A phase I study of capecitabine, oxaliplatin, and lapatinib in metastatic or advanced solid tumors.

BACKGROUND: Metastatic colorectal cancer (mCRC) is a leading cause of cancer-related mortality in the United States, and new treatment options are needed. This phase I study investigated a novel regimen combining 2 chemotherapy drugs with proven efficacy in mCRC (capecitabine and oxaliplatin) with a tyrosine kinase inhibitor (lapatinib). Lapatinib has already been approved by the US Food and Drug Administration for treatment of selected cases of breast cancer. PATIENTS AND METHODS: Patients with solid tumors responsive to fluoropyrimidines or oxaliplatin were eligible for enrollment. Treatment was given over a 21-day cycle with a fixed dosing of intravenous oxaliplatin of 130 mg/m(2) on day 1. Capecitabine and lapatinib were given orally at escalating doses, starting at capecitabine 1500 mg/m(2)/day on days 1-14 and lapatinib 1000 mg daily on days 1-21. RESULTS: Ten patients received treatment per study protocol. All had received previous systemic treatment. Diarrhea was one of the most common side effects and accounted for nearly all grade 3/4 toxicity. The starting dose level was determined to be the maximum tolerated dose. One patient with pancreatic cancer had evidence of a partial response. Three other patients demonstrated stable disease. There were no complete responses. CONCLUSION: Results of this study suggest the regimen of capecitabine, oxaliplatin, and lapatinib has some efficacy in types of advanced or metastatic solid malignancies with known responsiveness to fluoropyrimidines or oxaliplatin. Further research may help determine whether this regimen can improve on the response rates seen with current standard regimens for mCRC.

Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. WHAT THIS STUDY ADDS: Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed. AIM: Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. METHODS: Subjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14. RESULTS: Co-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,∞) by 55% (42%, 69%) and C(max) by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects. CONCLUSIONS: Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.

A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma. METHODS: Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m(2). The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks. RESULTS: The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m(2). The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles. CONCLUSIONS: The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m(2). The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.

Eltrombopag (75 mg) does not induce photosensitivity: results of a clinical pharmacology trial.

BACKGROUND/PURPOSE: Eltrombopag is an oral, small molecule, thrombopoietin receptor agonist approved in the United States for the treatment of chronic immune thrombocytopenic purpura and under investigation for treatment of thrombocytopenia due to other etiologies. In vitro studies identified a phototoxic potential for eltrombopag that was not confirmed in subsequent animal studies at exposures up to 11 times the human clinical exposure. A randomized study in healthy men and women was conducted to more fully characterize the photosensitizing potential of a therapeutic dose of eltrombopag (75 mg q.i.d.). METHODS: In this placebo-controlled, randomized, parallel group study, the photosensitizing potential of eltrombopag was evaluated in 36 healthy subjects with 12 subjects per group treated for 6 days with eltrombopag 75 mg q.i.d., placebo q.i.d., or positive control ciprofloxacin 500 mg b.i.d. (a mild photosensitizer). The primary endpoint was the photosensitizing potential of eltrombopag in comparison with the placebo on day 6 as measured by the phototoxic index (PI) at 24-h postirradiation, delayed erythema, and the change from baseline in minimum erythemal dose (MED) at 24-h postirradiation. The PI and MED were determined at discrete wavelengths in the ultraviolet (UV) and visible light spectrum from 290 to 430 nm. RESULTS: At wavelengths of 295±5, 300±5, 305±30 nm, and solar simulator whole spectrum (SS WS), there were no notable median differences in delayed PI or change from baseline MED at 24-h postirradiation after administration of eltrombopag 75 mg q.i.d., placebo, or ciprofloxacin 500 mg b.i.d. Mild phototoxicity induced by ciprofloxacin 500 mg b.i.d. was observed at wavelengths of 335±30 and 365±30 nm within the UVA region. Following administration of ciprofloxacin, the median difference in delayed PI relative to placebo at wavelengths of 335±30 and 365±30 nm was increased to 0.75 [95% confidence interval (CI), 0.222-2.037] and 1.20 (95% CI, 0.404-1.720), respectively. However, there was no evidence that photosensitivity was increased following administration of eltrombopag 75 mg q.i.d. There were no significant differences between median delayed PI following administration of repeat doses of eltrombopag 75 mg q.i.d. and repeat doses of placebo at wavelengths of 335±30 and 365±30 nm. Comparing eltrombopag 75 mg q.i.d. with ciprofloxacin 500 mg b.i.d., the median difference in delayed PI for wavelengths of 335±30 and 365±30 nm was decreased to -0.94 (95% CI, -2.037 to -0.289) and -1.38 (95% CI, -1.882 to -0.432), respectively. With 6 days of treatment, eltrombopag and placebo did not increase the photosensitivity of the skin, while the positive control ciprofloxacin did increase the photosensitivity of skin, resulting in mild phototoxicity. Administration of eltrombopag for 6 days was well tolerated; no deaths, serious adverse events (AEs), or drug-related AEs leading to discontinuation were observed during the study. There were no meaningful differences in AEs reported between the eltrombopag-treated group and either the placebo or ciprofloxacin-treated group. CONCLUSION: Repeat dosing of eltrombopag 75 mg q.i.d. for 6 days in healthy men and women did not induce photosensitivity at any wavelength tested (UVA, ultraviolet B) in this study. Eltrombopag is well tolerated and does not induce photosensitivity.

Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects.

AIMS: To characterize the impact of potent CYP3A4 inhibition and induction on lapatinib pharmacokinetics. METHODS: Two studies were conducted in healthy subjects. One study examined the effect of ketoconazole 200 mg b.i.d. for 7 days on a single 100-mg dose of lapatinib in 22 healthy subjects. The other study examined the effect of carbamazepine titrated up to 200 mg b.i.d. over 20 days on a single 250-mg dose of lapatinib in 24 healthy subjects. RESULTS: Ketoconazole altered lapatinib AUC, C(max) and half-life, with geometric mean [95% confidence interval (CI)] increases of 3.57-fold (3.07, 4.15), 2.14-fold (1.74, 2.64) and 1.66-fold (1.50, 1.84), respectively, but had no effect on absorption rate. Carbamazepine altered lapatinib AUC, C(max) and absorption rate, with geometric mean (95% CI) decreases of 72% (68, 77), 59% (49, 66) and 28% (4, 46), respectively, but had no effect on half-life. CONCLUSIONS: Systemic exposure to lapatinib was significantly altered by potent inhibition and induction of CYP3A4. Dose adjustments may be required when lapatinib is administered with orally administered drugs that potently alter the activity of this enzyme.

Phase I pharmacokinetic studies evaluating single and multiple doses of oral GW572016, a dual EGFR-ErbB2 inhibitor, in healthy subjects.

GW572016 is a dual EGFR-ErbB2 inhibitor that has promise as an anticancer agent. Two phase I studies were conducted to determine the safety, tolerability and pharmacokinetics of single and multiple doses given to healthy subjects. The single dose study evaluated two groups of eight subjects in an ascending dose, 4-way cross-over, while the multiple dose study evaluated twenty-seven healthy volunteers in an ascending dose, double-blind, randomized, placebo-controlled, staggered parallel design. No serious adverse events were seen in either study. The most common adverse events for subjects receiving GW572016 were headache, diarrhea, rash, cold symptoms, gastrointestinal symptoms, and elevated LFTs, which were similar between treatment and placebo groups. Absorption of single doses of GW572016 was slightly delayed, with median t(lag) of 15 minutes (range 0-90 minutes) and achieved peak serum concentrations at a median of three hours (range 1.5-6 hours) post-dose. Serum concentrations after multiple doses of GW572016 demonstrated no significant accumulation at the 25 mg dose, and approximately 50% accumulation at the 100 mg and 175 mg doses, achieving steady state in six to seven days. A modest time-dependent increase in serum concentrations also was detected with multiple doses of GW572016. Single and multiple oral doses of GW572016 were well tolerated in healthy subjects, and resulted in dose-related systemic exposure of GW572016.