Purpose: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial.Experimental Design: Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).Results: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500-and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort.Conclusions: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.

Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.

Purpose: The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acidcontaining peptide isolated from the marine herbivorous mollusk, Elysia rufescens.Experimental Design: Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 Ag per m 2 per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer.Results: Thirty-two patients were treated at nine dose levels (20-930 Ag per m 2 per day). The maximum tolerated dose on this schedule was 930 Ag per m 2 per day. The doselimiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 Ag per m 2 per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t 1/2 ) of 0.47 hour (0.11 hour). One patient at dose level 80 Ag per m 2 per day had a partial response with a prostate-specific antigen decline by at least 50% for _ >4 weeks. Five patients showed stable disease.Conclusions: KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 Ag per m 2 per day once every 3 weeks.

Purpose: Originally isolated on the basis of its ability to induce p53, serdemetan showed potent activity in various preclinical models, inducing S-phase arrest and apoptosis in TP53 wild-type and mutant tumors. This study evaluated the safety and tolerability of serdemetan, determined the pharmacokinetic and pharmacodynamic profiles, and identified a recommended phase II dose.Patients and Methods: Patients (71) with refractory solid tumors were allocated to dose-escalating cohorts (3þ3 patients each) and received oral serdemetan once daily in 21-day cycles to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT). Plasma was collected for pharmacokinetic analyses. Paired baseline and on-treatment skin and tumor biopsies were done; blood samples were collected for pharmacodynamic analyses, including p53 and macrophage inhibitory cytokine-1 induction.Results: The MTD of serdemetan was determined to be 350 mg once daily. During this study, grade 3 QTc prolongation was the most common DLT and nausea (66.2%) was the most frequent treatment-emergent adverse event. Serdemetan was rapidly absorbed after oral administration and exhibited dose-proportional pharmacokinetics. At steady state, mean maximum plasma concentration (C max ) was 2,330 ng/mL and mean area under plasma concentration curve (AUC 0-24h ) was 43.0 mg.h/mL, with serdemetan 300 mg/d. There was a dose-and exposure-dependent p53 induction. One patient with breast cancer showed a partial response; 22 (38.6%) patients had stable disease.Conclusions: Serdemetan treatment was associated with p53 induction in both tumor and surrogate tissue pharmacodynamic studies and modest clinical activity. Although serdemetan was well tolerated with dose-proportional pharmacokinetics, exposure-related QTc liability was observed.

Introduction and aim of the study: We examined the association between a DNA sequence variant in the aquaporin-1 (AQP1) gene and performance in Hispanic marathon runners. Materials and methods: DNA samples (N = 784) were obtained from apparently healthy, biologically unrelated, ethnically matched Hispanic marathon runners who participated in international level marathons in Spain and Mexico. Cases (n = 396; men= 225; women=171) finished in the top 3 rd percentile for their age and gender, while Controls (n = 388; men=221 women=167) finished in the lowest 3 rd percentile. The AQP1 gene DNA sequence variant was detected by the tetra-primer ARMS-PCR procedure which targeted an area of 984 base pairs in the 3' untranslated region that included the polymorphic site (C-G). Results: The three expected AQP1 genotypes were observed in both groups (Cases: CC = 15%. GC = 42%, GG = 43%; and Controls: CC = 10%, GC = 39%, GG = 51%). These genotype frequencies were in Hardy-Weinberg equilibrium (X 2 , P≥0.05) and significantly (X 2 = 6.94, P=0.03) different between the Cases and Controls. The Allelic frequencies (Cases; C = 0.36, G = 0.64 and Controls; C = 0.30, G = 0.70) were significantly (X 2 = 7.55, P=0.005) different between groups. The Odds ratio = 1.35; 95% confidence interval = 1.08-1.67, suggested that the C allele was more prevalent in Cases than Controls. Conclusions: This study showed an association between a DNA sequence variant in the aquaporin-1 gene or in its surrounding region and performance in Hispanic marathon runners.

Plitidepsin, a marine-derived cyclic-peptide, inhibits SARS-CoV-2 replication at nanomolar concentrations by targeting the host protein eukaryotic translation elongation factor 1A. Here, we show that plitidepsin distributes preferentially to lung over plasma, with similar potency against across several SARS-CoV-2 variants in preclinical studies. Simultaneously, in this randomized, parallel, open-label, proof-of-concept study (NCT04382066) conducted in 10 Spanish hospitals between May and November 2020, 46 adult hospitalized patients with confirmed SARS-CoV-2 infection received either 1.5 mg (n = 15), 2.0 mg (n = 16), or 2.5 mg (n = 15) plitidepsin once daily for 3 d. The primary objective was safety; viral load kinetics, mortality, need for increased respiratory support, and dose selection were secondary end points. One patient withdrew consent before starting procedures; 45 initiated treatment; one withdrew because of hypersensitivity. Two Grade 3 treatment-related adverse events were observed (hypersensitivity and diarrhea). Treatment-related adverse events affecting more than 5% of patients were nausea (42.2%), vomiting (15.6%), and diarrhea (6.7%). Mean viral load reductions from baseline were 1.35, 2.35, 3.25, and 3.85 log10 at days 4, 7, 15, and 31. Nonmechanical invasive ventilation was required in 8 of 44 evaluable patients (16.0%); six patients required intensive care support (13.6%), and three patients (6.7%) died (COVID-19-related). Plitidepsin has a favorable safety profile in patients with COVID-19.

The objective of this study was to evaluate the antitumor activity and safety profile of 5 mg/m2 plitidepsin administered as a 3-h continuous intravenous infusion every 2 weeks to patients with advanced malignant melanoma who relapsed or progressed after one line of systemic therapy. Objective response rate (primary efficacy endpoint) was evaluated according to Response Evaluation Criteria In Solid Tumors and toxicity was assessed using National Cancer Institute -Common Toxicity Criteria Version 2.0. Of 39 enrolled patients (median age: 53 years), 37 patients were treated who received a total of 167 treatment cycles (median: 3 cycles per patient; range: 1-32). All patients had received prior systemic therapy with a median of one line per patient (range: 1-6 lines). Of the 35 evaluable patients, two dacarbazine-resistant patients (5.7%) with metastatic cutaneous melanoma achieved partial responses. Five other patients (14.3%) reported stable disease (median stable disease duration: 3.5 months; range: 2.2-15.8 months). Therefore, the rate of tumor growth control was 20.0%. With a median follow-up of 11.0 months, the median progression-free survival was 1.3 months and the median overall survival was 3.5 months. Six patients (16.2%) had the following treatment-related grade 3/4 adverse events: myalgia (n = 3), injection-site reaction (n = 2), hypersensitivity, hypotension, and fatigue (n = 1 each). One patient was withdrawn from the trial because of grade 4 hypersensitivity reaction and hypotension. No severe neutropenia was reported. Plitidepsin showed a minor degree of antitumor activity in patients with refractory advanced malignant melanoma. Further evaluation of plitidepsin in combination schedules may be warranted.

This randomized phase II study evaluated two schedules of the marine compound Plitidepsin with or without co-administration of L-carnitine in patients with renal cell carcinoma. Patients had adequate performance status and organ function. The primary endpoint was the rate of disease control (no progression) at 12 weeks (RECIST). Other endpoints included the response rate and time dependent efficacy measures. The trial also assessed the efficacy of L-carnitine to prevent Plitidepsin-related toxicity. The two regimes given as 24 hour infusion every two weeks showed hints of antitumoral activity. Disease control at 12 weeks was 15.8% in Arm A (5mg/m2, no L-carnitine) and 11,1% in Arm B (7mg/m2 with L-carnitine). Two partial responses were observed in Arm A (19 patients), none in Arm B (20 patients). Both schedules had the same progression-free interval (2.1 months). The median overall survival was 7.0 and 7.6 months. The safety OPEN ACCESSMar. Drugs 2009, 7 58 profile was similar in both arms of the trial and adverse events were mainly mild to moderate (NCI CTC version 2.0). Increasing the dose to 7mg/m2 did not increase the treatment efficacy but the incidence of transaminase and CPK elevations and serious AEs. Coadministration of L-carnitine did not prevent muscular toxicity or CPK-elevation associated with Plitidepsin.