First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies.

PURPOSE: GSK2126458 (GSK458) is a potent inhibitor of PI3K (α, ß, γ, and δ), with preclinical studies demonstrating broad antitumor activity. We performed a first-in-human phase I study in patients with advanced solid tumors. MATERIALS AND METHODS: Patients received oral GSK458 once or twice daily in a dose-escalation design to define the maximum tolerated dose (MTD). Expansion cohorts evaluated pharmacodynamics, pharmacokinetics, and clinical activity in histologically and molecularly defined cohorts. RESULTS: One hundred and seventy patients received doses ranging from 0.1 to 3 mg once or twice daily. Dose-limiting toxicities (grade 3 diarrhea,n= 4; fatigue and rash,n= 1) occurred in 5 patients (n= 3 at 3 mg/day). The MTD was 2.5 mg/day (MTD with twice daily dosing undefined). The most common grade ≥3 treatment-related adverse events included diarrhea (8%) and skin rash (5%). Pharmacokinetic analyses demonstrated increased duration of drug exposure above target level with twice daily dosing. Fasting insulin and glucose levels increased with dose and exposure of GSK458. Durable objective responses (ORs) were observed across multiple tumor types (sarcoma, kidney, breast, endometrial, oropharyngeal, and bladder cancer). Responses were not associated withPIK3CAmutations (OR rate: 5% wild-type vs. 6% mutant). CONCLUSIONS: Although the MTD of GSK458 was 2.5 mg once daily, twice-daily dosing may increase duration of target inhibition. Fasting insulin and glucose levels served as pharmacodynamic markers of drug exposure. Select patients achieved durable responses; however,PIK3CAmutations were neither necessary nor predictive of response. Combination treatment strategies and novel biomarkers may be needed to optimally target PI3K.

Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors.

Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non-HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2-compartment model with a linear first-order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non-HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose-normalized exposure compared with non-HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.

A pharmacokinetic, pharmacodynamic, and safety study of intravenous cyclophosphamide with an oral casopitant antiemetic regimen in cancer patients.

Casopitant is a potent and selective neurokinin-1 receptor antagonist formerly under development for a number of indications, including the treatment of chemotherapy-induced nausea and vomiting. This study was an open-label, randomized, multi-center, two-period crossover casopitant-cyclophosphamide interaction study. Subjects were cancer patients receiving cyclophosphamide based chemotherapy. The objectives of the study were to assess the effect of 3-day, repeat-dose, 150 mg oral casopitant on the pharmacokinetics (PK), safety, tolerability, and pharmacodynamics (white blood cell count) of single-dose IV cyclophosphamide. PK data from 14 evaluable subjects showed the geometric least-squares mean ratios (90% CI) for cyclophosphamide and the metabolite 4-hydroxycyclophosphamide AUC (with:without casopitant) were 1.03 (0.975, 1.09) and 0.948 (0.835, 1.08), respectively. Administration of casopitant was well tolerated and did not impact the safety profile of the treatment regimen. Casopitant did not affect the expected bone marrow toxicity of cyclophosphamide. Co-administration of 150 mg oral casopitant with single-dose IV cyclophosphamide did not appear to result in a clinically relevant change in cyclophosphamide or 4-hydroxycyclophosphamide exposure or safety.

An open-label study of the safety and tolerability of pazopanib in combination with FOLFOX6 or CapeOx in patients with colorectal cancer.

BACKGROUND: Although combining targeted agents with conventional, first-line cytotoxic therapy has improved survival outcomes in patients with advanced colorectal cancer, further improvements in outcomes and tolerability are needed. METHODS: This phase I study evaluated the feasibility of combining oral pazopanib, an agent that targets multiple proangiogenic factors, with FOLFOX6 (oxaliplatin, leucovorin, and 5-fluorouracil) or CapeOx (oxaliplatin and capecitabine). This phase I study evaluated the optimally tolerated regimen of daily pazopanib (dose-escalated) plus standard FOLFOX6 or CapeOx in patients with advanced colorectal cancer. At the optimally tolerated regimen, each cohort was expanded to further evaluate safety and clinical response. RESULTS: The optimally tolerated regimens were pazopanib 800 mg plus FOLFOX6 and pazopanib 800 mg plus reduced CapeOx (capecitabine 850 mg/m(2)). The most commonly reported adverse events in the FOLFOX6 cohorts included decreased appetite, neutropenia, diarrhea, peripheral neuropathy, and vomiting. Similarly, the most commonly reported adverse events in the CapeOx cohorts included fatigue, vomiting, and decreased appetite. The overall response rate was 40 % (8/20 patients) in the pazopanib plus FOLFOX6 cohorts and 38 % (8/21 patients) in the pazopanib plus CapeOx cohorts. CONCLUSION: Pazopanib combined with FOLFOX6 or reduced CapeOx was adequately tolerated in this patient population.

Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma.

PURPOSE: Foretinib is an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors. Activating mutations or amplifications in MET have been described in patients with papillary renal cell carcinoma (PRCC). We aimed to evaluate the efficacy and safety of foretinib in patients with PRCC. PATIENTS AND METHODS: Patients were enrolled onto the study in two cohorts with different dosing schedules of foretinib: cohort A, 240 mg once per day on days 1 through 5 every 14 days (intermittent arm); cohort B, 80 mg daily (daily dosing arm). Patients were stratified on the basis of MET pathway activation (germline or somatic MET mutation, MET [7q31] amplification, or gain of chromosome 7). The primary end point was overall response rate (ORR). RESULTS: Overall, 74 patients were enrolled, with 37 in each dosing cohort. ORR by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli. CONCLUSION: Foretinib demonstrated activity in patients with advanced PRCC with a manageable toxicity profile and a high response rate in patients with germline MET mutations.

A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors.

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P<0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P<0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily.

A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors.

Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is a practical alternative. This open-label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer (Part 1). Patients completing Part 1 were eligible for continuous daily pazopanib 800 mg (Part 2). Administration of a single pazopanib 400 mg crushed tablet increased the area under the curve from 0 to 72 h (AUC((0-72)); 46%) and maximum observed plasma concentration (C(max); ~2-fold), and decreased time to achieve maximum plasma concentration (T(max); ~2 h), indicating increased rate and extent of oral absorption relative to whole-tablet administration. Similarly, a single dose of pazopanib 400 mg suspension increased AUC((0-72)) (33%) and C(max) (29%), and decreased T(max) (1 h). These changes in pharmacokinetic parameters were not associated with increases in the magnitude or duration of short-term (ie, up to 72 h) blood pressure elevation compared with whole-tablet administration.

A comparison of the pharmacokinetics of the anticancer MET inhibitor foretinib free base tablet formulation to bisphosphate salt capsule formulation in patients with solid tumors.

PURPOSE: This phase I, open-label, randomized, 2-part crossover study assessed the safety, pharmacokinetics and relative bioavailability of single doses of the anticancer MET inhibitor foretinib (formerly known as GSK1363089, EXEL-2880 and XL-880) free base tablet formulation compared to a bisphosphate salt capsule formulation (Part 1), and assessed the safety, efficacy, and pharmacokinetics of the bisphosphate salt capsule administered 3 times a week in cancer patients (Part 2). PATIENTS AND METHODS: In Part 1, patients were randomized in a crossover manner to receive a single oral dose of foretinib formulated as a bisphosphate salt capsule (240 mg; 183 mg free base equivalent) followed one week later by a single dose of a free base tablet (180 mg), or vice versa where the treatment sequence was reversed. In Part 2, patients self-administered oral doses of bisphosphate salt capsules (200 mg) 3 times a week until disease progression. RESULTS: Twelve patients with solid tumors were enrolled and completed Part 1, and 10 patients continued into Part 2. Most AEs were mild or moderate in severity. The most common drug-related AEs were fatigue, diarrhea, and nausea. The least-squares (LS) mean total area under the curve was 3144 and 3514 ng*h/mL for the free base tablet and bisphosphate salt capsule, respectively, with a ratio of 0.89 (90% confidence interval, CI: 0.69, 1.16). The LS mean maximal concentration (Cmax) was 81.6 and 98.5 ng/mL for the free base and bisphosphate salt, respectively, with a ratio of 0.83 (90% confidence interval, CI: 0.67, 1.02). The time to reach Cmax was ∼4 h for both formulations. The pharmacokinetics of foretinib were not clinically different between the 2 formulations. Of the 10 patients assessed for efficacy, 3 patients achieved stable disease. CONCLUSIONS: Foretinib was well tolerated as single doses of both the free base and bisphosphate salt formulations. The pharmacokinetics and relative bioavailability of the 2 formulations were not clinically different. The bisphosphate salt formulation was well tolerated on a 3-times a week dosing schedule, and reached steady-state plasma concentration after 2 weeks.

Lack of effect of casopitant on the pharmacokinetics of docetaxel in patients with cancer.

PURPOSE: The neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel. METHODS: Fourteen cancer patients were enrolled in this phase 1, open-label, randomized, two-period crossover study. Intravenous (i.v.) docetaxel was coadministered with oral ondansetron and dexamethasone with (Regimen B) or without (Regimen A) 150 mg single-dose oral casopitant. RESULTS: The geometric least-squares mean Regimen B: Regimen A ratios (90% confidence interval) for docetaxel maximum plasma concentration and area under the concentration-time curve from time 0 extrapolated to infinity were 0.97 (0.83, 1.12) and 1.06 (0.94, 1.19), respectively. Coadministration of casopitant and docetaxel was well tolerated, with adverse event profiles and absolute neutrophil count nadirs similar for both treatments. CONCLUSIONS: C(max) and AUC of docetaxel were similar when given as monotherapy or when given in combination with casopitant. Likewise, absolute neutrophil count nadirs were similar for docetaxel alone or docetaxel with casopitant.

Impact of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of ondansetron and dexamethasone.

INTRODUCTION: Pharmacokinetic interactions between casopitant (a substrate and weak to moderate inhibitor of CYP3A), dexamethasone (a substrate and weak inducer of CYP3A), and ondansetron (a mixed CYP substrate) were evaluated in a two-part, three-period, single-sequence study in two groups of healthy subjects. MATERIALS AND METHODS: Part 1: subjects received oral casopitant (regimen A); oral dexamethasone and IV ondansetron (regimen B); and oral casopitant, a reduced dose of oral dexamethasone, and IV ondansetron (regimen C). Part 2: subjects received oral casopitant (regimen D); IV dexamethasone and oral ondansetron (regimen E); and oral casopitant, IV dexamethasone, and oral ondansetron (regimen F). Each regimen was separated by 14 days. RESULTS: Casopitant AUC in regimen C was increased 28% on day 1 but decreased 34% on day 3 compared to casopitant alone in regimen A. When given with casopitant and ondansetron in regimen C, dexamethasone AUC was 17% lower on day 1, but similar on day 3, compared to regimen B (representing dose-normalized increases in exposure of 39% and 108%, respectively). Ondansetron exposure was equivalent in regimens B and C. Casopitant AUC in regimen F was similar to regimen D on days 1 and 3. Dexamethasone AUC increased 21% when given with oral casopitant and oral ondansetron (regimen F compared to regimen E). Ondansetron exposure was equivalent in regimens E and F. CONCLUSION: When repeat-dose oral dexamethasone is to be coadministered with oral casopitant, a reduction in dexamethasone dose may be considered; however, no change in casopitant dose is required. Ondansetron exposure was not affected by coadministration with casopitant.

Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron.

OBJECTIVE: The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron. MATERIALS AND METHODS: In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort. RESULTS: The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were <20%, and granisetron exposure was not altered to any relevant extent (<11%). CONCLUSION: None of the changes observed are considered clinically meaningful, and coadministration of casopitant with dolasetron or granisetron was well tolerated.

A phase I study of a new nucleoside analogue, OSI-7836, using two administration schedules in patients with advanced solid malignancies.

PURPOSE: To investigate the safety, tolerability, and pharmacokinetic profile of the novel nucleoside analogue OSI-7836 in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: OSI-7836 was initially given as a 60-minute i.v. infusion on day 1 every 21 days. In view of its dose-limiting toxicities, the administration time was amended to a 5-minute bolus, and subsequently, the schedule was amended to weekly for 4 weeks followed by a 2-week rest. Blood and urine samples were collected for pharmacokinetic studies. Analyses of cytokines and lymphocyte subsets were added later in the study to elucidate a mechanism for the severe fatigue and lymphocyte depletion observed in earlier patients. RESULTS: Thirty patients received a total of 61 treatment cycles. Fatigue was the main dose-limiting toxicity. Maximum-tolerated dose was defined as 300 mg/m2 in the 60-minute infusion, (three times per week) schedule; 400 mg/m2 in the 5-minute bolus infusion, (three times per week) schedule; and 100 mg/m2 in the weekly schedule. Other common toxicities were nausea, vomiting, rash, fever, and a flu-like syndrome. There were no clinically significant hematologic toxicities. Following the initial dose, OSI-7836 was eliminated from plasma with a median (range) elimination half-life of 48.3 minutes (22.6-64.8 minutes). Lymphocyte subset analysis showed a significant drop in B cell counts, which persisted to day 14 and beyond. Cytokine analysis showed significant elevations of interleukin-6 and interleukin-10 in all patients who received > or = 200 mg/m2 OSI-7836. Best response was disease stabilization in seven patients. CONCLUSION: OSI-7836 was associated with excessive fatigue, and despite changes in its schedule and duration of administration, we did not observe an improvement in its tolerability. Its potentially selective effect on B lymphocytes could be exploited in further studies in specific hematologic malignancies.