Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma

Abstract

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.

TP53Alterations Correlate with Response to VEGF/VEGFR Inhibitors: Implications for Targeted Therapeutics

“…In summary, there are at least 12 VEGF/VEGFR inhibitors that are approved, and many more in clinical trials; none have a biomarker for patient selection (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44). Yet, it is known that most of these agents improve survival by only a few weeks, most likely because a subset of patients respond, whereas others do not benefit or may even be harmed by these drugs.…”

Sleep quality and its association with fatigue, symptom burden, and mood in patients with advanced cancer in a clinic for early‐phase oncology clinical trials

“…The association between the MDASI disturbedsleep item and the global PSQI score was examined with Pearson's correlation (with the MDASI item as a continuous variable) and with chi-square tests (with the MDASI disturbed-sleep score trichotomized into normal sleep [0-3], moderately disturbed sleep [4][5][6], and severely disturbed sleep [7][8][9][10]). …”

“…2 Sleep problems have also been associated with poor clinical outcomes (eg, lower overall survival, more rapid disease progression, and poor treatment response) in patients with advanced cancer participating in a randomized phase 3 trial. Poor sleep quality is often not captured as an adverse event, and its association with fatigue, a frequently reported adverse event in early-phase clinical trials 4,5 and with any cancer therapy, 6,7 is not documented routinely. Poor sleep quality is often not captured as an adverse event, and its association with fatigue, a frequently reported adverse event in early-phase clinical trials 4,5 and with any cancer therapy, 6,7 is not documented routinely.…”

“…3 Nonetheless, although sleep may be a modifiable risk factor that could potentially affect clinical outcomes, sleep quality during early-phase clinical trials has not been well studied. Poor sleep quality is often not captured as an adverse event, and its association with fatigue, a frequently reported adverse event in early-phase clinical trials 4,5 and with any cancer therapy, 6,7 is not documented routinely. The relations among sleep quality, symptom burden, and mood in the early-phase clinical trial setting also have not been adequately explored.…”

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

“…Furthermore, the affordability, reliability, and accessibility of genome sequencing have been major attractions in oncology because physicians now have the ability to potentially match patients to treatments based on their individual molecular profiles. Previous studies have revealed variable efficacy in matching patients to FDA-approved or experimental treatments (precision medicine), and this suggests a fundamental need for continued investigation in this area, especially in the cancer setting [3–6]. Indeed, cancer genome landscapes and precision oncology medicine continue to evolve as a result of the development of therapies that target cancer-specific alterations [1–17].…”