Results of a phase II trial of S-1 as first-line treatment of metastatic pancreatic cancer (CESAR-study group).

PURPOSE: S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC. METHODS: Chemotherapy-naïve patients received S-1 orally at 30 mg/m(2) twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon's two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage. RESULTS: Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event. CONCLUSIONS: Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.

Pemetrexed combined with paclitaxel: a dose-finding study evaluating three schedules in solid tumors.

The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed-paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m(2) on d1; (S2) 400 mg/m(2) d1 and 40 mg/m(2) d1 and d8; S3) 400 mg/m(2) d8 and 30 mg/m(2) d1 and d8. MTD was 500/135 mg/m(2) (S1), 400/40 mg/m(2) (S2), and 500/120 mg/m(2) (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m(2) (d8) and paclitaxel 90 mg/m(2) (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.

Phase 1b dose escalation study of erlotinib in combination with infusional 5-Fluorouracil, leucovorin, and oxaliplatin in patients with advanced solid tumors.

PURPOSE: Erlotinib (Tarceva) is a potent epidermal growth factor receptor (HER1) inhibitor. Infusional 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) is a standard therapy for colorectal cancer. This trial assessed the maximum tolerated dose (MTD), safety, preliminary efficacy, and pharmacokinetics of erlotinib combined with FOLFOX. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were sequentially enrolled into three cohorts (cohort 1: 100 mg/d erlotinib, 65 mg/m(2) oxaliplatin, 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 400 mg/m(2) continuous infusion 5-FU; cohort 2: oxaliplatin increased to 85 mg/m(2) and 5-FU infusion increased to 600 mg/m(2); and cohort 3: erlotinib increased to 150 mg/d). RESULTS: Thirty-two patients were enrolled (23 with colorectal cancer): no dose-limiting toxicities (DLT) were observed in cohort 1. In cohort 2, two of nine patients experienced a DLT (both diarrhea). In cohort 3, two of nine patients had a DLT (diarrhea and staphylococcal septicemia). Cohort 3 determined the MTD cohort and expanded to 17 patients in total. The most common adverse events were diarrhea, nausea, stomatitis, and rash (primarily mild/moderate). No pharmacokinetics interactions were observed. One patient (colorectal cancer) had a complete response, seven patients had a partial response, and nine had stable disease. CONCLUSIONS: The MTD was defined as follows: 150 mg/d erlotinib, 85 mg/m(2) oxaliplatin; 200 mg/m(2) leucovorin, 400 mg/m(2) bolus 5-FU, and 600 mg/m(2) infusion 5-FU. At the MTD, the combination was well tolerated and showed antitumor activity, warranting further investigation in patients with advanced colorectal cancer and other solid tumors.

Reduction of HLA-DR+ lymphocytes after treatment with enzastaurin in patients with metastatic thyroid cancer.

BACKGROUND: Cytotoxic anti-tumor agents like methotrexate or cyclophosphamide have been used in the treatment of autoimmune diseases although the exact mechanism of their immunomodulatory function is unclear. By contrast, molecularly targeted anti-tumor agents, such as the serine/threonine kinase inhibitor enzastaurin, have not been evaluated for treatments other than cancer. METHODS: Blood was sampled from patients with metastatic thyroid cancer treated with enzastaurin followed by the combination treatment of enzastaurin and the anti-folate pemetrexed. During this sequential treatment, blood was drawn every 14 days to monitor changes in the lymphocyte population. RESULTS: We observed that enzastaurin monotherapy reduced the number of HLA-DR-expressing lymphocytes. No signs of infection were observed in any patient. CONCLUSION: Our findings suggest an immunomodulatory effect of enzastaurin in addition to the anti-tumor effect.

[Principles and practice of clinical phase I studies]. / Planung und Durchführung klinischer Phase-I-Studien.

There is clear evidence that the epidemiologic importance of malignant diseases will continue to rise in the future. This creates the ethical obligation to further intensify the search for improved systemic treatment options. This review is focussed on principles and practices of phase I trials. The trial methodology outlined here is not only used for first-in-human doses of new chemical entities but also for the investigation of new treatment schedules and combinations. The primary endpoints as well as preclinical requirements are addressed. Although for formal reasons antitumor activity cannot be an endpoint in phase I studies the careful observation and documentation of potential anticancer efficacy is of utmost importance in these early clinical trials. Signals of antitumor activity may serve as important guidance for subsequent clinical development plans. Inclusion criteria, dose escalation schemes, and the importance of the concept of the maximum tolerable dose (MTD) are addressed together with ethical principles of exposure to novel chemical agents.

A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression.

PURPOSE: This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression. EXPERIMENTAL DESIGN: Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B12 supplementation. Tumors were surgically removed after the last cycle of pemetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3. RESULTS: Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with "low" baseline TS (< or = 71) were more likely to respond to pemetrexed than patients with "high" baseline TS (>71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P > 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy. CONCLUSIONS: Our results suggest a potential association between "low" pretreatment TS expression levels and response to pemetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.

Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial.

UNLABELLED: Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 µM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug's half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster ('polyproline')-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound. TRIAL REGISTRATION: ClinicalTrial.gov NCT02191657.

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.

Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer.

PURPOSE: To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer. PATIENTS AND METHODS: Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (I.V.) infusion. RESULTS: Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m(2). No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m(2). At 220 mg/m(2), dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m(2)). Variability predicted with flat doses appears comparable with data based on body-surface area-normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma. CONCLUSION: CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m(2), the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.

Phase I and pharmacokinetic study of E7070, a chloroindolyl-sulfonamide anticancer agent, administered on a weekly schedule to patients with solid tumors.

PURPOSE: E7070 is a sulfonamide that induces arrest at the G(1)-S boundary with subsequent dose and exposure-dependent apoptosis. The objectives of this study were (a) to determine the maximum-tolerated dose (MTD) and recommended safe dose (RD) of E7070 for additional evaluation, (b) to define the dose limiting toxicity(ies) [DLT(s)], (c) to study the pharmacokinetics of E7070, and (d) to seek preliminary evidence of antitumor activity. EXPERIMENTAL DESIGN: Patients with solid tumors who had either failed or were not amenable to established forms of treatment were eligible for the study. E7070 was administered i.v. at weekly intervals for 4 consecutive weeks to cohorts of 3-6 patients at each dose level. Treatment was repeated six weekly in the absence of tumor progression. A Fibonacci-like scheme was used for dose escalation. The MTD was determined in a stepwise procedure for two cohorts of patients; the "initial patient cohort" who met the original inclusion criteria (group A) and the "better prognosis cohort" (group B) who had adequate hepatic function, less extensive tumor involvement of the liver, and no more than three previous lines of chemotherapy. The RD was defined as the highest dose at which the incidence of definitely drug-related DLTs was <33%. The pharmacokinetic profile of E7070 was determined. RESULTS: Overall, 46 patients entered the study; information from 36 of the 37 patients forming group A was used to determine the overall MTD. An additional 9 patients plus 9 patients from group A who met the more restrictive inclusion criteria made up group B. The MTD was 500 mg/m(2)/week for both groups. Reversible neutropenia and thrombocytopenia were the most common DLTs. Other DLTs included stomatitis, hyperglycemia, sepsis, fever, hemorrhage, diarrhea, nausea, and fatigue. The pharmacokinetics of E7070 were nonlinear over the dose range 160-500 mg/m(2). One partial response was observed in a patient with an endometrial adenocarcinoma who had previously been treated with radiotherapy. Twelve other patients had stable disease as their best response (27%); among them. 1 patient with metastatic melanoma who received 21 cycles of therapy. CONCLUSIONS: The RD for further study of E7070 using this administration schedule is 400 mg/m(2)/week. Using this schedule, the predominant toxicity of E7070 is myelosuppression. E7070 has anticancer activity in pretreated patients.

Pemetrexed: translational research in breast cancer.

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel antifolate/antimetabolite with activity in breast cancer and has well-defined molecular targets, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. In a phase II trial in patients with T3-4, N0-2 breast cancer, expression of thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, p53, and c-erb-B2 (at the mRNA or protein level) is being examined before and 24 hours after the first dose of neoadjuvant pemetrexed and after three cycles of single-agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity. Full biomarker and clinical data are not yet available from this study; however, clinical responses to pemetrexed treatment have been observed in patients. Results of this trial should provide both an idea of the activity of neoadjuvant pemetrexed in breast cancer and information on biomarker association with clinical performance that can be used in the design of additional clinical studies to assess the predictive value of these markers.

Pemetrexed safety and dosing strategy.

Pemetrexed is a novel antifolate/antimetabolite that inhibits several folate-dependent enzymes, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide transformylase. As a class, antifolates have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities carries a high risk of potentially life-threatening complications. Severe toxicity from pemetrexed-based therapy has become more predictable using the vitamin deficiency marker homocysteine and, to a lesser extent, methylmalonic acid. Evidence now suggests that reducing total plasma homocysteine levels by supplementation with folic acid and vitamin B(12) leads to a better safety profile for pemetrexed, while not adversely affecting its efficacy.

The role of Alimta in the treatment of malignant pleural mesothelioma: an overview of preclinical and clinical trials.

Malignant pleural mesothelioma (MPM) is a rare tumor, but its annual incidence is rapidly increasing. While most patients have locally advanced disease at presentation, to date there is no proven standard chemotherapy for MPM that has shown to increase survival in randomized studies. Therefore, the development of new therapeutic agents is urgent for this disease. Alimta is a novel, multitargeted antifolate with activity as single agent in patients with MPM. Recently, a phase III trial showed that the combination of Alimta with cisplatin resulted in a significantly increased efficacy compared with cisplatin alone. In addition, vitamin supplementation reduced treatment associated toxicities with no apparent affect on activity. This review summarizes preclinical and clinical data to define the future role of Alimta in the treatment of patients with MPM.

Translational research with pemetrexed in breast cancer.

Pemetrexed (Alimta) is a novel folate antimetabolite that primarily inhibits the enzymes thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyl transferase (GARFT), all of which are involved in pyrimidine and purine synthesis. In a phase II trial of patients with T3/4, N0-2 breast cancer, expression of thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), p53, and c-erb-B2 (at the mRNA or protein level) was examined in tumor biopsy specimens before and 24 hours after the first dose of pemetrexed and after three cycles of single-agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity. Although final data are not available, initial indications are that clinical response may correlate with decreased or low TS expression. The results obtained from clinical data are supported by laboratory results in three cell lines (MDA-231, MCF-7, and ZR-75). These results suggest that in vitro transcript profiling to identify which genes are important predictors of successful cytotoxic chemotherapy, followed by a focused clinical trial to confirm the in vitro results, may be the best approach for translational research.

Overview of phase I/II pemetrexed studies.

Pemetrexed (Alimta) is an antifolate that is effective in the inhibition of multiple enzyme targets including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The compound has been evaluated in several phase I trials, both as single agent and in combination with other cytotoxic agents. The initial schedule selected for further investigation in phase II trials was pemetrexed 600 mg/m2 as a 10-minute infusion on day 1 every 21 days. During the subsequent phase II development the dose of pemetrexed was adjusted to 500 mg/m2 due to bone marrow and gastrointestinal toxicities. The adjusted dose of pemetrexed was well tolerated throughout the late-phase drug development program. Preclinical evidence suggests that pemetrexed has additive or synergistic activity when combined with many other clinically important anticancer agents, including gemcitabine (Gemzar), fluorouracil, carboplatin (Paraplatin), oxaliplatin (Eloxatin), paclitaxel, and vinorelbine (Navelbine). Dose-limiting toxicities in these studies were primarily hematologic, and there was no evidence of cumulative hematologic toxicity. During the drug development program it was discovered that supplementation with folic acid and vitamin B12 profoundly increased the tolerability of pemetrexed. The studies discussed in this review demonstrate that pemetrexed is well tolerated as a single agent and will be an important contribution to combination chemotherapy regimens.

Drug-induced reactivation of apoptosis abrogates HIV-1 infection.

HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.

DNA copy number profiles correlate with outcome in colorectal cancer patients treated with fluoropyrimidine/antifolate-based regimens.

For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5-FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy.

Pharmacological aspects of the enzastaurin-pemetrexed combination in non-small cell lung cancer (NSCLC).

Conventional regimens have limited impact against NSCLC. Current research is focusing on multiple pathways as potential targets, and this review describes pharmacological aspects underlying the combination of the PKCbeta-inhibitor enzastaurin with the multitargeted antifolate pemetrexed. Pemetrexed is commonly used, alone or combined with platinum compounds, in NSCLC treatment, and ongoing studies are evaluating its target, thymidylate synthase (TS), as predictor of drug activity. Enzastaurin is a biological targeted agent being actively investigated against different tumors as single agent or in combination. All the downstream events following PKCbeta inhibition by enzastaurin are not completely known, and assays to evaluate possible biomarkers, such as expression of PKC, VEGF and GSK3beta, in tissues and/or in blood samples, are being developed. Enzastaurin-pemetrexed combination was synergistic in preclinical models, including NSCLC cells, where enzastaurin reduced phosphoCdc25C, resulting in G2/M-checkpoint abrogation, and Akt and GSK3beta; phosphorylation, favoring apoptosis induction in pemetrexed-damaged cells. Enzastaurin also significantly reduced VEGF secretion and pemetrexed-induced upregulation of TS expression, possibly via E2F-1 reduction, while the combination decreased TS activity. Similarly, the accumulation of deoxyuridine (a marker of TS inhibition) and the reduction of GSK3beta phosphorylation were detectable in clinical samples from a phase-Ib trial of pemetrexed-enzastaurin combination. In conclusion, the favorable toxicity profile and the multiple effects of enzastaurin on signaling pathways involved in cell cycle control, apoptosis and angiogenesis, as well as on proteins involved in pemetrexed activity, provide experimental basis for future studies on enzastaurin-pemetrexed combination and their possible pharmacodynamic markers in NSCLC patients.

First-time-in-man and pharmacokinetic study of weekly oral perifosine in patients with solid tumours.

AIM: To identify the maximum-tolerated dose (MTD) and pharmacokinetics of oral perifosine. METHODS: Patients with solid tumours received perifosine at dosages ranging from 100-800mg/week. Eligibility criteria included life expectancy>12weeks, WHO performance status2, normal blood, liver and renal functions and no recent anticancer treatment. Drug concentrations were analysed by HPLC-MS/MS. RESULTS: Thirty six patients were recruited (75% males, mean age 54.7years, performance status 1 in 72.2%). Adverse events included nausea (69.4%), diarrhoea (55.6%), vomiting (52.8%) and abdominal pain (13.9%). Antiemetic regimens including glucocorticoids, dopamine antagonists and 5-HT3-antagonists were used as treatment and/or prophylaxis in 50% of the patients. Though MTD was formally not reached with 800mg/week, the treatment discontinuation due to diarrhoea and vomiting likely related to perifosine in two cases led to the decision to stop further dose escalation. Pharmacokinetics after a single dose were median t(max)=8.0-24.2h, median t(1/2)=81.0-115.9h and mean(geo) CL/f=0.28-0.43mL/min/kg. Urinary excretion was below 1%. Perifosine slightly accumulated and steady state was nearly reached after 2-3weeks. CONCLUSION: Oral perifosine was tolerable up to 600mg/week in cancer patients when administered with meal and prophylactic antiemetics. Based on its half-life of about 4days, a weekly regimen may be appropriate.

Multiple-pool cell lifespan models for neutropenia to assess the population pharmacodynamics of unbound paclitaxel from two formulations in cancer patients.

PURPOSE: Our objective was to build a mechanism-based pharmacodynamic model for the time course of neutropenia in cancer patients following paclitaxel treatment with a tocopherol-based Cremophor-free formulation (Tocosol Paclitaxel) and Cremophor EL-formulated paclitaxel (Taxol). METHODS: A randomized two-way crossover trial was performed with 35 adult patients who received 175 mg/m(2) paclitaxel as either 15 min (Tocosol Paclitaxel) or 3 h (Taxol) intravenous infusions. Paclitaxel concentrations were measured by LC-MS/MS. NONMEM VI was used for population pharmacodynamics. RESULTS: The cytotoxic effect on neutrophils was described by four mechanism-based models predicated on known properties of paclitaxel that used unbound concentrations in the central, deep peripheral or an intracellular compartment as forcing functions. Tocosol Paclitaxel was estimated to release 9.8% of the dose directly into the deep peripheral compartment (DPC). All models provided reasonable fitting of neutropenic effects. The model with the best predictive performance assumed that this dose fraction was released into 22.5% of the DPC which included the site of toxicity. The second-order cytotoxic rate constant was 0.00211 mL/ng per hour (variability: 52% CV). The relative exposure at the site of toxicity was 2.21 +/- 0.41 times (average +/- SD) larger for Tocosol Paclitaxel compared to Taxol. Lifespan was 11.0 days for progenitor cells, 1.95 days for maturating cells, and 4.38 days for neutrophils. Total drug exposure in blood explained half of the variance in nadir to baseline neutrophil count ratio. CONCLUSIONS: The relative exposure of unbound paclitaxel at the site of toxicity was twice as large for Tocosol Paclitaxel compared to Taxol. The proposed mechanism-based models explained the extent and time course of neutropenia jointly for both formulations.