Molecular profiling of melanoma brain metastases compared to primary cutaneous melanoma and to extracranial metastases.

BACKGROUND: Brain metastases are a significant cause of mortality and morbidity for patients with melanoma. We hypothesize that the development of brain metastases may be explained by molecular heterogeneity between primary cutaneous melanoma (PCM) or extracranial (ECM) and brain (MBM) melanoma metastases. MATERIALS AND METHODS: We compared next-generation sequencing, tumor mutational burden (TMB), and immunohistochemical staining for PD-L1 expression, among 132 MBM, 745 PCM, and 1190 ECM. RESULTS: The most common genetic alterations among MBM included: BRAF (52.4%), NRAS (26.6%), CDKN2A (23.3%), NF1 (18.9%), TP53 (18%), ARID2 (13.8%), SETD2 (11.9%), and PBRM1 (7.5%). Four genes were found with higher frequency among MBM compared to PCM or ECM: BRAF (52.4% v 40.4% v 40.9%), SETD2 (11.9% v 1.9% v 3.9%), PBRM1 (7.5% v 1.6% v 2.6%), and DICER1 (4.4% v 0.6% v 0.4%). MBM showed higher TMB ( CONCLUSIONS: Our findings suggest a unique molecular profile for MBM, including higher rates of BRAF mutations, higher TMB and higher PD-L1 expression, and also implicate chromatin remodeling in the pathogenesis of MBM

Pharmacokinetic evaluation of axitinib.

INTRODUCTION: The role of angiogenic inhibitors is clearly established in the treatment of diverse malignancies. The field of antiangiogenesis is expanding rapidly, with an increasing number of agents currently approved by the FDA. Axitinib is a vascular endothelial growth factor receptor (VEGFR)-specific inhibitor currently being developed for the treatment of various malignancies. The pharmacokinetic (PK) properties of axitinib may provide a selective treatment effect while minimizing adverse reactions and enhancing safety. It is paramount that health-care providers understand the properties and nuances of each agent inclusive of PK variability in the patient population as well as current safety and tolerability data. AREAS COVERED: This article provides a comprehensive and critical review of the PK properties of axitinib as they relate to safety and tolerability, as well as potential pharmacodynamic and efficacy parameters. EXPERT OPINION: Axitinib is a unique VEGFR tyrosine kinase inhibitor (TKI), which acts through greater receptor specificity compared with many other VEGFR TKIs. An understanding of axitinib\u27s PK characteristics and common adverse events may allow for a tailored dosing approach in patients with cancer, in an attempt to maximize efficacy while minimizing toxicity

An Open-Label, Phase 1 Study Evaluating the Safety and Pharmacokinetics of Pralatrexate in Relapsed/Refractory Advanced Solid Tumors or Advanced Lymphoma/Myeloma Patients with Mild, Moderate, and Severe Renal Impairment

Abstract Introduction: Pralatrexate is a folate analogue indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) that is preferentially taken up in cancer cells through the reduced folate carrier. While 34% of pralatrexate is excreted unchanged in the urine following a single, 30 mg/m2 dose administered as an IV push, a population PK analysis showed that drug clearance decreased with decreasing creatinine clearance. In addition, methotrexate, also a folate analogue, does need to be dose-reduced for patients with moderate or severe renal impairment. Pralatrexate, however, has not been formally tested in patients with renal impairment, and previous studies excluded patients with severe renal impairment. This study was, therefore, conducted to determine the need for pralatrexate dosing adjustments in patients with renal impairment. Methods: This was an open label, nonrandomized, Phase 1 study to determine the PK profile of pralatrexate in patients with relapsed/refractory advanced solid tumors or advanced lymphoma/myeloma with renal impairment. Primary objective of the study was to establish dosing recommendation of pralatrexate in renally compromised patients and to determine the pharmacokinetic profile in these patients. Four cohorts (n=6 per cohort) were planned to be enrolled in this study for a total of 24 patients. Patients with normal renal function (eGFR ≥90 mL/min/1.73 m2, Cohort A), mild (eGFR= 60 to <90 mL/min/1.73 m2, Cohort B) and moderate renal function (eGFR = 30 to < 60 mL/min/1.73 m2, Cohort C) were dosed with 30 mg/m2 pralatrexate once weekly for 6-weeks in a 7-week cycle. The pralatrexate dose was empirically reduced to 20 mg/m2 in patients with severe renal impairment (eGFR = 15 to < 30 mL/min/1.73 m2, Cohort D). Plasma and urine samples were collected at pre-specified time points to determine the PK profile. Patients who continued treatment with pralatrexate were then followed for safety and tolerability. Results: A total of 29 patients (14 male and 13 female) were enrolled in the study with 6 patients in each cohort. There were slightly more male patients (n=14, 52%) than female patients (n=13, 48%) enrolled; fewer males (33%) were in the mild renal impairment group and more males (83%) were in the moderate renal impairment group. The median age was 62.0 years. The majority of patients were White (n=22, 81%); the remaining patients were Black (n=5, 19%). Because of a qualifying toxicity in Cohort C, the starting dose was reduced to 15 mg/m2 in Cohort D. The major effect of chronic renal impairment was to decrease renal clearance of the pralatrexate diastereomers, PDX-10a and PDX-10b, but systemic exposure to these diastereomers was not dramatically affected by renal impairment. Mean total exposures of PDX-10a and PDX-10b were comparable across cohorts, including Cohort D. The empiric dose reduction to 15 mg/m2 in Cohort D was able to match the average exposures for Cohort A (with normal dose of 30 mg/m2). Although Cohorts B and C had elevated mean exposures and higher inter-patient variability than Cohorts A and D, it appears to be a result of non-renal factors. In summary, total exposures of PDX-10a and PDX-10b after a single IV injection of racemic pralatrexate are not dramatically affected by renal impairment. There was no apparent difference in either the incidence or types of TEAEs between the four treatment cohorts, and, therefore, the safety of pralatrexate was not affected by differences in renal function. The most common treatment related AEs were stomatitis (n=23, 83%), nausea (n=10, 37%), anemia (n=7, 26%) and fatigue (n=6, 22%). Conclusion: The pralatrexate exposure in patients with mild or moderate renal impairment is similar to the patients with normal renal function at a dose of 30 mg/m2. For patients with severe renal impairment, a pralatrexate dose of 15 mg/m2 is recommended. Disclosures Gabrail: Sanofi: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; Onyx: Honoraria, Speakers Bureau; BI: Honoraria, Speakers Bureau. Edenfield:Celgene: Research Funding. Reddy:spectrum: Employment, Equity Ownership

Electrocardiographic Characterization of Ramucirumab on the Corrected QT Interval in a Phase II Study of Patients With Advanced Solid Tumors

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139908/1/onco0402.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139908/2/onco0402-sup-0001.pd

A Phase I dose-escalation study of LCL161, an oral IAP inhibitor, in patients with advanced solid tumors

Purpose LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human, dose-escalation study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. Patients and Methods LCL161 was administered orally once-weekly on a 21-day cycle to adult patients with advanced solid tumors. An adaptive Bayesian Logistic Regression Model with overdose control guided dose escalation. A second part of the study assessed the relative bioavailability of tablet versus solution formulation. Results Fifty-three patients received at least one dose of LCL161 (range 10–3000 mg). LCL161 was well tolerated at doses up to 1800 mg, with cytokine release syndrome (CRS) the only dose-limiting toxicity (3/53; 6%) and most common grade 3/4 event (5/53; 9%). Although the MTD was not reached, a dose of 1800 mg was selected for further study given the occurrence of CRS at higher doses and evidence of pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed. The tablet formulation of LCL161 was better tolerated than the solution with similar exposure, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor, and increased circulating cytokine levels consistent with LCL161’s mechanism of action. Conclusion Single-agent LCL161 administered in tablet formulation at a dose of 1800 mg once-weekly was well tolerated, with significant pharmacodynamic activity, warranting further investigation in future studies

The Effect of Food on the Absorption of Abiraterone Acetate from a Fine Particle Dosage Form: A Randomized Crossover Trial in Healthy Volunteers

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s40487-017-0054-2">https://link.springer.com/article/10.1007/s40487-017-0054-2</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

Abstract C188: A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers

Abstract Background: RXDX-105 is a potent RET, BRAF and EGFR tyrosine kinase inhibitor (TKI) that exhibits high target affinity at low nanomolar concentrations. The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signaling molecules. RET gain of function alterations are associated with the development of various types of human cancer, including non-small cell lung cancer (NSCLC). BRAF plays a key role in regulating the MEK/ERK signaling pathway, which affects cell division and differentiation. Acquired BRAF mutations can result in constitutive activation of this pathway, thereby fueling cancer growth. RXDX-105 is being developed as an oral therapy for patients with solid tumors that harbor RET or BRAF mutations or gene rearrangements. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design to determine the recommended Ph 2 dose. Oral RXDX-105 was given as a fixed dose on a continuous daily schedule. Tumor response was assessed at baseline and every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) assessment was also a study objective. Results: To date, 35 pts (17 M and 18 F) received RXDX-105 across 7 dose levels (20 to 275 mg QD). Median age was 60.5 years (range 27-81). The most frequent tumors (pts) were metastatic CRC (13), ovarian cancer (3), NSCLC (3), cholangiocarcinoma (3), and pancreatic cancer (3). Median number of cycles was 2 (range 1 to 23). 34 pts experienced AEs; 6 pts experienced treatment-related G3 AEs, including anemia, hypophosphatemia, fatigue, diarrhea, abdominal pain, rash and muscle weakness. 22 SAEs were reported from 9 pts, with none considered treatment-related. No treatment-related deaths occurred. The most common AEs were: fatigue (17 pts), vomiting (13 pts), abdominal pain (12 pts), nausea (11 pts), decreased appetite (10 pts), and rash (10 pts). At the time of this report, 3 pts have had DLTs; 1 pt at 200 mg with G2 hand and foot syndrome, 1 pt at 275 mg with G3 fatigue, and 1 pt at 275 mg with G3 asymptomatic hypophosphatemia. The protocol was amended to exclude hypophosphatemia as a DLT since it has been observed with approved TKIs and can be managed by supplementation. The PK data to date have demonstrated that RXDX-105 is absorbed with a median Tmax between 2 and 6 hrs at steady state. RXDX-105 plasma concentrations declined slowly after reaching Cmax with an average terminal half-life of 28 to 42 hrs across dose levels. There was a loss of dose proportionality at doses above 150 mg, possibly due to pH-dependent drug dissolution in the stomach. The impact of the fed state on exposure is being explored. 11 pts have been on treatment for ≥ 12 weeks. No objective responses have been observed; however, 1 pt with BRAF V600E-positive papillary thyroid cancer, previously treated with RAI, EBRT and multiple surgical resections, has been on study with stable disease for almost 2 years (23 cycles). Additionally, 2 heavily pre-treated pts with squamous NSCLC achieved clinical benefit with SD for &amp;gt; 6 months; 1 patient continues. Conclusions: To date, treatment with RXDX-105 demonstrates an acceptable safety profile. Improvements in bioavailability are being investigated. Dose escalation continues. Citation Format: Ding Wang, Manish Patel, Marwan Fakih, A. Craig Lockhart, Anthony J. Olszanski, Rupal Patel, Peter D. Brown, Jennifer W. Oliver, Pratik S. Multani. A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C188.</jats:p