Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study.

BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.

Phase I study of the indoleamine 2,3-dioxygenase 1 inhibitor navoximod (GDC-0919) as monotherapy and in combination with the PD-L1 inhibitor atezolizumab in Japanese patients with advanced solid tumours.

Navoximod (GDC-0919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1. This study investigated the safety, tolerability and pharmacokinetics of navoximod alone and in combination with atezolizumab in Japanese patients with advanced solid tumours. This was a phase I, open-label, dose-escalation study. Patients received monotherapy with navoximod 400 mg, 600 mg or 1000 mg orally twice daily (BID) in Stage 1 and navoximod 200 mg, 400 mg, 600 mg or 1000 mg orally BID plus atezolizumab 1200 mg intravenously every 21 days in Stage 2. Objectives included safety, tolerability, efficacy and pharmacokinetic outcomes.Overall, 20 patients were enrolled (Stage 1: n = 10; Stage 2: n = 10). No dose-limiting toxicities were observed. In Stage 1, treatment-related adverse events (TRAEs) of any grade that occurred in ≥20% of patients were chromaturia (50%) and maculopapular rash (20%). Grade ≥ 3 TRAEs were reported in two patients (20%; maculopapular rash and lipase increased). In Stage 2, TRAEs that occurred in ≥30% of patients were chromaturia (60%) and, decreased appetite (40%). Grade ≥ 3 TRAEs were reported in three patients (30%; hyponatraemia, aspartate aminotransferase increased, alanine aminotransferase increased, lymphopaenia and neutropaenia). Stable disease was observed in five patients (50%) in Stage 1 and eight patients (80%) in Stage 2. Navoximod showed linear pharmacokinetics. The recommended dose of navoximod monotherapy was determined as 1000 mg orally BID, and could be considered 1000 mg orally BID in combination with atezolizumab. Navoximod as monotherapy and in combination with atezolizumab was well tolerated in Japanese patients with advanced solid tumours.

Safety, tolerability and pharmacokinetics of shorter duration of infusion of obinutuzumab in Japanese patients with B-cell non-Hodgkin lymphoma: final results of the phase II GATS study.

BACKGROUND: Shorter duration of infusion of monoclonal antibody treatments may reduce treatment burden and improve healthcare resource utilization. METHODS: This phase II study recruited Japanese patients with previously untreated CD20+ B-cell non-Hodgkin lymphoma. Patients received intravenous obinutuzumab 1000 mg by regular infusion on Days 1, 8 and 15 of Cycle 1, followed by 90-min shorter duration of infusion in up to seven subsequent cycles, provided they received ≥3 regular infusions without any grade ≥3 infusion-related reactions and had a lymphocyte count <5.0 × 109 cells/l. Standard cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy was given in Cycles 1-6. The primary endpoints were as follows: incidence of grade ≥3 infusion-related reactions in Cycle 2 in patients who started shorter duration of infusion in Cycle 2, serum obinutuzumab concentrations and pharmacokinetic parameters and the time course of cytokine release. Adverse events and serious adverse events were monitored. RESULTS: Of 35 patients treated, 28 completed eight cycles; 31 started shorter duration of infusion in Cycle 2 and two patients in subsequent cycles. Two patients discontinued before starting shorter duration of infusion. No grade ≥3 infusion-related reactions occurred in Cycle 2. Twenty-one infusion-related reactions (all grades 1-2) were reported in 17/35 (49%) patients overall, mostly in Cycle 1 (18/21 infusion-related reactions [86%]). Grade ≥3 AEs occurring in ≥10% of patients included neutropenia/neutrophil count decreased (66%) and leukopenia/white blood cell count decreased (23%). Steady-state pharmacokinetics of obinutuzumab were attained in Cycle 2 and were not affected by shorter duration of infusion. No relevant cytokine elevations were reported with shorter duration of infusion. CONCLUSIONS: Regular infusion and shorter duration of infusion of obinutuzumab have comparable tolerability and pharmacokinetics in Japanese patients.

Effective use of modeling and simulation in designing bioequivalence and comparability studies of large-molecule compounds: the case of erythropoietin.

OBJECTIVE: Bioequivalence and comparability studies are necessary for changing formulations of large-molecule drugs, such as antibody drugs and protein products, and in the development of their biosimilars. This study is the first application of modeling and simulation (M&S) in the design of bioequivalence and comparability studies of erythropoietin as an example of a large-molecule drug. METHODS: A novel population pharmacokinetic and pharmacodynamic (PPK/PD) model was developed for erythropoietin. Based on this PPK/PD model, the probabilities of success of bioequivalence and comparability studies were simulated with various numbers of subjects and samples. RESULTS: The simulation indicated that the minimum numbers of subjects and samples required to satisfy the criteria for bioequivalence and comparability studies were as follows: fewest for the area under the serum concentration-time curve, more for the area under the efficacy-time curve, and most for the maximum serum concentration of erythropoietin. CONCLUSION: These results suggested that M&S could be successfully applied in the design of bioequivalence and comparability studies of large-molecule drugs.

The optimal oral dose selection of ibandronate in Japanese patients with osteoporosis based on pharmacokinetic and pharmacodynamic properties.

Ibandronate is a drug widely used outside Japan for the treatment of osteoporosis. It is available in formulations for intermittent intravenous (i.v.) administration and for intermittent (once monthly) oral administration. Ibandronate was recently approved in Japan as an i.v. injection with a dosing regimen of 1.0 mg once a month. To establish the optimal dose for oral administration of ibandronate in Japanese osteoporotic patients, we investigated the pharmacokinetics of and pharmacodynamic response to ibandronate following oral and intravenous administrations to Japanese subjects. Ibandronate (20, 50, 100, or 150 mg) was given orally to healthy postmenopausal Japanese women and to Japanese patients with primary osteoporosis. Serial measurements were obtained for the concentrations of serum ibandronate and urinary cross-linked C-telopeptide of Type I collagen (uCTX). Pharmacokinetic parameters and the time profiles of creatinine-corrected uCTX were compared with those obtained from postmenopausal Japanese women with osteopenia after administration of 1.0 mg i.v. ibandronate. Following oral administration of ibandronate, the area under the serum ibandronate concentration-time curve (AUCinf) increased dose-proportionally for doses up to 100 mg; at 150 mg, AUCinf increased beyond the dose-proportionality seen with doses up to 100 mg. The AUCinf within the linear range following administration of 100 mg oral ibandronate was similar to that following 1.0 mg i.v. ibandronate. Additionally, corrected uCTX decreased after administration of 100 mg oral ibandronate and remained decreased for 1 month; the magnitude of the decrease was similar to or greater than that obtained after 1.0 mg i.v. ibandronate. From a clinical pharmacological perspective, administration of 100 mg/month oral ibandronate was equivalent to that of 1.0 mg/month i.v. ibandronate.

Application of modeling and simulation to a long-term clinical trial: a direct comparison of simulated data and data actually observed in Japanese osteoporosis patients following 3-year ibandronate treatment.

Ibandronate, a nitrogen-containing bisphosphonate, is a bone resorption inhibitor widely used to prevent and treat osteoporosis. To optimize the design for a long-term clinical study of ibandronate, modeling and simulation (M&S) was performed based on the result of population pharmacodynamic analysis using the data of a short-term clinical study. A population pharmacodynamic model was constructed by the urinary C-terminal telopeptide of type I collagen (uCTx) and the lumbar spine bone mineral density (BMD) data obtained in clinical studies, including a phase II study of Japanese osteoporosis patients treated with ibandronate for 6 months. Changes in BMD over a period of 3 years were simulated from the population pharmacodynamic parameters of the patients in this phase II study. The relationship between uCTx and BMD was well described by this modeling. The functions of disease progression and supplemental treatment were incorporated into the model to simulate a long-term clinical study with high accuracy. A long-term clinical study with a 3-year treatment was conducted after this M&S. The percentage change from baseline in observed BMD values were found to be similar to the prospectively simulated values. This study showed that M&S could be a useful and powerful tool for designing and conducting long-term clinical studies when carried out in the following sequence: (1) conduct a short-term clinical study; (2) perform M&S; and (3) conduct the long-term clinical study. Application of this procedure to various other treatment agents will establish the usefulness of M&S for long-term clinical studies and bring further efficiencies to drug development.

Studies on the metabolic fate of M17055, a novel diuretic (4): species difference in metabolic pathway and identification of human CYP isoform responsible for the metabolism of M17055.

The metabolic profile of M17055, a novel diuretic, after administration to experimental animals and after incubation with human liver microsomes was investigated. 1. Extensive metabolism was observed in rats and monkeys and the structures of six metabolites (RU1, RU2, and RU3 from rat urine or liver perfusate; MU1, MU2 and MU3 from monkey urine) were assumed or identified. The clear species difference of metabolism was revealed between rats and a monkey with different structures of the isolated metabolites. 2. When these metabolites were quantified using radioactive material, RU3, RU1 and MU3 were considered to be major metabolites in rat urine, rat bile and monkey urine respectively, while in a dog, unchanged drug was observed as the major component indicating only little metabolism occurred in dog, when administered intravenously. 3. RU1 and RU2 were also generated from [(14)C]M17055 after incubation with human liver microsomes, suggesting that the metabolic pathway of M17055 in humans involves that observed in rats. 4. [(14)C]M17055 metabolism in human liver microsomes was inhibited by CYP2C8/9 and CYP3A4/5 inhibitors, and also by the antibodies that recognize CYP2C8/9/19 and CYP3A4. Significant correlations were observed between the rate of [(14)C]M17055 metabolism and the activity of testosterone 6beta-hydroxylation or tolbutamide methyl-hydroxylation. cDNA-expressed CYP3A4 and CYP2C9 could catalyze the metabolism of [(14)C]M17055. These results suggest that the metabolism of M17055 in human liver microsomes is catalyzed mainly by CYP3A4 and CYP2C9.

Studies on the metabolic fate of m17055, a novel diuretic (5): pharmacokinetics and pharmacodynamics of unchanged drug in rat and dog after intravenous administration of M17055.

The pharmacokinetics and pharamacodynamics of M17055, a novel diuretic were studied after a single intravenous administration to rats and dogs, the two species used in the pharmacological and toxicological studies. No gender dependent response to systemic exposure was observed at the high dose level in rats, in agreement with the determined LD(50). A gender difference in urinary excretion of M17055, however, was clearly observed in rats. The slower elimination and the lower total body clearance (CLtot) values of M17055 in dogs reflect the difference of the no-effect level (NOEL) between rats (0.1 mg/kg) and dogs (0.03 mg/kg) well. The diuretic response was well correlated with the urinary M17055 excretion rate by fitting to a sigmoid E(max) model in both rats and dogs. The derived ER(50) value of M17055 in dogs was approximately 10 times less than that reported for furosemide, suggesting that the intrinsic potency of M17055 is equal to or higher than those of other powerful loop diuretics. Although diuretic sensitivity was considered to be lower in dogs than in rats, the higher amount of M17055 reaching the dog kidney is likely to compensate for this. The diuretic response in female rats was predictable by using the pharmacodynamic parameters derived from male rats. These results show that the apparent high diuretic potency and the other pivotal observations for M17055 found in the pharmacological and toxicological studies can be rationalized by the pharmacokinetic and pharmacodynamic properties of the unchanged compound.

Modeling and simulation of orlistat to predict weight loss and weight maintenance in obesity patients.

Orlistat is used clinically worldwide as anti-obesity drug. It is a chemically synthesized hydrogenated derivative of lipstatin and is an inhibitor of gastric and pancreatic lipases. It has been found to reduce the absorption of dietary fat in the gastrointestinal tract. Modeling and simulation based on pharmacokinetic/pharmacodynamic analysis is becoming increasingly used in the design of clinical trials to assure that the trials are of high quality and are conducted efficiently. We developed a clinical trial simulation model for orlistat based on Phase III clinical study data. This innovative weight loss model includes the relationships between orlistat dose, changes in fecal fat excretion, and weight loss, and also incorporates a dropout function. The model guided the dose-finding strategy and allowed simulation of long-term clinical outcomes of orlistat.