Orangutans and the evolution of sharp stone tools.

Orangutans use stone tools in a variety of modes, including cutting. This behavior appears to be learned from trusted social partners.

Orangutan strategies for solving a visuospatial memory task.

The popular game known as Concentration (also commonly referred to as Memory), in which players search for matching pairs among a grid of face-down cards, provides a robust platform for examining visuospatial memory in a simple and nonverbal way. Five orangutans (Pongo ssp.) at the Indianapolis Zoo were given a modified version of the Concentration Game in which three cards were shown face-down on a computer screen, two of which matched each other while the third was a foil.

Evolution of water conservation in humans.

To sustain life, humans and other terrestrial animals must maintain a tight balance of water gain and water loss each day. However, the evolution of human water balance physiology is poorly understood due to the absence of comparative measures from other hominoids. While humans drink daily to maintain water balance, rainforest-living great apes typically obtain adequate water from their food and can go days or weeks without drinking.

Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer.

Purpose: Patients with advanced endometrial carcinoma have limited treatment options. We report final primary efficacy analysis results for a patient cohort with advanced endometrial carcinoma receiving lenvatinib plus pembrolizumab in an ongoing phase Ib/II study of selected solid tumors.

Methods: Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles.

An Open-Label Phase 1 Study to Determine the Effect of Lenvatinib on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Patients with Advanced Solid Tumors.

Background And Objective: Lenvatinib is a multikinase inhibitor that inhibits enzyme activity but induces gene expression of cytochrome P450 3A4 (CYP3A4), an important enzyme for drug metabolism. We evaluated the impact of lenvatinib on CYP3A4 using midazolam as a probe substrate in patients with advanced solid tumors. The primary objective was to determine the pharmacokinetic effects of lenvatinib on midazolam, and the secondary objective was to assess the safety of lenvatinib.

Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors.

Purpose: Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors.

Methods: Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non-small-cell lung cancer (NSCLC), or urothelial cancer.

Orangutans show active voicing through a membranophone.

Active voicing - voluntary control over vocal fold oscillation - is essential for speech. Nonhuman great apes can learn new consonant- and vowel-like calls, but active voicing by our closest relatives has historically been the hardest evidence to concede to. To resolve this controversy, a diagnostic test for active voicing is reached here through the use of a membranophone: a musical instrument where a player's voice flares a membrane's vibration through oscillating air pressure.

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial.

Background: Lenvatinib is a multikinase inhibitor of VEGFR1, VEGFR2, and VEGFR3, and other receptor tyrosine kinases. Pembrolizumab, an antibody targeting PD-1, has moderate efficacy in biomarker-unselected endometrial cancer. We aimed to assess the combination of lenvatinib plus pembrolizumab in patients with advanced endometrial carcinoma, after establishing the maximum tolerated dose in a phase 1b study.

Correction to: 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018).

After publication of this supplement [1, 2], it was brought to our attention that due to an error authors were missing in the following abstracts. This has now been included in this correction.

Exposure-response analysis and simulation of lenvatinib safety and efficacy in patients with radioiodine-refractory differentiated thyroid cancer.

Purpose: Once-daily lenvatinib 24 mg is the approved dose for radioiodine-refractory differentiated thyroid cancer. In a phase 3 trial with lenvatinib, the starting dose of 24 mg was associated with a relatively high incidence of adverse events that required dose reductions. We used an exposure-response model to investigate the risk-benefit of different dosing regimens for lenvatinib.

Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor.

Lenvatinib is a multikinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor-alpha, and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer in the United States (US), European Union (EU), Canada, Japan, and Switzerland. It is also approved in combination with everolimus for the treatment of advanced renal cell carcinoma following ≥1 VEGF-targeted treatment in the US and EU.

Vocal fold control beyond the species-specific repertoire in an orang-utan.

Vocal fold control was critical to the evolution of spoken language, much as it today allows us to learn vowel systems. It has, however, never been demonstrated directly in a non-human primate, leading to the suggestion that it evolved in the human lineage after divergence from great apes. Here, we provide the first evidence for real-time, dynamic and interactive vocal fold control in a great ape during an imitation "do-as-I-do" game with a human demonstrator.

Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: a cross-species comparison.

Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor. Preclinical drug metabolism studies showed unique metabolic pathways for lenvatinib in monkeys and rats. A human mass balance study demonstrated that lenvatinib related material is mainly excreted via feces with a small fraction as unchanged parent drug, but little is reported about its metabolic fate.

Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer.

Aims: Lenvatinib was recently approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). Here, we characterized the pharmacokinetic (PK) profile of lenvatinib and identified intrinsic and extrinsic factors that explain interindividual PK variability in humans.

Methods: This population PK analysis used pooled data from 15 clinical studies, including eight phase 1 studies in healthy subjects, four phase 1 studies in patients with solid tumours, two phase 2 studies in patients with thyroid cancer and one phase 3 study in patients with RR-DTC.

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.

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 per os twice daily in 28-day cycles. Safety and response were assessed for all patients.

Effects of Ketoconazole on the Pharmacokinetics of Lenvatinib (E7080) in Healthy Participants.

Background: Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein.

Methods: In this Phase I, single-center, randomized, open-label, two-period, crossover study, healthy adults (18-55 years; N = 18) were randomized to one of two sequences (ketoconazole → placebo or vice versa).

Pre-Sleep and Sleeping Platform Construction Behavior in Captive Orangutans (Pongo spp.): Implications for Ape Health and Welfare.

The nightly construction of a 'nest' or sleeping platform is a behavior that has been observed in every wild great ape population studied, yet in captivity, few analyses have been performed on sleep related behavior. Here, we report on such behavior in three female and two male captive orangutans (Pongo spp.), in a natural light setting, at the Indianapolis Zoo.

Orangutans (Pongo spp.) have deeper, more efficient sleep than baboons (Papio papio) in captivity.

The nightly construction of arboreal sleeping platforms or "nests" has been observed among every great ape population studied to date. However, this behavior has never been reported in any other nonhuman primate and comparisons between ape and monkey sleep illuminate the link between sleeping substrates, positional behavior, and sleep efficiency. Here, we compare sleep depth and efficiency and night-time positional behavior between a large-bodied cercopithecoid (Papio papio) and a large-bodied hominoid (Pongo spp.

Speech-like rhythm in a voiced and voiceless orangutan call.

The evolutionary origins of speech remain obscure. Recently, it was proposed that speech derived from monkey facial signals which exhibit a speech-like rhythm of ∼5 open-close lip cycles per second. In monkeys, these signals may also be vocalized, offering a plausible evolutionary stepping stone towards speech.

Pharmacokinetics and excretion of (14)C-lenvatinib in patients with advanced solid tumors or lymphomas.

Lenvatinib is an orally available multi-targeted tyrosine kinase inhibitor with anti-angiogenic and antitumor activity. To get more insight into the disposition of lenvatinib, a mass balance study was performed in patients with advanced solid tumors. A single oral 24 mg (100 μCi) dose of (14)C-lenvatinib was administered to six patients, followed by collection of blood, plasma, urine and feces for 7 to 10 days.

Effect of repeated exposures and sociality on novel food acceptance and consumption by orangutans.

Hundreds of rehabilitant great apes have been released into the wild, and thousands await release. However, survival rates after release can be as low as 20%. Several factors influence individuals' survival rates, one of which is the capacity to obtain an adequate diet once released.

Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral administration.

This open-label, single-dose study assessed lenvatinib pharmacokinetics (PK) in subjects with normal hepatic function (n = 8) and mild, moderate, or severe hepatic impairment (n = 6 each). Subjects received 10 mg oral lenvatinib, except those with severe hepatic impairment (5 mg). Plasma and urine samples were collected over 14 days; free and total lenvatinib and its metabolites were analyzed using validated chromatography/spectrometry.

Effect of rifampicin on the pharmacokinetics of lenvatinib in healthy adults.

Background And Objectives: Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor under clinical investigation in solid tumours. This study evaluated the influence of P-glycoprotein (P-gp) inhibition (single-dose rifampicin) and simultaneous cytochrome P450 3A4 (CYP3A4)/P-gp induction (multiple-dose rifampicin) on lenvatinib pharmacokinetics.

Methods: This Phase I, single-centre, single-dose (lenvatinib mesylate 24 mg), open-label, sequential study enrolled 15 healthy volunteers.

Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT study in healthy volunteers.

Purpose: QT assessment of oncology drugs is generally challenging because they are genotoxic and, of necessity,they require multisite evaluation in cancer patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT)study with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing healthy volunteers and concentration effect modeling to project the TQT effect at high plasma levels.

Methods: Fifty-two healthy subjects randomly received single doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way crossover study.