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1.  The role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(−/−) mice 
Molecular pharmaceutics  2012;9(9):2442-2449.
Ribavirin is frontline treatment for hepatitis C virus infection. To determine the role of nucleoside transporters in the intestinal absorption of orally administered ribavirin, we perfused the intestines of Ent1(−/−) and wild-type mice, in situ, with [3H] ribavirin (20, 200 and 5000 μM) in the presence and absence of sodium. The decrease in luminal ribavirin concentration over 30 minutes was measured at 5-minute intervals. Blood samples were collected approximately every 10 minutes. Ribavirin plus phosphorylated metabolite concentrations (hereafter referred to as ribavirin) were determined in tissue, blood and plasma by HPLC fractionation and scintillation counting. There was no significant difference between wild-type and Ent1(−/−) mice in intestinal loss of ribavirin at any ribavirin concentration studied. Perfusions without sodium drastically reduced the intestinal loss of ribavirin in both wild-type and Ent1(−/−) mice. After 20 μM ribavirin perfusions, Ent1(−/−) intestinal tissue contained 8-fold greater ribavirin than wild-type mice (p<0.01). Ribavirin concentrations in the wild-type intestinal tissue were 70-fold higher after 200 vs. 20 μM perfusions (p<0.001), indicating saturation of intestinal ribavirin efflux and possibly other processes as well. Ribavirin plasma concentrations were significantly higher in wild-type mice (2.7-fold) vs. Ent1(−/−) mice at 30 minutes after the 20 μM perfusion (p<0.01). These results suggest that, at lower intestinal concentrations of ribavirin, concentrative and equilibrative nucleoside transporters are important in the intestinal absorption of ribavirin. At higher intestinal concentrations, these transporters are saturated and other processes in the intestine (transport and/or metabolism) play an important role in the absorption of ribavirin.
doi:10.1021/mp200647a
PMCID: PMC3443246  PMID: 22812541
Ribavirin; nucleoside transporter; hepatitis C; absorption; perfusion
2.  Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies—results of a phase I dose-escalation study 
Investigational New Drugs  2013;31(6):1487-1498.
Summary
Objectives The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies. Methods In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400–500 mg/m2 IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated. Results Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m2 and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand–foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83 %) and leukopenia (83 %). Pharmacokinetic data revealed no clinically significant drug–drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60 %). Conclusions With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.
doi:10.1007/s10637-013-0010-4
PMCID: PMC3825543  PMID: 23963796
Solid tumors; Non-small cell lung cancer; Sunitinib; Pemetrexed; Carboplatin
3.  Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: phase I study results 
Purpose
To evaluate the maximum tolerated dose (MTD), safety, and antitumor activity of sunitinib combined with paclitaxel and carboplatin.
Methods
Successive cohorts of patients with advanced solid tumors received oral sunitinib (25, 37.5, or 50 mg) for 2 consecutive weeks of a 3-week cycle (Schedule 2/1) or as a continuous daily dose for 3-week cycles (CDD schedule) in combination with paclitaxel (175–200 mg/m2) plus carboplatin (AUC 6 mg•min/mL) on day 1 of each of 4 cycles. Dose-limiting toxicities (DLTs) and adverse events (AEs) were evaluated to determine the MTD. Efficacy parameters were analyzed in patients with measurable disease.
Results
Forty-three patients were enrolled (n = 25 Schedule 2/1; n = 18 CDD schedule). Across all doses, 6 DLTs were observed (grade 4 papilledema, grade 5 GI hemorrhage, grade 3 neutropenic infection, grade 4 thrombocytopenia [n = 3]). The MTD for Schedule 2/1 was sunitinib 25 mg plus paclitaxel 175 mg/m2 and carboplatin AUC 6 mg•min/mL. The MTD was not determined for the CDD schedule. Treatment-related AEs included neutropenia (77%), thrombocytopenia (56%), and fatigue (47%). Of 38 evaluable patients, 4 (11%) had partial responses and 12 (32%) had stable disease. PK data indicated an increase in maximum and total plasma exposures to sunitinib and its active metabolite when given with paclitaxel and carboplatin compared with sunitinib monotherapy.
Conclusions
Myelosuppression resulting in prolonged dose delays and frequent interruptions was observed, suggesting that this treatment combination is not feasible in the general cancer population.
doi:10.1007/s00280-010-1536-1
PMCID: PMC3400085  PMID: 21140147
Sunitinib; Phase I; Solid tumor; NSCLC; Antiangiogenesis; Chemotherapy
4.  Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors 
Investigational New Drugs  2012;30(6):2352-2363.
Summary
Background Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. Methods This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. Results Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional ‘3 + 3’ design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. Conclusions Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.
doi:10.1007/s10637-011-9789-z
PMCID: PMC3523469  PMID: 22249430
Dacomitinib; PF-00299804; Epidermal growth factor receptor; Tyrosine kinase inhibitor; Japanese patients; Phase I
5.  Phase II study of sunitinib as second-line treatment for advanced gastric cancer 
Investigational New Drugs  2010;29(6):1449-1458.
Summary
Purpose. This phase II, open-label, multicenter study assessed the oral, multitargeted, tyrosine kinase inhibitor sunitinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma who had received prior chemotherapy. Experimental design. Patients received sunitinib 50 mg/day on Schedule 4/2 (4 weeks on treatment, followed by 2 weeks off treatment). The primary endpoint was objective response rate; secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), pharmacokinetics, pharmacodynamics, safety and tolerability, and quality of life. Results. Of 78 patients enrolled, most had gastric adenocarcinoma (93.6%) and metastatic disease (93.6%). All were evaluable for safety and efficacy. Two patients (2.6%) had partial responses and 25 patients (32.1%) had a best response of stable disease for ≥6 weeks. Median PFS was 2.3 months (95% confidence interval [CI], 1.6–2.6 months) and median OS was 6.8 months (95% CI, 4.4–9.6 months). Grade ≥3 thrombocytopenia and neutropenia were reported in 34.6% and 29.4% of patients, respectively, and the most common non-hematologic adverse events were fatigue, anorexia, nausea, diarrhea, and stomatitis. Pharmacokinetics of sunitinib and its active metabolite were consistent with previous reports. There were no marked associations between baseline soluble protein levels, or changes from baseline, and measures of clinical outcome. Conclusions. The progression-delaying effect and manageable toxicity observed with sunitinib in this study suggest that although single-agent sunitinib has insufficient clinical value as second-line treatment for advanced gastric cancer, its role in combination with chemotherapy merits further study.
doi:10.1007/s10637-010-9438-y
PMCID: PMC3171673  PMID: 20461441
Sunitinib; Gastric cancer; Tyrosine kinase inhibitor; Pharmacokinetics; Pharmacodynamics
6.  A phase 2 trial of dacomitinib (PF‐00299804), an oral, irreversible pan‐HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non–small cell lung cancer after failure of prior chemotherapy and erlotinib 
Cancer  2014;120(8):1145-1154.
BACKGROUND
This phase 2 trial (ClinicalTrials.gov identifier NCT00548093) assessed the efficacy, safety, and impact on health‐related quality of life of dacomitinib (PF‐00299804), an irreversible tyrosine kinase inhibitor (TKI) of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, in patients with KRAS wild‐type non–small cell lung cancer (NSCLC).
METHODS
Patients with advanced NSCLC, progression on 1 or 2 regimens of chemotherapy and erlotinib, KRAS wild‐type or known EGFR‐sensitizing mutant tumor, and Eastern Cooperative Oncology Group performance status of 0 to 2 received 45 mg of dacomitinib once daily continuously in 21‐day cycles.
RESULTS
A total of 66 patients enrolled (adenocarcinoma, n = 50; those without adenocarcinoma [nonadenocarcinoma], n = 16). The objective response rate (ORR) for patients with adenocarcinoma (primary endpoint) was 5% (2 partial responses; 1‐sided P = .372 for null hypothesis [H0]: ORR ≤ 5%) and 6% (1 partial response) for patients with nonadenocarcinoma. Responders included: 2 of 25 EGFR mutation‐positive tumors; 1 of 3 EGFR wild‐type with HER2 amplification. Median progression‐free survival was 12 weeks overall (n = 66) and 18 weeks (n = 26) for patients with EGFR mutation‐positive tumors. Common treatment‐related adverse events were of grade 1 or 2 severity, manageable with standard supportive care, and included diarrhea (grade 3 [G3], 12%), acneiform dermatitis (G3, 6%), exfoliative rash (G3, 3%), dry skin (G3, 0%), fatigue (G3, 3%), and stomatitis (G3, 2%). Six patients (9%) discontinued due to treatment‐related adverse events. By patient report, NSCLC symptoms of dyspnea, cough, and pain (chest, arm/shoulder) showed improvement first observed after 3 weeks on therapy.
CONCLUSIONS
Dacomitinib demonstrated preliminary activity and acceptable tolerability in heavily pretreated patients, and may offer benefit in molecularly defined patient subsets. Cancer 2014;120:1145–1154. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
This study investigated the efficacy and safety of dacomitinib in advanced, refractory non–small cell lung cancer (NSCLC), selecting for patients with KRAS wild‐type tumors to exclude those least likely, and simultaneously enrich for those most likely, to benefit from therapy. Although the observed response rate was low, a number of patients experienced prolonged disease control accompanied by rapid and durable lung cancer symptom relief, suggesting that dacomitinib has relevant activity against KRAS wild‐type NSCLC.
doi:10.1002/cncr.28561
PMCID: PMC4164026  PMID: 24501009
dacomitinib; PF‐00299804; non–small cell lung cancer; erlotinib; adenocarcinoma; nonadenocarcinoma

Results 1-6 (6)