Relative bioavailability and food effect of the galectin-3 inhibitor selvigaltin (GB1211) administered as a tablet in healthy participants (GALBA-1).

PURPOSE: Overexpression of galectin-3, a ß-galactoside-binding lectin, is associated with fibrotic diseases and cancer. Selvigaltin is an oral galectin-3 inhibitor, previously administered as a 50 mg capsule. This study aimed to evaluate the relative bioavailability and food effect of selvigaltin as a 100 mg tablet in healthy volunteers. METHODS: In this single-dose, randomized, three-period, crossover study (GALBA-1; NCT05747573), participants received selvigaltin as a 100 mg tablet (under fasted and fed conditions) or as two 50 mg capsules (under fasted conditions). Primary endpoints included plasma and urine pharmacokinetic (PK) parameters. Secondary endpoints were safety and tolerability. RESULTS: Of the 13 enrolled participants, 12 completed the study. Under fasted conditions, geometric mean maximum observed plasma concentration (Cmax) and systemic exposure (AUC0─inf) of selvigaltin were 161.0% and 84.0% higher, respectively, after administration of a tablet vs. capsules. Under fed vs. fasted conditions, geometric mean Cmax of the selvigaltin tablet was 20.0% lower, whereas AUC0─inf was unaffected. Geometric mean percentage of total dose of selvigaltin excreted in urine over 0─96 h was 30.3% and 35.9% for the tablet under fasted and fed conditions, respectively, and 14.5% for the capsules. No treatment-emergent severe or serious adverse events or study discontinuations due to a treatment-emergent adverse event were reported. CONCLUSION: The tablet formulation of selvigaltin displayed higher bioavailability vs. the capsule formulation, with minimal effect of food on PK. Selvigaltin was well-tolerated during all treatments. These findings warrant further clinical development of the tablet formulation of selvigaltin without specific food restrictions. CLINICAL TRIAL REGISTRATION: NCT05747573; February 28, 2023.

Safety and pharmacokinetics of GB1211, an oral galectin-3 inhibitor: a single- and multiple-dose first-in-human study in healthy participants.

PURPOSE: Galectin-3, a ß-galactoside-binding lectin, plays a key role in several cellular pathways involved in chronic inflammation, heart disease and cancer. GB1211 is an orally bioavailable galectin-3 inhibitor, developed to be systemically active. We report safety and pharmacokinetics (PK) of GB1211 in healthy participants. METHODS: This phase 1, double-blind, placebo-controlled, first-in-human study (NCT03809052) included a single ascending-dose phase (with a food-effect cohort) where participants across seven sequential cohorts were randomized 3:1 to receive oral GB1211 (5, 20, 50, 100, 200 or 400 mg) or placebo. In the multiple ascending-dose phase, participants received 50 or 100 mg GB1211 or placebo twice daily for 10 days. All doses were administered in the fasted state except in the food-effect cohort where doses were given 30 min after a high-fat meal. RESULTS: All 78 participants received at least one GB1211 dose (n = 58) or placebo (n = 20) and completed the study. No safety concerns were identified. Following single and multiple oral doses under fasted conditions, maximum GB1211 plasma concentrations were reached at 1.75-4 h (median) post-dose; mean half-life was 11-16 h. There was a ~ twofold GB1211 accumulation in plasma with multiple dosing, with steady-state reached within 3 days; 30% of the administered dose was excreted in urine as unchanged drug. Absorption in the fed state was delayed by 2 h but systemic exposure was unaffected. CONCLUSION: GB1211 was well tolerated, rapidly absorbed, and displayed favorable PK, indicating a potential to treat multiple disease types. These findings support further clinical development of GB1211. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifier: NCT03809052).

Multiple administrations of fluconazole increase plasma exposure to ruxolitinib in healthy adult subjects.

PURPOSE: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects. METHODS: The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined. RESULTS: All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters Cmax, AUClast, and AUCinf increased by 47%, 234%, and 232%, respectively, vs ruxolitinib alone. The median Tmax decreased slightly, apparent clearance decreased approximately threefold, and elimination half-life increased approximately 2.5-fold, upon ruxolitinib administration with fluconazole vs ruxolitinib alone. These results were consistent with the prospective predictions from a SimCYP PBPK model. Adverse events (AEs) were reported in six subjects (none were suspected to be related to ruxolitinib); no death or on-treatment serious AE was reported. CONCLUSIONS: Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib.

Eltrombopag treatment during induction chemotherapy for acute myeloid leukaemia: a randomised, double-blind, phase 2 study.

BACKGROUND: Patients with acute myeloid leukaemia frequently have thrombocytopenia during induction chemotherapy. Eltrombopag, an oral thrombopoietin receptor agonist, stimulates platelet production by a similar mechanism to endogenous thrombopoietin. This study investigated safety and efficacy of eltrombopag versus placebo during anthracycline-based induction treatment of patients with acute myeloid leukaemia. METHODS: In this randomised, double-blind, phase 2 study, treatment-naive patients were recruited from clinical centres across 10 countries (Australia, Belgium, Canada, Greece, Hungary, Israel, South Korea, Poland, Russia, and the USA). Patients with acute myeloid leukaemia of any subtype except M3 and M7 were stratified by antecedent malignant haematological disorder (yes or no) and age (18-60 years or >60 years) and were then randomly assigned (1:1) using an automated interactive voice-response system randomisation schedule. Investigators and patients were blinded to study treatment. Starting on day 4, patients received standard induction chemotherapy (daunorubicin bolus intravenous infusion on days 1-3 [90 mg/m2 for patients aged 18-60 years or 60 mg/m2 for patients aged >60 years], plus cytarabine continuous intravenous infusion on days 1-7 [100 mg/m2]), with eltrombopag 200 mg (100 mg for east Asians) or placebo once daily, until platelet counts were 200 × 109/L or higher, until remission, or after 42 days from the start of induction chemotherapy. The primary objective of the study was safety and tolerability assessed by adverse events, changes in left ventricular ejection fraction (LVEF), and clinical laboratory parameters in all treated patients. This study has been completed and is registered with ClinicalTrials.gov, number NCT01890746. FINDINGS: Between Sept 7, 2013, and Jan 30, 2015, 149 patients were assessed for eligibility and 148 were then randomly assigned to receive eltrombopag (n=74) and placebo (n=74). Groups were matched in mean (SD) age (56·7 years [12·3] in the eltrombopag group vs 56·6 years [11·6] in the placebo group), mean (SD) initial platelet count (59·5 × 109/L [43·3] vs 63·7 × 109/L [48·0]), and poor-risk karyotype (16 [22%] of 74 patients in both groups). The most common grade 3-4 adverse events (≥10% in either group) were febrile neutropenia (31 [42%] vs 28 [39%]), decreased white blood cell count (8 [11%] vs 5 [7%]), and hypophosphataemia (3 [4%] vs 9 [13%]). Serious adverse events occurred in 24 (32%) patients in the eltrombopag group compared with 14 (20%) patients in the placebo group. 39 (53%) patients in the eltrombopag group died versus 29 (41%) patients in the placebo group. Thromboembolic events (5 [7%] vs 4 [6%]) and mean (SD) change in LVEF (-2·5% [7·8] vs -4·3% [8·5]) were similar. INTERPRETATION: Data from this trial do not support combining eltrombopag with induction chemotherapy in patients with acute myeloid leukaemia. FUNDING: Novartis Pharma AG.

Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers.

PURPOSE: Eltrombopag is indicated in patients with severe aplastic anemia (SAA) refractory to prior immunosuppressive therapy. The combination of eltrombopag and immunosuppressive therapy (such as cyclosporine) is currently being evaluated in patients with treatment-naive SAA. Cyclosporine is a human breast cancer resistance protein (BCRP) inhibitor, and can potentially alter plasma exposure to eltrombopag, a BCRP substrate. This phase 1, open-label, randomized, 3-period, crossover study evaluated the effect of cyclosporine on the pharmacokinetics of eltrombopag in healthy adults. METHODS: Thirty-nine subjects were randomized to either single dose of eltrombopag 50 mg, cyclosporine 200 mg + eltrombopag 50 mg or cyclosporine 600 mg + eltrombopag 50 mg treatment groups. Eltrombopag pharmacokinetic parameters (Cmax, tmax, AUClast, AUCinf, %AUCex, t1/2, and CL/F) were determined using noncompartmental methods. RESULTS: Geometric mean AUCinf, AUClast, and Cmax, were decreased by 18, 20, and 25%, respectively, for cyclosporine 200 mg + eltrombopag and by 24, 22, and 39%, respectively, for cyclosporine 600 mg + eltrombopag groups compared to the eltrombopag alone group. The median tmax was prolonged by ~ 1 h in both coadministration treatments. The geometric mean t1/2 was ≈ 21, ≈ 24, and ≈ 26 h, respectively, in cyclosporine 200 mg + eltrombopag, cyclosporine 600 mg + eltrombopag and eltrombopag alone groups. All the treatments were safe and well-tolerated. No serious adverse event or death was reported during the study. CONCLUSION: These changes in exposure were not considered clinically meaningful as the dose of eltrombopag is adjusted using within-patient dose titration based on platelet counts.

Modeling and Simulation Support Eltrombopag Dosing in Pediatric Patients With Immune Thrombocytopenia.

Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in two clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including three pharmacokinetic and four pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules. This work supported initial eltrombopag doses of 50 mg once daily (q.d.) for non-Asian patients aged ≥ 6 years and 25 mg q.d. for Asian patients, regardless of age, and for all patients aged 1-5 years, regardless of ethnic origin. Doses were escalated at 2-week intervals or reduced as needed according to each patient's platelet counts to both minimize the time to achieve target platelet counts and mitigate thrombocytosis. Clinicaltrials.gov Identifier: NCT00908037, NCT01520909.

Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma.

Purpose: Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated BRAF-mutant melanoma.Experimental Design: The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50-700 mg) or twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic BRAF-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar-plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4-not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9-3.7).Conclusions: Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. Clin Cancer Res; 23(18); 5339-48. ©2017 AACR.