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1.  Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice 
Purpose
AZD6244 (ARRY-142886) (AstraZeneca, Macclesfield, UK) is a novel small molecule MEK1/2 inhibitor that is currently being tested in Phase II trials. With the recent publication of human pharmacokinetic data from clinical studies, we now know the achievable levels and range of AZD6244 exposure in humans. This study aimed to describe the pharmacokinetic profile of AZD6244 in mice in order to design preclinical studies that recapitulate exposure levels in humans.
Methods
Male athymic, nude mice received subcutaneous inoculation of A375 human melanoma cells. Once tumors reached 400–700 mm3, mice were given a single dose of either 5 or 10 mg/kg AZD6244 via oral gavage. Additionally, a subset of mice was dosed once daily for 1 week (10 mg/kg). Mice were killed and plasma and tissues were collected at various time points after the last dose. Samples were analyzed by LC/MS/MS for AZD6244 concentration. Additionally, pharmacodynamic endpoints such as tumor proliferation and ERK phosphorylation were analyzed at various time points after the last dose.
Results
After either a single dose or at steady state, at clinically equivalent exposures, AZD6244 effectively inhibits ERK phosphorylation and suppresses proliferation. Furthermore, we describe a hysteretic relationship between the pharmacokinetics and the pharmacodynamics of AZD6244 and both target and pharmacologic responses.
Conclusions
The information presented herein will drive the rational design of pre-clinical studies that are not only relevant to the clinical setting, but also pave the way to understand the biological response to AZD6244 treatment.
doi:10.1007/s00280-010-1323-z
PMCID: PMC4332869  PMID: 20407895
AZD6244; MEK inhibitor; PK/PD relationship; Hysteresis
2.  Differential roles of Trk and p75 neurotrophin receptors in tumorigenesis and chemoresistance ex vivo and in vivo 
Cancer chemotherapy and pharmacology  2009;65(6):1047-1056.
The neurotrophin receptors TrkA (NGF receptor) and TrkC (NT-3 receptor) have been shown to be important in staging disease and predicting progression and drug response for various neoplasias such as neuroblastoma, medulloblastoma and prostate cancer. Less is known about the role of the p75 neurotrophin receptor in cancer, but it influences metastatic potential in glioblastoma. To determine the effect of each neurotrophin receptor or coreceptor expression in tumorigenesis, we examined PC12 pheochromocytomas. PC12 wild type (TrkA+, p75++) were compared to three PC12-derived cell lines expressing varying levels of TrkA or TrkC and/or p75. Growth rates, tumorigenic potential ex vivo and in vivo, and chemotherapeutic drug response profiles differed depending on the neurotrophin receptor phenotype. The ability of neurotrophins to rescue cells from doxorubicin or cisplatin induced cell death also varied depending on phenotype. Thus, unique neurotrophin receptor tumor profiles may determine tumor aggressiveness and chemoresistance. This work may help to develop tailored therapies for specific tumor phenotypes by combining traditional chemotherapy with neurotrophin receptor modulators.
doi:10.1007/s00280-009-1110-x
PMCID: PMC4315186  PMID: 19701634
Neurotrophin; Receptor; Trk; p75; Neural crest tumors; Growth kinetics; Tumorigenic potential; Drug resistance
3.  [No title available] 
PMCID: PMC3946636  PMID: 24241210
4.  [No title available] 
PMCID: PMC3946654  PMID: 24253178
5.  A Phase I and Pharmacologic Study of the Combination of Bortezomib and Pegylated Liposomal Doxorubicin in Patients with Refractory Solid Tumors 
Purpose
Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We therefore conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.
Methods
Patients received bortezomib, 0.9-1.5 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m2, on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.
Results
A total of 37 patients with 4 median prior therapies were treated. Frequent grade 1-2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1/6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1/6 patients receiving bortezomib at 1.5 mg/m2. Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m2 levels, bortezomib at 1.3 mg/m2 and PLD at 30 mg/m2 are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.
Conclusions
A regimen of bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 with PLD, 30 mg/m2, on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
doi:10.1007/s00280-008-0716-8
PMCID: PMC4312589  PMID: 18327587
phase I; proteasome inhibition; bortezomib; pegylated liposomal doxorubicin; breast cancer
6.  Pharmacokinetics and pharmacogenomics of daunorubicin in children: a report from the Children’s Oncology Group 
Purpose
We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.
Patients and methods
Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95 % for age or as body fat >30 %. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters.
Results
A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m2/h ± 14 % and 68.1 L/m2 ± 24 %, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m2/h ± 5.6 % and 232 L/m2 ± 10 %, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/ H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction.
Conclusions
We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.
doi:10.1007/s00280-014-2535-4
PMCID: PMC4282931  PMID: 25119182
Daunorubicin; Daunorubicinol; Pharmacokinetics; Pharmacogenetics; Pediatrics; Body composition; Obesity
7.  Calcium carbonate does not affect imatinib pharmacokinetics in healthy volunteers 
Cancer chemotherapy and pharmacology  2013;73(1):10.1007/s00280-013-2337-0.
Purpose
Imatinib mesylate (Gleevec®/Glivec®), has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumors (GIST), and there is evidence for an exposure response relationship. Calcium carbonate is increasingly used as a calcium supplement and in the setting of gastric upset associated with imatinib therapy. Calcium carbonate could conceivably elevate gastric pH and complex imatinib, thereby influencing imatinib absorption and exposure. We aimed to evaluate whether use of calcium carbonate has a significant effect on imatinib pharmacokinetics.
Methods
Eleven healthy subjects were enrolled in a 2-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg of imatinib p.o.. In the other period, 4000 mg calcium carbonate (Tums Ultra®) was administered p.o. 15 min before 400 mg of imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS; data were analyzed non-compartmentally, and compared after log transformation.
Results
Calcium carbonate administration did not significantly affect the imatinib area under the plasma concentration versus time curve (AUC) (41.2 μg/mL•h alone versus 40.8 μg/mL•h with calcium carbonate, P=0.99), maximum plasma concentration (Cmax) (2.35 μg/mL alone versus 2.39 μg/mL with calcium carbonate, P=0.89).
Conclusions
Our results indicate that the use of calcium carbonate does not significantly affect imatinib pharmacokinetics.
doi:10.1007/s00280-013-2337-0
PMCID: PMC3880632  PMID: 24170263
imatinib; calcium; CML; GIST; interaction
8.  Toll-like receptor signaling regulates cisplatin-induced mechanical allodynia in mice 
Purpose
Cisplatin treated mice develop a persistent pain state and a condition wherein otherwise innocuous tactile stimuli evoke pain behavior, e.g. tactile allodynia. The allodynia is associated with an up-regulation of Activation Transcription Factor 3 (ATF3) in the dorsal root ganglia (DRG), a factor, which is activated by Toll-like receptors (TLR). Accordingly, we sought to examine the role of the TLR signaling cascade on allodynia, weight and changes in DRG ATF3 in cisplatin-treated mice.
Methods
Cisplatin (2.3 mg/kg/day × 6 injections every other day) or vehicle was administered to male wild type (WT) C57BL/6, Tlr3−/−, Tlr4−/−, Myd88−/−, Triflps2 and Myd88/Triflps2 mice. We examined allodynia and body weight at intervals over 30 days, when we measured DRG ATF3 by immunostaining.
Results
i) WT cisplatin-treated mice showed tactile allodynia from day 3 through day 30. ii) The Myd88/Triflps2, mice did not show allodynia. iii) In Tlr3−/−, Tlr4−/−, and Myd88−/− mice, withdrawal thresholds were elevated towards normal versus WT cisplatin treated mice, but remained decreased as compared to vehicle mice. iv) In Triflps2 mice, cisplatin allodynia showed a delayed onset, but persisted. v) In Tlr3−/−, Tlr4−/−, Myd88−/−, and Myd88/Triflps2 mice, the increase in DRG ATF3 was abolished. vi) Weight loss occurred during cisplatin administration, which was exacerbated in mutant as compared to WT mice.
Conclusions
Cisplatin evoked a persistent allodynia and DRG ATF3 expression in WT mice, but these effects were reduced in mice with TLR signaling deficiency. TLR signaling may thus be involved in the mechanisms leading to the cisplatin-polyneuropathy.
doi:10.1007/s00280-013-2304-9
PMCID: PMC3917999  PMID: 24162377
Allodynia; cisplatin; Toll-like receptor; mouse; dorsal root ganglion
9.  A phase 1 multiple-dose study of orteronel in Japanese patients with castration-resistant prostate cancer 
Purpose
Orteronel (TAK-700) is a non-steroidal, selective, reversible inhibitor of 17,20-lyase. We evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effect of orteronel with or without prednisolone in Japanese patients with castration-resistant prostate cancer (CRPC).
Methods
We conducted a phase 1 study in men with progressive and chemotherapy-naïve CRPC. Patients received orteronel orally at doses of 200–400 mg twice daily (BID) with or without oral prednisolone (5 mg BID). Dose-limiting toxicity (DLT) was assessed during Cycle 1 (28 days). Patients could continue study treatment until any of criteria for treatment discontinuation were met. Gonadotropin-releasing hormone therapy was continued in patients without prior orchidectomy.
Results
Fifteen patients were enrolled and administered at least one dose of orteronel. No DLTs were reported during Cycle 1 in this study. Adverse events (AEs) were reported in all 15 patients. Most common AEs (>30 %) were hyperlipasemia (47 %), hyperamylasemia (40 %), and constipation (33 %). Acute pancreatitis (Grades 2 and 3) and pancreatitis (Grade 1) were complicated in three patients during the study. Dose-dependent increase in plasma orteronel concentrations was indicated over the 200–400 mg BID dose range. Prednisolone coadministered did not alter PK of orteronel. Serum testosterone was rapidly suppressed below the lower limit of quantification across all doses. Of 15 subjects, 13 achieved at least a 50 % reduction from baseline in prostate-specific antigen.
Conclusions
Orteronel at doses up to 400 mg BID was tolerable in Japanese CRPC patients. The present results support further evaluation of orteronel with or without prednisolone.
doi:10.1007/s00280-014-2654-y
PMCID: PMC4305367  PMID: 25537627
Orteronel; Castration-resistant prostate cancer; 17,20-Lyase inhibitor; Phase 1
10.  A phase I dose escalation study of a pharmacobiologically based scheduling of capecitabine and mitomycin C in patients with gastrointestinal malignancies 
Background
Mitomycin C (MMC) produces significant upregulation of thymidine phosphorylase, a principal determinant of the therapeutic index of capecitabine-based treatment, starting 4–6 days after treatment. On the basis of the time-dependency of this upregulation, we performed a phase I dose escalation study of capecitabine and MMC in patients with gastrointestinal malignancies.
Methods
A total of 29 patients with advanced gastrointestinal malignancies received MMC at 6 mg/m2 on day 1 and capecitabine escalated in four successive patient cohorts of doses 500–1,000 mg/m2/day twice daily on days 8–21, every 28 days. MMC was capped at 36 mg/m2.
Results
A total of 29 patients were enrolled and 90% had at least one prior treatment in the metastatic setting. There was one DLT, grade 3 hand and foot syndrome, at dose level four. The most common toxicity was fatigue (61%). No patients experienced grade 4 toxicities. Nine patients experienced prolonged stability of disease.
Conclusion
Capecitabine in combination with MMC in the proposed schedule is well-tolerated with evidence of preliminary activity. The recommended dose for phase II studies are MMC at 6 mg/m2 on day 1 of a 28-day cycle with the dose capped at 36 mg/m2, in combination with capecitabine at 1,000 mg/m2 twice daily on days 8–21.
doi:10.1007/s00280-009-1091-9
PMCID: PMC4261191  PMID: 19657639
Capecitabine; Mitomycin C; Gastrointestinal malignancies
11.  Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice 
Cancer chemotherapy and pharmacology  2013;72(6):10.1007/s00280-013-2296-5.
Purpose
Benzaldehyde dimethane sulfonate (DMS612, NSC281612, BEN) is an alkylator with activity against renal cell carcinoma, currently in phase I trials. In blood, BEN is rapidly metabolized into its highly reactive carboxylic acid (BA), presumably the predominant alkylating species. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH) and aimed to increase BEN exposure in blood and tissues by inhibiting ALDH with disulfiram thereby shifting BA production from blood to tissues.
Methods
Female CD2F1 mice were dosed with 20 mg/kg BEN iv alone or 24 h after 300 mg/kg disulfiram ip. BEN, BA and metabolites were quantitated in plasma and urine, and toxicities were assessed.
Results
BEN had a plasma t½ <5 min and produced at least 12 products. The metabolite half-lives were <136 min. Disulfiram increased BEN plasma exposure 368-fold, (AUC0-inf from 0.11 to 40.5 mg/L•min), while plasma levels of BA remained similar. Urinary BEN excretion increased (1.0% to 1.5% of dose) while BA excretion was unchanged.
Hematocrit, white blood cells counts and %lymphocytes decreased after BEN administration. Co-administration of disulfiram appeared to enhance these effects. Profound liver pathology was observed in mice treated with disulfiram and BEN.
Conclusions
BEN plasma concentrations increased after administration of disulfiram, suggesting that ALDH mediates the rapid metabolism of BEN in vivo, which may explain the increased toxicity seen with BEN after administration of disulfiram. Our results suggest that the co-administration of BEN with drugs that inhibit ALDH or to patients that are ALDH deficient may cause liver damage.
doi:10.1007/s00280-013-2296-5
PMCID: PMC3836906  PMID: 24061865
Aldehyde dehydrogenase; disulfiram; alkylating agent; dimethane sulfonate; BEN
12.  The role of antioxidants in the era of cardio-oncology 
Cancer chemotherapy and pharmacology  2013;72(6):1157-1168.
Although most chemotherapeutic drugs have the potential to exert cardiotoxicity, these drugs have been chosen for use in cancer treatment because survival and curability benefits outweigh the risk of these complications. Anthracyclines, for example, are a powerful class of chemotherapeutic agents; however, their use is restricted by dose-related cardiotoxicity. Experimental evidence strongly supports the role of reactive oxygen species in this process, suggesting that antioxidants may be effective in protecting the heart from toxicity. Clinical use of antioxidants to protect the heart during anthracycline chemotherapy has been controversial due to the potential for reduced cytotoxic efficacy toward cancer cells. Results from randomized clinical trials addressing whether antioxidants either reduce the incidence of clinical heart failure among patients undergoing anthracycline-based chemotherapy or reduce the response rates to anthracycline-based chemotherapy have been unclear. While anthracyclines are by far the most well-studied antitumor agents with cardiotoxic properties, evidence now shows that reactive oxygen species may play roles in cardiotoxicity induced by other chemotherapeutic agents such as cyclophosphamide, cisplatin, 5-fluorouracil, and trastuzumab. Thus, in the new era of combination therapy and long-term survival of cancer patients, the use of antioxidants to support cancer therapy should be revisited.
doi:10.1007/s00280-013-2260-4
PMCID: PMC3947340  PMID: 23959462
antioxidants; cancer; cardioprotection; cardiotoxicity; chemotherapy; free radicals; reactive oxygen species
13.  AZ64 inhibits TrkB and enhances the efficacy of chemotherapy and local radiation in neuroblastoma xenografts 
Neuroblastoma is a common pediatric tumor characterized by clinical heterogeneity. Because it is derived from sympathetic neuroblasts, the NTRK family of neurotrophin receptors plays an integral role in neuroblastoma cell survival, growth, and differentiation. Indeed, high expression of NTRK1 is associated with favorable clinical features and outcome, whereas expression of NTRK2 and its ligand, brain-derived neurotrophic factor (BDNF), are associated with unfavorable features and outcome. AZ64 (Astra Zeneca) is a potent and selective inhibitor of the NTRK tyrosine kinases that blocks phosphorylation at nanomolar concentrations. To determine the preclinical activity of AZ64, we performed intervention trials in a xenograft model with NTRK2-overexpressing neuroblastomas. AZ64 alone significantly inhibited tumor growth compared to vehicle-treated animals (p = 0.0006 for tumor size). Furthermore, the combination of AZ64 with conventional chemotherapeutic agents, irinotecan and temozolomide (irino–temo), showed significantly enhanced anti-tumor efficacy compared to irino–temo alone [(p < 0.0001 for tumor size, p < 0.0005 for event-free survival (EFS)]. We also assessed the combination of AZ64 and local radiation therapy (RT) on a neuroblastoma hindlimb xenograft model, and the efficacy of local RT was significantly increased when animals were treated simultaneously with AZ64 (p < 0.0001 for tumor size, p = 0.0006 for EFS). We conclude that AZ64 can inhibit growth of NTRK-expressing neuroblastomas both in vitro and in vivo. More importantly, it can significantly enhance the efficacy of conventional chemotherapy as well as local RT, presumably by inhibition of the NTRK2/BDNF autocrine survival pathway.
doi:10.1007/s00280-012-1879-x
PMCID: PMC4242714  PMID: 22623209
TrkA; TrkB; AZ64; Neuroblastoma; Inhibition; Signaling; Differentiation
14.  Phase I trial of lestaurtinib for children with refractory neuroblastoma: a new approaches to neuroblastoma therapy consortium study 
Cancer chemotherapy and pharmacology  2011;68(4):1057-1065.
Purpose
TrkB acts as an oncogenic kinase in a subset of human neuroblastomas. Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated activity in preclinical models of neuroblastoma.
Methods
Patients with refractory high-risk neuroblastoma received lestaurtinib twice daily for 5 days out of seven in 28-day cycles, starting at 70% of the adult recommended Phase 2 dose. Lestaurtinib dose was escalated using a 3 + 3 design. Pharmacokinetics and plasma phospho-TrkB inhibitory activity were evaluated in the first cycle.
Results
Forty-seven subjects were enrolled, and 10 dose levels explored starting at 25 mg/M2/dose BID. Forty-six subjects were evaluable for response, and 42 subjects were fully evaluable for determination of dose escalation. Asymptomatic and reversible grade 3–4 transaminase elevation was dose limiting in 4 subjects. Reversible pancreatitis (grade 2) was observed in 3 subjects after prolonged treatment at higher dose levels. Other toxicities were mild and reversible. Pharmacokinetic analyses revealed rapid drug absorption, however inter-patient variability was large. Plasma inhibition of phospho-TrkB activity was observed 1 h post-dosing at 85 mg/M2 with uniform inhibition at 120 mg/M2. There were two partial responses and nine subjects had prolonged stable disease at dose levels ≥ 5, (median: 6 cycles). A biologically effective and recommended phase 2 dose of 120 mg/M2/dose BID was established.
Conclusions
Lestaurtinib was well tolerated in patients with refractory neuroblastoma, and a dose level sufficient to inhibit TrkB activity was established. Safety and signs of activity at the higher dose levels warrant further evaluation in neuroblastoma.
doi:10.1007/s00280-011-1581-4
PMCID: PMC4238911  PMID: 21340605
Neuroblastoma; Receptor tyrosine kinase; Targeted therapy; Lestaurtinib; Signal transduction
15.  Phase II and pharmacokinetic trial of rebeccamycin analog in advanced biliary cancers 
Purpose
Advanced cancers of the bile duct and gallbladder carry an ominous prognosis. Rebeccamycin analogue (RA) is a novel antitumor antibiotic where phase I trials suggested clinical efficacy in patients with biliary cancers.
Methods
The primary objective was to determine the response rate to RA in patients with advanced gallbladder and bile duct tumors. Secondary endpoints were survival and pharmacokinetic characterization. RA was given at a dose 165 mg/(m2 day) × 5 days every 3 weeks.
Results
Forty-six patients were enrolled. Nine patients were removed from study before their first planned imaging study for response. Two patients had partial responses and 16 had stable disease. On an intent-to-treat analysis the median survival was 6.3 months. A >20% drop in CA 19.9 was seen in 43% of patients with initial high levels. Grade 4 neutropenia and thrombocytopenia were seen in 35 and 5% of patients, respectively. Febrile neutropenia occurred in 16% of patients. The pharmacokinetic profile of this trial closely resembles those of prior phase I trials. Measured biliary concentrations of RA were as much as 100× greater than simultaneous plasma concentration.
Conclusion
Although RA has a response rate of 5% in advanced biliary cancers, it is associated with significant numbers of patients experiencing prolonged stable disease. Biliary concentrations of RA are significantly greater than plasma concentrations.
doi:10.1007/s00280-009-1005-x
PMCID: PMC4220168  PMID: 19399502
Biliary cancer; Gallbladder cancer; Phase II trial
16.  Phase I Study Evaluating the Combination of Lapatinib (a Her2/Neu and EGFR Inhibitor) and Everolimus (an mTOR Inhibitor) in Patients with Advanced Cancers: South West Oncology Group (SWOG) Study S0528 
Cancer chemotherapy and pharmacology  2013;72(5):1089-1096.
Purpose
Everolimus, an oral inhibitor of mTOR, can augment the efficacy of HER inhibitors in pre-clinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus, and to describe its antitumor activity in the Phase I setting.
Methods
In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction.
Results
Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis and fatigue. The MTD of the combination was 1250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44% and mean clearance was decreased by 25% when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response (thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months); eleven patients attained stable disease of at least 4 months
Conclusions
Lapatinib and everolimus are well tolerated at doses of 1250 mg and 5 mg po daily, respectively. Stable disease >4 months/PR was achieved in 13 of 78 patients (17%).
doi:10.1007/s00280-013-2297-4
PMCID: PMC4072025  PMID: 24057042
everolimus; lapatinib; phase I; mTOR; Her2
17.  Calcium carbonate does not affect nilotinib pharmacokinetics in healthy volunteers 
Cancer chemotherapy and pharmacology  2013;72(5):10.1007/s00280-013-2283-x.
Purpose
Nilotinib is a second-generation oral tyrosine kinase inhibitor (TKI) with superior efficacy compared with imatinib mesylate in the treatment of chronic phase chronic myelogenous leukemia (CML). Calcium carbonate is commonly used as a source of calcium supplementation or as antacid to ameliorate the gastrointestinal side effects associated with nilotinib, which could have unknown effects on nilotinib absorption. The purpose of this study was to provide information on the effect of calcium carbonate on the PK of nilotinib in healthy volunteers.
Methods
Healthy subjects were enrolled in a 2-period, open-label, single-institution, randomized, cross-over, fixed-schedule study. In one period, each subject received 400 mg of nilotinib p.o. In the other period, 4000 mg calcium carbonate (4 X Tums Ultra 1000®) were administered p.o. 15 minutes prior to the nilonitib dose. Plasma samples were collected at specified timepoints, concentrations of nilotinib were quantitated by LC-MS, and data were analyzed non-compartmentally.
Results
Eleven subjects were evaluable. Calcium supplementation did not significantly affect nilotinib pharmacokinetic parameters including area under the plasma concentration versus time curve (AUC) (18.4 μg/mL•h alone versus 16.9 μg/mL•h with calcium carbonate, P=0.83; 80% power); maximum plasma concentration (Cmax) (0.670 μg/mL alone versus 6.18 μg/mL with calcium carbonate, P=0.97); or half-life (18.9 h alone versus 17.2 h with calcium carbonate, P=0.18).
Conclusions
Our results indicate that the use of calcium carbonate does not significantly affect nilotinib pharmacokinetics.
doi:10.1007/s00280-013-2283-x
PMCID: PMC3818249  PMID: 24036846
nilotinib; calcium; CML; interaction
18.  A multi-center phase II study of oxaliplatin, irinotecan, and capecitabine in advanced gastric/gastroesophageal junction carcinoma 
Background
There is no standard first-line therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma and the prognosis remains poor. Our institution conducted a phase I study of oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule. The regimen was tolerated; pharmacodynamic studies revealed no drug interactions, and there was one confirmed response in a gastric cancer patient. We performed a phase II trial in advanced gastric and GEJ adenocarcinoma to determine response rate and response duration.
Methods
This was a multi-center single treatment arm study involving six sites. Only prior adjuvant therapy was allowed. Patients had ECOG performance status of 0–2, adequate organ function, and were able to tolerate oral medications. All patients received oxaliplatin 60 mg/m2 intravenously (IV) and irinotecan 50 mg/m2 IV weekly times 4 weeks with a 2-week rest period. Capecitabine 450 mg bid orally was received on days 1 through 5 every week for 4 weeks, followed by a 2-week rest. Patients were assessed for response after the first two cycles; response duration, overall survival, and adverse events were also recorded. We estimated an improvement in historical response rate by 30% would have clinical meaning.
Results
A total of 39 patients were accrued and all were assessed for toxicity; 30 patients were evaluable for response. The median age was 57.8 years (31–79 years) and 74% were male. Two patients had a complete response, with nine patients achieving a partial response. The total response rate was 28%, with nine patients not evaluable for response. The median response duration was noted at 5.97 months and median overall survival was 8.98 months. There were no grade 5 treatment related events, with all deaths secondary to disease progression. Only five grade 4 events occurred (neutropenia, hyperkalemia, hypokalemia (2), thrombosis/embolism) without grade 4 diarrhea or sensory neuropathy.
Conclusions
Oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule does induce responses in advanced gastric and GEJ adenocarcinoma. However, the total response rate is modest and not an improvement over other regimens.
doi:10.1007/s00280-008-0807-6
PMCID: PMC4209292  PMID: 18670776
Gastric cancer; Phase II; Chemotherapy; Metastatic
19.  Addition of bevacizumab enhances antitumor activity of erlotinib against non-small cell lung cancer xenografts depending on VEGF expression 
Cancer Chemotherapy and Pharmacology  2014;74(6):1297-1305.
Purpose
Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, are promising therapies for advanced non-small cell lung cancer (NSCLC). Our study was aimed to determine whether there were conditions under which the addition of bevacizumab would enhance the antitumor activity of erlotinib against NSCLC tumors in vitro and in vivo.
Methods
MTS was for NSCLC cell (PC9, 11–18, H1975, H157, H460 and A549) growth assay in vitro. ELISA was for VEGF protein assay in cells and tumor tissues. Mouse xenograft models were established with H157, H460 and A549 with primary resistance to erlotinib and treated with erlotinib plus bevacizumab or each agent alone. Erlotinib concentrations in tumors were determined by high-performance liquid chromatography.
Results
Bevacizumab alone did not inhibit NSCLC cell growth in vitro. In primarily erlotinib-resistant NSCLC cells, the levels of VEGF protein were highest in H157 cell followed in order by H460 and A549 cells. In vivo, bevacizumab alone significantly inhibited tumor growth only in xenograft models with high (H157) and/or moderate (H460) levels of VEGF protein. A combination of erlotinib and bevacizumab partially reversed resistance to erlotinib in H157 xenografts (high VEGF level) with increasing intratumoral erlotinib concentrations, but not in H460 (moderate) or A549 (low) xenografts.
Conclusions
These results support that combined with anti-VEGF therapy could enhance antitumor activity of anti-EGFR therapy and/or partially reverse resistance to EGFR TKI, by increasing EGFR TKI concentration in specific tumors that express high levels of VEGF protein.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2610-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2610-x
PMCID: PMC4236614  PMID: 25344762
Bevacizumab; Drug concentration; Erlotinib; Non-small cell lung cancer; VEGF protein
20.  Trastuzumab, in combination with carboplatin and docetaxel, does not prolong the QT interval of patients with HER2-positive metastatic or locally advanced inoperable solid tumors: results from a phase Ib study 
Cancer Chemotherapy and Pharmacology  2014;74(6):1251-1260.
Purpose
This study evaluated the potential effect of trastuzumab on the electrocardiogram (ECG) QT interval and assessed the potential pharmacokinetic interaction between trastuzumab and carboplatin. Here, we report the QT and safety results.
Methods
Patients with metastatic or inoperable HER2-positive solid tumors received docetaxel and carboplatin on Day 1 of each 3-week (q3w) cycle. Trastuzumab was administered intravenously, as an accelerated loading dose regimen, on Cycle 1, Day 2 and Cycle 1, Day 8, and then on Day 1 of each subsequent q3w cycle. ECG assessments were performed pre- and posttrastuzumab infusion in the first two cycles. Fridericia’s correction was applied to QT intervals (QTcF). Baseline-adjusted QTcF intervals (the change from baseline) and their 90 % confidence intervals (CIs) were calculated.
Results
The study enrolled 59 patients. At all time points, the 90 % CI upper bound for the mean baseline-adjusted QTcF was <10 ms. At steady-state serum trastuzumab concentrations, the mean baseline-adjusted QTcF interval was −8.4 ms (90 % CI −11.1, −5.7). No patient exhibited an absolute QTcF interval of >480 ms. No relationship was observed between trastuzumab concentration and baseline-adjusted QTcF interval. At data cutoff, 84.5 % of patients had experienced grade ≥3 adverse events, the most common of which were hematologic and as expected. Left ventricular ejection fraction remained ≥45 % in all patients during the study.
Conclusions
The results suggest that trastuzumab had no clinically relevant effect on QTcF interval. The safety profile of trastuzumab in combination with carboplatin and docetaxel was consistent with the known safety profile of this combination.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2603-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2603-9
PMCID: PMC4236615  PMID: 25344761
Carboplatin; Electrocardiogram; Human epidermal growth factor receptor 2; Trastuzumab; QT interval
21.  A pharmacokinetic and pharmacodynamic investigation of Modufolin® compared to Isovorin® after single dose intravenous administration to patients with colon cancer: a randomized study 
Purpose
Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin®. The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin® or Isovorin® (levo-leucovorin).
Methods
Thirty-two patients scheduled for colon resection were randomized to receive Modufolin® or Isovorin® at dosage of 60 or 200 mg/m2. The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS.
Results
MethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m2) after Modufolin® as compared to Isovorin® administration. The results correlated with PK observations. The Modufolin® to Isovorin®Cmax ratio for methyleneTHF was 113 at 200 mg/m2 and 52 at 60 mg/m2; the AUClast ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (Cmax ratio 23, AUClast ratio 13 at 200 mg/m2; Cmax ratio 15, AUClast ratio 11 at 60 mg/m2).
Conclusion
Modufolin® administration resulted in significantly higher methyleneTHF levels than Isovorin® and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin® as a substitute to Isovorin® including the potential clinical benefits.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2611-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2611-9
PMCID: PMC4281361  PMID: 25342290
Colon cancer; 5-FU-based chemotherapy; Levo-leucovorin; Methylenetetrahydrofolate; CH2THF; Tissue and plasma folates; LC-MS/MS
22.  Phase I trial of sunitinib and gemcitabine in patients with advanced solid tumors 
Purpose
Combining cytotoxic agents with bevacizumab has yielded significant benefits in a number of solid tumors. Combining small-molecule kinase inhibitors of VEGFR with chemotherapy has yet to demonstrate clinical benefit. The dose, schedule and agents used may be critical to the development of this combinatorial therapy.
Methods
We performed a phase I trial of sunitinib and gemcitabine in patients with advanced solid tumor malignancies based on strong preclinical rationale.
Results
Two different MTDs were determined. The schedule of gemcitabine 800 mg/m2 on days 1, 8, 15 and sunitinib 25 mg daily was considered to be a MTD. However, omission of day 15 gemcitabine was common, and thus, a second MTD of gemcitabine of 675 mg/m2 on days 1 and 8 with sunitinib 25 mg daily was determined to be the recommended phase II dose. Grade 4 neutropenia and thrombocytopenia occurred in 33 and 6 %, respectively. Grade 3/4 non-hematological toxicities were uncommon. Four of 33 patients had a partial response. Another 11 patients had stable disease ranging from 3 to 36 months. Thus, the recommended phase II dose of this combination is gemcitabine 675 mg/m2 on days 1 and 8 on an every 21-day schedule along with sunitinib 25 mg continuous daily.
Conclusions
This combination is well-tolerated and has significant clinical activity.
doi:10.1007/s00280-012-1936-5
PMCID: PMC4199746  PMID: 22868341
Phase I; Sunitinib; Gemcitabine; Pancreatic cancer
23.  A Phase II trial of axitinib in patients with various histologic subtypes of advanced thyroid cancer: long-term outcomes and pharmacokinetic/pharmacodynamic analyses 
Cancer Chemotherapy and Pharmacology  2014;74(6):1261-1270.
Purpose
Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, has shown activity in advanced thyroid cancer in a Phase II study. We report updated overall survival and pharmacokinetic/pharmacodynamic (PK/PD) analyses from the study.
Methods
Patients (N = 60) with advanced thyroid cancer of any histology for whom iodine-131 (131I) failed to control the disease or 131I was not appropriate therapy were administered axitinib 5 mg twice daily. Objective response rate (primary endpoint), duration of response, progression-free survival, overall survival, safety, and PK/PD relationships were assessed.
Results
Objective response rate was 38 % [23 partial responses; 95 % confidence interval (CI) 26–52], and 18 (30 %) patients had stable disease lasting ≥16 weeks. Responses occurred in all histologic subtypes. With median follow-up of 34 months (95 % CI 32–37), median overall survival was 35 months (95 % CI 19–not estimable), median progression-free survival was 15 months (95 % CI 10–20), and median duration of response was 21 months (95 % CI 13–46). Most common Grade 3/4 treatment-related adverse events included hypertension (13 %), proteinuria (8 %), diarrhea (7 %), weight decrease (7 %), and fatigue (5 %). PK/PD analyses revealed trends toward greater tumor size reduction and response probability with higher axitinib plasma exposures.
Conclusions
Axitinib appears active and well tolerated in patients with various histologic subtypes of advanced thyroid cancer, demonstrating durable responses and long overall survival. Axitinib may be useful for the treatment of advanced thyroid cancer.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-014-2604-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-014-2604-8
PMCID: PMC4236619  PMID: 25315258
Axitinib; Iodine-refractory; Pharmacokinetic; Pharmacodynamic; Thyroid cancer
24.  Pretreatment with anti-oxidants sensitizes oxidatively stressed human cancer cells to growth inhibitory effect of suberoylanilide hydroxamic acid (SAHA) 
Purpose
Most prostate, colon and breast cancer cells are resistant to growth inhibitory effects of suberoylanilide hydroxamic acid (SAHA). We have examined whether the high oxidative stress in these cells causes a loss of SAHA activity and if so, whether pretreatment with an anti-oxidant can sensitize these cells to SAHA.
Methods
A DNA-Hoechst dye fluorescence measured cell growth and dichlorfluorescein-diacetate (DCF-DA) dye fluorescence measured reactive oxygen species (ROS). Growth inhibitory and ROS-generating activities of SAHA in androgen-treated or untreated LNCaP cells and PC-3 prostate cancer cells, HT-29 and HCT-115 colon cancer cells, MDA-MB231 breast cancer cells and A549 and NCI-H460 lung cancer cells with or without pretreatment with an anti-oxidant Vitamin E was determined. SAHA activity against LNCaP cells treated with another anti-oxidant N-acetyl cysteine (NAC) was also determined. Liquid chromatography–mass spectrometry (LC–MS) was used to determine intracellular SAHA level.
Results
SAHA treatment markedly inhibits LNCaP cell growth, when the cells are at a low ROS level. SAHA is, however, inactive against the same cell line, when the cells are at a high ROS level. A significant decrease in SAHA level was observed in LNCaP cells with high ROS after 24-and 72-h treatment when compared to cells with low ROS. Vitamin E pretreatment that reduces cellular ROS, synergistically sensitizes oxidatively stressed LNCaP, PC-3, HT-29, HCT-115 and MDA-MB231 cells, but not the A-549 and NCI-H460 cells with low ROS to SAHA. NAC treatment also sensitized androgen-treated LNCaP cells to the growth inhibitory effects of SAHA.
Conclusion
Response to SAHA could be improved by combining anti-oxidants such as Vitamin E with SAHA for the treatment of oxidatively stressed human malignancies that are otherwise resistant to SAHA.
doi:10.1007/s00280-010-1364-3
PMCID: PMC4190041  PMID: 20512578
Histone deacetylase; Oxidative stress; Prostate cancer; Drug metabolism
25.  Reversibility of regorafenib effects in hepatocellular carcinoma cells 
Cancer chemotherapy and pharmacology  2013;72(4):10.1007/s00280-013-2269-8.
Purpose
Multikinase growth inhibitors inhibit their target kinases with varying potency. Patients often require lower doses or therapy breaks due to drug toxicities. To evaluate the effects of drug withdrawal on hepatocellular carcinoma cells after incubation with growth-inhibitory concentrations of regorafenib, cell growth, migration and invasion, and signaling were examined.
Methods
Cell proliferation, motility, and invasion were analyzed by MTT, wound healing, and invasion assays, respectively, and MAPK pathway protein markers were analyzed by Western blot.
Results
After regorafenib removal, cell growth, migration, and invasion recovered. Repeated drug exposure resulted in changes in cell growth patterns. Recovery could be blocked by sub-growth-inhibitory concentrations of either doxorubicin or vitamin K1. Recovery of growth was associated with increased phospho-JNK, phospho-p38, and phospho-STAT3 levels. The recovery of growth, migration, and signaling were blocked by a JNK inhibitor.
Conclusions
Removal of regorafenib from growth-inhibited cells resulted in a JNK-dependent recovery of growth and migration.
doi:10.1007/s00280-013-2269-8
PMCID: PMC3836575  PMID: 23959464
Hepatocarcinoma; Regorafenib; Reversibility; Migration, invasion; Growth

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