuals in the United States and the role of colorism in motivating these behaviors., Methods: A cross-sectional survey was administered to SOC individuals through ResearchMatch, an online national health registry. Demographics, rates of SL, SL habits, and perceived colorism among SL users and nonusers were collected and analyzed with χ 2 , Fisher's exact, Analysis of variance (ANOVA), Spearman correlation, and t tests., Results: A total of 455 participants completed the survey. Ninety-seven participants (21.3%) reported using SL agents: 73.2% (71/97) used SL agents for the treatment of a skin condition and 26.8% (26/97) used the products for general SL. Only 22.6% (22/97) of SL users consulted a medical provider before using the products. Forty-four participants (45.4%) were unaware of their SL product ingredients, and 35.1% (34/97) reported using hydroquinone-based products. Composite colorism scores were significantly higher in SL users than nonusers (20.03 vs 18.20; P < .001)., Limitations: This study used self-reported racial/ethnic groups to characterize those with SOC rather than assessing actual skin tones of participants, which could have led to variability., Conclusion: SL among SOC individuals is prevalent in the U.S. and poses a health risk, as many SL users are unaware of product ingredients, do not consult a medical provider before use, and have access to potentially unsafe formulations. Dermatologists should address skin tone and pigmentary concerns with their SOC patients., Competing Interests: None., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Women’s Dermatologic Society.)

Introduction: Understanding of human T-lymphotropic virus (HTLV) remains largely based on epidemiologic and clinical data from endemic areas. Globalization has resulted in migration of persons living with HTLV (PLHTLV) from endemic to non-endemic areas, and a rise of HTLV infection in the United States. Yet, due to the historical rarity of this disease, affected patients are often under- and mis-diagnosed. Thus, we sought to characterize the epidemiology, clinical features, comorbidities, and survival of HTLV-1- or HTLV-2-positive individuals identified in a non-endemic area., Methods: Our study was a single institution, retrospective case-control analysis of HTLV-1 or HTLV-2 patients between 1998 and 2020. We utilized two HTLV-negative controls, matched for age, sex, and ethnicity, for each HTLV-positive case. We evaluated associations between HTLV infection and several hematologic, neurologic, infectious, and rheumatologic covariates. Finally, clinical factors predictive of overall survival (OS) were assessed., Results: We identified 38 cases of HTLV infection, of whom 23 were HTLV-1 and 15 were HTLV-2 positive. The majority (~54%) of patients in our control group received HTLV testing for transplant evaluation, compared to ~24% of HTLV-seropositive patients. Co-morbidities associated with HTLV, hepatitis C seropositivity were higher in HTLV-seropositive patients compared to controls (OR 10.7, 95% CI = 3.2-59.0, p  < 0.001). Hepatitis C and HTLV co-infection resulted in decreased OS, compared to no infection, hepatitis C infection alone, or HTLV infection alone. Patients with any cancer diagnosis and HTLV infection had worse OS compared to patients with cancer or HTLV alone. HTLV-1 positive patients had lower median OS compared to HTLV-2 patients (47.7 months vs. 77.4 months). In univariate analysis, the hazard for 1-year all-cause mortality was increased among patients with HTLV-seropositivity, adult T-cell leukemia, acute myelogenous leukemia, and hepatitis C infection. When corrected, multivariate analysis showed that HTLV seropositivity was no longer associated with 1 year all-cause mortality; however association with AML and hepatitis C infection remained significant., Conclusion: HTLV-seropositivity was not associated with increased 1 year mortality in multivariate analysis. However, our study is limited by our small patient sample size, as well as the biased patient control population due to selection factors for HTLV testing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JCR declared a past collaboration with the author LR to the handling editor., (Copyright © 2023 Gang, Gao, Poondru, Thomas and Ratner.)

Background: Keloids are pathologic scars that pose a significant functional and cosmetic burden. They are challenging to treat, despite the multitude of treatment modalities currently available., Objective: The aim of this study was to conduct an evidence-based review of all prospective data regarding keloid treatments published between 2010 and 2020., Methods: A systematic literature search of PubMed (National Library of Medicine), Embase (Elsevier), and Cochrane Library (Wiley) was performed in November of 2020. Search strategies with the keywords "keloid" and "treatment" were performed by a medical librarian. The search was limited to prospective studies that were peer-reviewed, reported on clinical outcomes of keloid therapies, and were published in the English language between January 1, 2010, and November 24, 2020., Results: A total of 3462 unique citations were identified, of which 108 studies met inclusion criteria. Current literature supports silicone gel or sheeting with corticosteroid injections as first-line therapy for keloids. Adjuvant intralesional 5-fluorouracil (5-FU), bleomycin, or verapamil can be considered, although mixed results have been reported with each. Laser therapy can be used in combination with intralesional corticosteroids or topical steroids with occlusion to improve drug penetration. Excision of keloids with immediate post-excision radiation therapy is an effective option for recalcitrant lesions. Finally, silicone sheeting and pressure therapy have evidence for reducing keloid recurrence., Conclusions: This review was limited by heterogeneity of subject characteristics and study outcome measures, small sample sizes, and inconsistent study designs. Larger and more robust controlled studies are necessary to further understand the variety of existing and emerging keloid treatments, including corticosteroids, cryotherapy, intralesional injections, lasers, photodynamic therapy, excision and radiation, pressure dressings, and others., (© 2023. The Author(s).)

Drug-drug interaction (DDI) is an important consideration for clinical decision making in prostate cancer treatment. The objective of this study was to evaluate the effect of enzalutamide, an oral androgen receptor inhibitor, on the pharmacokinetics (PK) of digoxin (P-glycoprotein [P-gp] probe substrate) and rosuvastatin (breast cancer resistance protein [BCRP] probe substrate) in men with metastatic castration-resistant prostate cancer (mCRPC). This was a phase I, open-label, fixed-sequence, crossover study (NCT04094519). Eligible men with mCRPC received a single dose of transporter probe cocktail containing 0.25 mg digoxin and 10 mg rosuvastatin plus enzalutamide placebo-to-match on day 1. On day 8, patients started 160 mg enzalutamide once daily through day 71. On day 64, patients also received a single dose of the cocktail. The primary end points were digoxin and rosuvastatin plasma maximum concentration (C max ), area under the concentration-time curve from the time of dosing to the last measurable concentration (AUC last ), and AUC from the time of dosing extrapolated to time infinity (AUC inf ). Secondary end points were enzalutamide and N-desmethyl enzalutamide (metabolite) plasma C max , AUC during a dosing interval, where tau is the length of the dosing interval (AUC tau ), and concentration immediately prior to dosing at multiple dosing (C trough ). When administered with enzalutamide, there was a 17% increase in C max , 29% increase in AUC last , and 33% increase in AUC inf of plasma digoxin compared to digoxin alone, indicating that enzalutamide is a "mild" inhibitor of P-gp. No PK interaction was observed between enzalutamide and rosuvastatin (BCRP probe substrate). The PK of enzalutamide and N-desmethyl enzalutamide were in agreement with previously reported data. The potential for transporter-mediated DDI between enzalutamide and digoxin and rosuvastatin is low in men with prostate cancer. Therefore, concomitant administration of enzalutamide with medications that are substrates for P-gp and BCRP does not require dose adjustment in this patient population., (© 2022 Astellas Pharma Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lessons Learned: The primary endpoint of this phase II study that evaluated the efficacy and safety of the investigational compound, AGS-16C3F, versus axitinib in previously treated patients with metastatic renal cell carcinoma (mRCC) was not met. Median progression-free survival, the primary endpoint, was 2.9 months with AGS-16C3F and 5.7 months with axitinib (HR, 1.676; 95% CI, 1.107-2.537; p = .015), per investigator assessment The safety profile for each study drug was as expected, with the most commonly reported adverse events being fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. These results provide a benchmark for axitinib use in heavily pretreated patients with mRCC., Background: AGS-16C3F is a novel antibody-drug conjugate that targets cell-surface ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) and is conjugated to a microtubule disruptive agent. Here we present findings from a phase II study of AGS-16C3F versus axitinib in metastatic renal cell carcinoma (mRCC)., Methods: Patients with mRCC of any histology and disease progression during or after their last treatment regimen were randomized 1:1 to intravenous AGS-16C3F 1.8 mg/kg every 3 weeks or oral axitinib 5 mg twice daily (starting dose). The primary objective was investigator-assessed progression-free survival (PFS) of AGS-16C3F versus axitinib (RECIST version 1.1)., Results: In the total population (N = 133), 63% (n = 84) of patients had completed the study at data cutoff (August 21, 2019). Median PFS was 2.9 months with AGS-16C3F and 5.7 months with axitinib (hazard ratio [HR], 1.676; 95% confidence interval [CI], 1.107-2.537; p = .015). There were no significant differences between arms in secondary efficacy endpoints, including overall survival (13.1 months, AGS-16C3F and 15.4 months, axitinib; HR, 1.079; 95% CI, 0.681-1.707; p = .747). In the safety population (n = 131), the most commonly reported adverse events were fatigue (53%) and nausea (47%) in the AGS-16C3F arm and fatigue (57%) and diarrhea (48%) in the axitinib arm. The incidence of diarrhea was lower in the AGS-16C3F arm than in the axitinib arm (17% vs. 48%), and ocular toxicities were more frequent in the AGS-16C3F arm than in the axitinib arm (44% vs. 26%)., Conclusion: The investigational compound, AGS-16C3F, did not meet the primary endpoint of this trial. These study results provide a benchmark for axitinib use in heavily pretreated patients with mRCC., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: Linsitinib, an oral, dual inhibitor of insulin-like growth factor-1 receptor and insulin receptor, in combination with weekly paclitaxel, may improve clinical outcomes compared with paclitaxel alone in patients with refractory or platinum-resistant ovarian cancer., Patients and Methods: This open-label phase 1/2 clinical trial (NCT00889382) randomized patients with refractory or platinum-resistant ovarian cancer (1:1:1) to receive either oral intermittent linsitinib (600mg once daily on Days 1-3 per week) combined with paclitaxel (80mg/m 2 on Days 1, 8, and 15; Arm A) or continuous linsitinib (150mg twice daily) in combination with paclitaxel (Arm B), or paclitaxel alone (Arm C). Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety/tolerability., Results: A total of 152 women were randomized to treatment (n=51 Arm A; n=51 Arm B, n=50 Arm C). In combination with paclitaxel, neither intermittent linsitinib (median PFS 2.8months; 95% confidence interval [CI]:2.5-4.4) nor continuous linsitinib (median PFS 4.2months; 95% CI:2.8-5.1) improved PFS over weekly paclitaxel alone (median PFS 5.6months; 95% CI:3.2-6.9). No improvement in ORR, DCR, or OS in either linsitinib dosing schedule was observed compared with paclitaxel alone. Adverse event (AE) rates, including all-grade and grade 3/4 treatment-related AEs, and treatment-related AEs leading to discontinuation, were higher among patients receiving intermittent linsitinib compared with the other treatment arms., Conclusion: Addition of intermittent or continuous linsitinib with paclitaxel did not improve outcomes in patients with platinum-resistant/refractory ovarian cancer compared with paclitaxel alone., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Acquired EGFR T790M mutations are the most frequently identified resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) in patients with EGFR -mutant lung cancers. ASP8273 is a third-generation EGFR TKI with antitumor activity in preclinical models of EGFR-mutant lung cancer that targets mutant EGFR, including EGFR T790M. Experimental Design: In this multicohort, phase I study (NCT02113813), escalating doses of ASP8273 (25-500 mg) were administered once daily to non-small cell lung cancer (NSCLC) patients with disease progression after prior treatment with an EGFR TKI. EGFR T790M was required for all cohorts, except the dose escalation cohort. Primary endpoints were safety/tolerability; secondary endpoints were determination of the RP2D, pharmacokinetic profile, and preliminary antitumor activity of ASP8273. Evaluation of the use of EGFR mutations in circulating free DNA (cfDNA) as a biomarker of ASP8273 treatment effects was an exploratory endpoint. Results: A total of 110 patients were treated with ASP8273 across dose escalation ( n = 36), response-expansion ( n = 36), RP2D (300 mg; n = 19) and food-effect ( n = 19) cohorts. The most common treatment-emergent adverse events included diarrhea, nausea, fatigue, constipation, vomiting, and hyponatremia. Across all doses, in patients with EGFR T790M, the response rate was 30.7% ( n = 27/88; 95% CI, 19.5%-44.5%), and median progression-free survival was 6.8 months (95% CI, 5.5-10.1 months). EGFR mutations in cfDNA, both the activating mutation and EGFR T790M, became undetectable in most patients in the setting of clinical response and reemerged upon disease progression. Conclusions: ASP8273 was well tolerated and promoted antitumor activity in patients with EGFR -mutant lung cancer with disease progression on prior EGFR TKI therapy. Clin Cancer Res; 23(24); 7467-73. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Maintenance therapy is important in advanced/metastatic non-small cell lung cancer (NSCLC). Erlotinib as switch maintenance following platinum-based chemotherapy increases survival. Cross-talk between the epidermal growth factor receptor and insulin-like growth factor receptor (IGFR) pathways mediate resistance to individual receptor blockade. This study compared maintenance linsitinib plus erlotinib vs erlotinib plus placebo in patients with NSCLC., Methods: In this Phase II randomised trial, patients without progression following four cycles of first-line platinum-based chemotherapy (N=205) received continuous schedule maintenance oral linsitinib 150 mg or placebo BID combined with erlotinib 150 mg QD for 21-day cycles. The primary endpoint was progression-free survival (PFS)., Results: The study was unblinded early due to linsitinib non-superiority. No difference was found between the two treatment groups in median PFS of 125 days linsitinib vs 129 days placebo (P=0.601); no difference in overall survival (OS) was observed. Tolerability was similar, although in the linsitinib group, treatment-related adverse events and discontinuations were more frequent. No drug-drug interaction was implicated., Conclusions: Linsitinib maintenance therapy added to erlotinib did not improve PFS or OS in non-progressing NSCLC patients. This highlights the need for robust biomarkers of response for combinations that incorporate IGFR-targeted therapies in maintenance or other therapeutic settings.

Introduction: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non-small-cell lung cancer with EGFR-activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin-like growth factor 1 receptor (IGF-1R) may contribute to resistance; dual blockade of IGF-1R and EGFR may improve outcomes., Patients and Methods: We performed a randomized, double-blind, placebo-controlled phase II study of linsitinib, a dual IGF-1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy-naive patients with EGFR-mutation positive, advanced non-small-cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21-day cycles. The primary end point was progression-free survival., Results: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression-free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug-drug interaction was suggested by pharmacokinetic and pharmacodynamic results., Conclusion: Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF-1R inhibitors in lung cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib., Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1-3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100-150 mg once daily; and a non-small cell lung cancer (NSCLC) expansion cohort., Results: Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks., Conclusions: The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897-907. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted., Methods: Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics., Results: One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients., Conclusions: OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.

Purpose: This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C-linsitinib dose., Methods: Five patients received a single oral dose of 150 mg (14)C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150 mg of unlabeled linsitinib administered twice daily until disease progression was also assessed., Results: The median time to reach the maximum plasma concentration of linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of (14)C-linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1-M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib., Conclusions: (14)C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.

Background: Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate efficacy in patients with advanced adrenocortical carcinoma., Methods: In this international, double-blind, placebo-controlled phase 3 study, adult patients with histologically confirmed locally advanced or metastatic adrenocortical carcinoma were recruited at clinical sites in nine countries. Patients were randomly assigned (2:1) twice-daily 150 mg oral linsitinib or placebo via a web-based, centralised randomisation system and stratified according to previous systemic cytotoxic chemotherapy for adrenocortical carcinoma, Eastern Cooperative Oncology Group performance status, and use of one or more oral antihyperglycaemic therapy at randomisation. Allocation was concealed by blinded block size and permuted block randomisation. The primary endpoint was overall survival, calculated from date of randomisation until death from any cause. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00924989., Findings: Between Dec 2, 2009, and July 11, 2011, 139 patients were enrolled, of whom 90 were assigned to linsitinib and 49 to placebo. The trial was unblinded on March 19, 2012, based on data monitoring committee recommendation due to the failure of linsitinib to increase either progression-free survival or overall survival. At database lock and based on 92 deaths, no difference in overall survival was noted between linsitinib and placebo (median 323 days [95% CI 256-507] vs 356 days [249-556]; hazard ratio 0·94 [95% CI 0·61-1·44]; p=0·77). The most common treatment-related adverse events of grade 3 or worse in the linsitinib group were fatigue (three [3%] patients vs no patients in the placebo group), nausea (two [2%] vs none), and hyperglycaemia (two [2%] vs none). No adverse events in the linsitinib group were deemed to be treatment related; one death (due to sepsis and megacolon) in the placebo group was deemed to be treatment related., Interpretation: Linsitinib did not increase overall survival and so cannot be recommended as treatment for this general patient population. Further studies of IGF-1R and insulin receptor inhibitors, together with genetic profiling of responders, might pave the way toward individualised and improved therapeutic options in adrenocortical carcinoma., Funding: Astellas., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors., Patients and Methods: This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules., Results: Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified., Conclusions: At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors., (©2014 American Association for Cancer Research.)

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors., Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study., Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses., Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors., (©2014 American Association for Cancer Research.)

Purpose: OSI-930 is a novel, potent, oral small-molecule receptor tyrosine kinase inhibitor, predominantly against VEGF receptors (VEGFR), c-Kit, and platelet-derived growth factor receptors. A phase I trial was undertaken to determine safety, maximum-tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and antitumor activity of OSI-930 in patients with advanced solid tumors., Experimental Design: OSI-930 was administered once or twice a day using a modified accelerated titration design. Pharmacokinetics and plasma soluble VEGFR2 (sVEGFR2) studies were undertaken. Dynamic contrast-enhanced MRI (DCE-MRI) and 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) MTD expansion cohorts were conducted., Results: Fifty-eight patients received OSI-930 in 2 schedules; once a day schedule: 12 patients at doses up to 1,600 mg without reaching MTD; twice a day schedule: 46 patients at 400 mg (n = 7), 500 mg (n = 31), and 600 mg (n = 8). Dose-limiting toxicities were observed at 600 mg twice a day (n = 3): G3 rash (n = 2) and G4 γ-glutamyltransferase, establishing the MTD at 500 mg twice a day. Common G1-2 toxicities included fatigue, diarrhea, nausea, and rash. Antitumor responses were seen in 2 patients with advanced ovarian cancer [Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR) (n = 1); GCIG CA125 response (n = 1)]. Eleven of 19 heavily pretreated imatinib-resistant patients with gastrointestinal stromal tumors achieved RECIST stable disease (median duration: 126 days), with FDG-PET scans showing PRs in 4 of 9 patients. OSI-930 exposure increased with dose; substantial decreases in sVEGFR levels were observed with OSI-930 twice a day doses ≥400 mg, while DCE-MRI responses were shown in 4 of 6 patients., Conclusions: OSI-930 is safe and well tolerated, with pharmacokinetic-pharmacodynamic data supporting proof-of-mechanism with clinically relevant antitumor activity., (©2012 AACR.)