Purpose This “3+3” phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. Experimental Design Ascending doses of lenvatinib were administered po bid in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort. Results Seventy-seven patients were treated in 3 cohorts: 18 with intermittent bid dosing (7 days on, 7 days off) of 0.1–3.2 mg; 33 with bid dosing of 3.2–12 mg; and 26 with bid dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg po bid. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n=9) or unconfirmed PR (uPR, n=3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD≥23 weeks was 40.3% (n=31). Responses (PR/uPR) by disease were: melanoma, 5/29 patients (includes 1 patient with NRAS mutation); thyroid, 3/6; pancreatic, 1/2; lung, 1/1; renal, 1/1; endometrial, 1/4; and ovarian, 1/5. AUC0-24 and Cmax increased dose-proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P=0.041 and P=0.03, respectively). Conclusions The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.
Objectives: Ultrasound-guided regional anesthesia (UGRA) can be a powerful tool in the treatment of painful conditions commonly encountered in emergency medicine (EM) practice. UGRA can benefit patients while avoiding the risks of procedural sedation and opioid-based systemic analgesia. Despite these advantages, many EM trainees do not receive focused education in UGRA and there is no published curriculum specifically for EM physicians. The objective of this study was to identify the components of a UGRA curriculum for EM physicians.Methods: A list of potential curriculum elements was developed through an extensive literature review. An expert panel was convened that included 13 ultrasound faculty members from 12 institutions and from a variety of practice environments and diverse geographical regions. The panel voted on curriculum elements through two rounds of a modified Delphi process. Results:The panelists voted on 178 total elements, 110 background knowledge elements, and 68 individual UGRA techniques. A high level of agreement was achieved for 65 background knowledge elements from the categories: benefits to providers and patients, indications, contraindications, risks, ultrasound skills, procedural skills, sterile technique, local anesthetics, and educational resources. Ten UGRA techniques achieved consensus: interscalene brachial plexus, supraclavicular brachial plexus, radial nerve, median nerve, ulnar nerve, serratus anterior plane, fascia iliaca, femoral nerve, popliteal sciatic nerve, and posterior tibial nerve blocks. Conclusions:The defined curriculum represents ultrasound expert opinion on a curriculum for training practicing EM physicians. This curriculum can be used to guide the development and implementation of more robust UGRA education for both residents and independent providers.
8594 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses were observed in melanoma as well as thyroid, endometrial, and renal cancers. Methods: Patients (pts) with stage 4 or unresectable stage 3 melanoma were treated in sequential cohorts of escalating doses of lenvatinib by continuous once daily dosing and temozolomide (TMZ) days 1-5 every 28 days. Cohort 1: lenvatinib 20mg, TMZ 100 mg; cohort 2: lenvatinib 24 mg, TMZ 100 mg; cohort 3: lenvatinib 24 mg, TMZ 150 mg. Adverse events were recorded according to CTCAE v3.0 and tumor response assessed according to RECIST 1.0. Results: 32 pts were treated: cohort 1: 6 pts, cohort 2: 4 pts, cohort 3: 22 pts. Demographics: median age: 58; males: 63%. Dose limiting toxicities occurred in 0/6 pts in cohort 3 leading to cohort expansion to a total of 22 pts to enable more extensive assessment of toxicity and a preliminary estimate of efficacy. The most common treatment related adverse events in the cohort 3 were fatigue: 50% (gr3: 9%), hypertension: 50% (gr3: 9%), proteinuria: 50% (no gr3), vomiting: 46% (no gr3), hypothyroidism: 46% (no gr3), anorexia: 41% (no gr3), nausea: 41% (no gr3), diarrhea: 36% (gr3: 5%), thrombocytopenia: 32% (no gr3). No treatment-related gr4 events were reported in these categories. The best overall responses per RECIST were partial responses: 5/22 (23%) for cohort 3 pts and 6/32 (19%) for all pts treated at all dose levels. Six-month progression free survival (PFS) rate was 37% and median PFS was 5.4 months. PK/PD analysis and correlation of response with genetic mutational status (BRAF mutations in 31% pts; NRAS mutations in 19% pts) will be presented. Conclusions: Lenvatinib 24 mg once daily in combination with TMZ 150 mg days1-5 every 28 days was given without apparent worsening of either lenvatinib or TMZ related toxicities. Modest clinical efficacy for this combination was observed.
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