Investigation of bioavailability and pharmacokinetics of treosulfan capsules in patients with relapsed ovarian cancer

Purpose: Treosulfan (l-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days. Methods: A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration. Results: The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 ± 0.18 (mean ± SD) using the values AUC_oral=82.1 ± 39.4 μg/ml h and AUC_i.v.=85.4 ± 30.3 μg/ml h. The peak plasma concentration c_max (29 ± 14 μg/ml vs 65 ± 23 μg/ml) was significantly (P < 0.01) higher after i.v. administration and the t_max after oral administration was 1.5 ± 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6–26%). Conclusions: The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases. Received: 28 July 1999 / Accepted: 16 December 1999     

Population pharmacokinetics of cabazitaxel in patients with advanced solid tumors

Purpose

To develop a population pharmacokinetic (PK) model for cabazitaxel in patients with advanced solid tumors and examine the influence of demographic and baseline parameters.

Methods

One hundred and seventy patients who received cabazitaxel (10–30 mg/m², 1-h IV infusion) every 7 or 21 days in five Phase I–III studies were analyzed by non-linear mixed-effect modeling (NONMEM VI). Model evaluation comprised non-parametric bootstrap and visual predictive checks.

Results

Cabazitaxel PK was best described by a linear three-compartment model with: first-order elimination; interindividual variability on clearance (CL), central volume of distribution (V1), and all intercompartmental rate constants except K21; interoccasion variability in CL and V1; proportional residual error of 27.8 %. Cabazitaxel CL was related to body surface area (BSA) and tumor type (breast cancer; finding confounded by study). Typical CL for a non-breast cancer patient with a BSA of 1.84 m² was 48.5 L/h, with V1 26.0 L, steady-state volume of distribution 4,870 L and alpha, beta, and gamma half-lives of 4.4 min, 1.6, and 95 h, respectively. Sex, height, weight, age, Caucasian race, renal/hepatic function, and cytochrome P450 inducer use did not significantly further explain the PK of cabazitaxel. Bootstrap and posterior predictive checks confirmed the adequacy of the model.

Conclusions

Cabazitaxel PK appears unaffected by most baseline patient factors, and the influence of BSA on CL is addressed in practice by BSA-dependent doses. This analysis suggests consistent cabazitaxel PK and exposure across most solid tumor types, although the potential influence of breast cancer on CL requires further confirmation.     

Clinical pharmacokinetics of bevacizumab in patients with solid tumors

Objective  To characterize the population pharmacokinetics of bevacizumab and the influence of demographic factors, disease severity, and concomitantly used chemotherapy agents on it’s pharmacokinetic behavior. Patients and methods  Data from eight clinical trials with bevacizumab administered by intravenous infusion were included. A total of 4,629 bevacizumab concentrations from 491 patients with solid tumors, who received bevacizumab doses ranging from 1 to 20 mg/kg at a dosing frequency ranging from weekly to every 3 weeks, were analyzed using a nonlinear mixed-effects modeling approach (NONMEM). Results  The best structural model was a two-compartment model with first-order elimination. In the final model, estimated clearance (CL) and central compartment volume of distribution (V _c) were 0.207 L/day and 2.39 L for a typical female. The terminal half-life estimate was ∼20 days for both men and women. Body weight and gender were the most significant covariates to explain interpatient variability for CL and V _c. Clearance was 26% faster in men than in women. Patients with low serum albumin and high serum alkaline phosphatase had 19 and 23% faster CL, respectively, than a typical patient. Consistent with the long elimination half life, simulations showed that similar steady-state exposures can be maintained when the weekly mg/kg dose rate is maintained, therefore allowing administration of bevacizumab to coincide with the frequency of administration of the cytotoxic agents. Conclusion  The PK parameters were consistent with those of other IgG molecules. The results support dosing bevacizumab on a once every 2 weeks or once every 3 weeks dosing schedule on a mg/kg basis.     

Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients

PURPOSE: The alkylating agent treosulfan exerts a high cytotoxic activity against various malignant cells. Due to limited non-hematological toxicity, treosulfan might be a promising compound in myeloablative therapy for hematopoietic transplantation in children. Since in vitro data regarding the activity of treosulfan against childhood leukemic cells are limited, we compared the effect of treosulfan and busulfan against pediatric leukemic and non-malignant cells. EXPERIMENTAL DESIGN: Both agents were tested alone and in combination with fludarabine by means of the MTT and/or a five color-flow cytometric assay. Moreover, the induction of apoptosis by treosulfan was investigated via regulation of the proteinase caspase 3. RESULTS: Treosulfan was more active against leukemic cells of 20 children as well as against 3 leukemia-derived cell lines than busulfan, with increasing IC(50) values from initial diagnosis to relapse. Overall purified stem cells were most sensitive, followed by CD56(+)CD3(-) NK and CD3(+) T cells. The combination of treosulfan with fludarabine resulted in a synergistic effect against leukemic cells. In malignant cells, treosulfan induced rapid cell apoptosis measured by the activation of the centrally proteinase caspase 3. CONCLUSION: Our results indicate that treosulfan has activity against pediatric leukemic cells, myeloablative potential and immunosuppressive properties suitable for conditioning regimen in childhood malignancies.     

Initial clinical trial and pharmacokinetics of ThymitaqTM (AG337) by 10-day continuous infusion in patients with advanced solid tumors

Purpose: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters of a 10-day infusion of the nonclassical antifolate Thymitaq^TM. Methods: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m² per day with escalation to 572 and 716 mg/m² per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. Results: The dose of 716 mg/m² per day × 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade IV myelotoxicity. At 572 mg/m² per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing to a high incidence of thrombotic phenomena, no further patients were added. Conclusion: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done. Received: 4 March 1997 / Accepted: 14 July 1997     

Safety and pharmacokinetics of panitumumab in Japanese patients with advanced solid tumors

Background  

Panitumumab is a fully human, monoclonal antibody against the epidermal growth factor receptor. Previous studies in non-Japanese patients with solid tumors showed that panitumumab exhibited nonlinear pharmacokinetics, was well tolerated (skin toxicities were the most common treatment-related adverse events), and had antitumor activity in some patients. This open-label, phase 1 study investigated panitumumab safety and pharmacokinetics in Japanese patients.     

A phase IB study of the pharmacokinetics of gemcitabine and pemetrexed, when administered in rapid sequence to patients with advanced solid tumors

Background We have previously demonstrated that pemetrexed is clinically active when administered 90 min after gemcitabine in a phase I study. The present study was undertaken to evaluate the efficacy, toxicity, and pharmacokinetics of gemcitabine and pemetrexed when pemetrexed is administered immediately after gemcitabine.Patients and Methods A total of 14 patients received 84 cycles of treatment. Gemcitabine 1250 mg/m² was administered on days 1 and 8 of each 21-day cycle, and pemetrexed 500 mg/m² on day 8 immediately following gemcitabine administration. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria and recorded as maximum grade per patient for all treatment cycles. Pharmacokinetic analyses of plasma gemcitabine and pemetrexed concentrations were performed.Results Neutropenia was the most common severe toxicity. Non-hematologic toxicities, which included nausea, vomiting, fatigue, diarrhea, rash, and elevated transaminases were of mild-to-moderate severity. No increased toxicity was observed with this schedule in comparison to the previous phase I schedule. There was no pharmacokinetic interaction between the two drugs. One partial response was documented in a patient with non-small-cell lung cancer. Eight patients had disease stabilization for five or more cycles.Conclusion Gemcitabine immediately followed by pemetrexed is well tolerated and clinically active, and deserves further evaluation in phase II trials.     

A Phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumors

 Preclinical studies of 2-chlorodeoxyadenosine (2-CdA) against solid tumors in the human tumor cloning assay and evidence that 2-CdA is active against slow-growing or resting tumor cells have stimulated interest in the clinical activity of this agent against solid tumors. This study sought to estimate the maximum tolerated dose, dose-limiting toxicity, and plasma and urine pharmacokinetics accompanying the intravenous administration of 2-CdA by 120-h continuous infusion in patients with solid tumors. Treated patients were also assessed for other toxicities of therapy and for antitumor response. A total of 23 patients received 35 courses of treatment given at doses of 3.5, 5.3, 6.5 and 8.1 mg/m² per day by continuous intravenous infusion for 5 days and repeated every 28 days. Blood and urine specimens were collected before, during, and after drug infusion. The dose-limiting toxicity at 8.1 mg/m² per day manifested as granulocytopenia in 2 of 5 patients (3 of 7 courses of treatment) and as thrombocytopenia in 3 of 5 patients (3 of 7 courses of treatment). At the dose levels of 6.5 and 8.1 mg/m² per day, recovery from thrombocytopenia was often delayed. Severe lymphocytopenia (<1,000/μl) was observed at all dose levels of 2-CdA. Dose-related anemia and leukopenia were observed and were infrequently severe. Nonhematological toxicities were confined to mild-to-moderate nausea, vomiting, fatigue, and anorexia. Fever of 37^°–40^°C was induced during drug infusion in 19 patients. No antitumor response was observed. Average plasma concentrations at steady-state (Cp_ss) ranged from 3 ng/ml at the initial dose level to 13 ng/ml at the dose level of 8.1 mg/m² per day. Both the Cp_ss and the area under the plasma concentration-time curve (AUC) were proportional to the dose. A relationship was observed between the percentage of change in absolute neutrophil count and the AUC. Renal excretion accounted for only 18% of the elimination of 2-CdA over the 5-day infusion period. The maximum tolerated dose for 2-CdA given by 5-day continuous infusion was 8.1 mg/m² per day in this study. The recommended dose on this schedule for phase II studies is 6.5 mg/m² per day. Granulocytopenia and thrombocytopenia were dose-limiting. No antitumor activity was observed during this study. On the basis of the plasma concentrations of 2-CdA observed, it is unlikely that this schedule of drug administration will permit achievement of the concentrations consistent with antitumor activity observed in preclinical studies. Received: 14 March 1994/Accepted: 22 July 1994     

Cisplatin, gemcitabine and treosulfan is effective in chemotherapy-pretreated relapsed stage IV uveal melanoma patients

Purpose  The efficacy of cisplatin, gemcitabine, and treosulfan (CGT) was evaluated in patients with chemotherapy pretreated relapsed AJCC stage IV uveal malignant melanoma. Methods  Patients received i.v./intrahepatic cisplatin, i.v. gemcitabine, and i.v. treosulfan (CGT) on day 1 and 8 as first-line (n = 1), second-line (n = 9), third-line (n = 1) or fourth-line (n = 1) therapy. Cisplatin, gemcitabine, and treosulfan (CGT)-therapy was repeated every 5 weeks until progression of disease occurred. A maximum of six CGT-cycles (mean, 2 cycles) was administered per patient. Results  No objective response was observed, six patients (50%) had stable disease and six (50%) patients progressed upon first reevaluation. Overall survival of all the 12 patients was 6 months. Patients with stable disease reached a median overall survival of 12 months, while patients with disease progression upon first reevaluation had a median overall survival of 4 months, only. Grade III/IV related hematotological side effects were experienced in six (leukopenia) and four (thrombocytopenia) patients. Conclusions  Treatment with CGT may lead to disease stabilization and prolonged survival in a substantial proportion of progressive stage IV uveal melanoma patients, even following heavy chemotherapy treatment.     

Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors

 A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m² per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R ² = 0.71, n = 18, P<0.0001). The mean±SE concentrations were 93±16, 230±6 and 302±27 μM at 1, 2 and 3.2 g/m² per day, respectively. The mean±SE renal and nonrenal clearances of hydroxyurea were 2.14±0.18 and 3.39±0.28 l/h per m² (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean±SE half-life of 3.25±0.18 h (n = 17). The steady-state concentration of hydroxyurea was >200 μM in all nine patients treated at 2 g/m² per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents. Received: 28 November 1995 / Accepted: 18 May 1996     

A phase I and pharmacokinetics study of intravenous calcitriol in combination with oral dexamethasone and gefitinib in patients with advanced solid tumors

Purpose

The primary objective of this study was to determine the maximum tolerated dose (MTD) of intravenously (i.v.) calcitriol administered in combination with a fixed oral dose of dexamethasone and gefitinib in patients with refractory solid tumors.

Methods

A fixed oral dose of dexamethasone of 4 mg/day was given every 12 h × 3 doses starting 12 h prior to i.v. calcitriol administration. Calcitriol was administered i.v. over 1 h on weeks 1, 3, and weekly thereafter. The starting calcitriol dose level was 57 μg and escalation occurred in cohorts of three patients until the MTD was defined. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Serum calcitriol PK studies were performed on day 1 (calcitriol + dexamethasone) and on day 15 (calcitriol + dexamethasone + gefitinib).

Results

A total of 20 patients were treated. Dose-limiting hypercalcemia was observed in two out of the four patients receiving 163 mcg/week of calcitriol. Mean (±SE) peak serum calcitriol concentration (C _max) at the MTD (125 μg/week calcitriol) was 11.17 ± 2.62 ng/ml and the systemic exposure (AUC_0–72 h) of 53.30 ± 10.49 ng h/ml. The relationship between calcitriol dose and either C _max or AUC was linear over the 57–163 μg dose range.

Conclusions

The addition of a low dose of dexamethasone allowed the safe escalation of calcitriol to the MTD of 125 μg/week. This dose level resulted in serum calcitriol concentrations that are associated with pre-clinical antitumor activity. However, no antitumor activity was noted clinically in patients with solid tumors.     

A phase I pharmacokinetics study of 9-nitrocamptothecin in patients with advanced solid tumors

Purpose

9-Nitrocamptothecin (9-NC) is a novel orally administered camptothecin analog. The purpose of this study is to evaluate the pharmacokinetics and safety of 9-nitrocamptothecin in patients with advanced solid tumors.

Methods

The 23 patients for a single-dose pharmacokinetic experiment were divided into 3 dosing cohorts. The dosage of 9-nitrocamptothecin capsule was 1.25, 1.5 and 1.75 mg/m², respectively. The 8 patients for a multiple-dose pharmacokinetic study were orally administered 9-nitrocamptothecin 1.5 mg/m² for 5 consecutive days. Determination of the plasma concentration of 9-nitrocamptothecin was performed by high-performance liquid chromatography-ultraviolet detector technique, and determination of plasma concentration of 9-aminocamptothecin was performed by high-performance liquid chromatography-fluorescence detector technique.

Results

In the single-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin C _max were 94.49 ± 41.38, 115.56 ± 63.27 and 147.57 ± 38.19 ng/mL; AUC_0–36 were 877.14 ± 360.90, 961.33 ± 403.58 and 1,189.75 ± 405.80 ng h/mL, respectively; the mean ± SD 9-aminocamptothecin C _max were 12.85 ± 6.46, 10.72 ± 6.58 and 28.74 ± 31.94 ng/mL; AUC_0–36 were 157.61 ± 111.61, 88.71 ± 39.51 and 173.52 ± 122.19 ng h/mL, respectively. In the multiple-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin AUC_ss was 907.04 ± 736.47 ng h/mL, C _max was 85.98 ± 47.52 ng/mL, C _min was 18.91 ± 22.50 ng/mL, C _av was 37.79 ± 30.69 ng/mL, DF was 2.16 ± 0.87; the mean ± SD 9-aminocamptothecin AUC_ss was 442.73 ± 308.39 ng h/mL, C _max was 34.83 ± 18.31 ng/mL, C _min was 10.32 ± 6.95 ng/mL, C _av was 18.45 ± 12.85 ng/mL, DF was 1.34 ± 0.42. Comparing single-dose 1.5 mg/m² group with multiple-dose 1.5 mg/m² group, no significant difference was observed in 9-NC pharmacokinetic parameters, but with respect to the metabolite, significant differences were observed in C _max and AUC. The toxicity of 9-NC varied from mild to moderate. No grade 3 or grade 4 toxicity was observed during the study. There was 2- to 13-fold variabilities in 9-NC and 9-AC exposure among different patients for any given dose of 9-NC.

Conclusions

All participants had good tolerance throughout the study. 9-NC and 9-AC exposure did not increase proportionally to the dose ranging from 1.25 to 1.75 mg/m². After 5-day continuous administration, accumulation was observed in the metabolite 9-AC, but not in 9-NC.     

A phase I escalating single-dose and weekly fixed-dose study of cetuximab pharmacokinetics in Japanese patients with solid tumors

Purpose  Cetuximab is a therapeutic immunoglobulin G1 monoclonal antibody that recognizes the epidermal growth factor receptor (EGFR). This phase I dose-escalation study was designed to assess the safety and pharmacokinetics (PK) of cetuximab in Japanese patients with EGFR-expressing, advanced, solid tumors and also to look for evidence of antitumor efficacy. Patients and methods  Thirty patients were enrolled in the study; 29 with colorectal adenocarcinomas and one with an adenocarcinoma of the lung. Patients received an initial/weekly infusion of cetuximab at dose levels of 100/100 (dose level 1), 250/250 (dose level 2), 400/250 (dose level 3), 500/250 (dose level 4) or 400/250 (dose level 5) mg/m², for 7 or more weeks, with an interval between the initial and second infusion of 1 (dose level 5 representing the standard regimen) or 2 weeks (dose levels 1–4 of the non-standard regimens). Results  No dose-limiting toxicities (DLTs) were observed during the evaluation period. All patients had at least one adverse event (AE). The most common cetuximab-related AEs were skin toxicity (93% of patients), including acneiform dermatitis (83% of patients). Two patients experienced cetuximab-related grade 3 AEs of skin toxicity and diarrhea after DLT evaluation. C _max and AUC_0–∞ after the initial infusion showed dose-proportional increases. Mean total body clearance (CL) values decreased with dose at the lower dose levels. At doses of ≥400 mg/m², CL values appeared to level off. Mean trough concentrations for dose level 5 were constant from week 4 (day 29) onward. Two patients (8%) achieved partial response (at 100/100 mg/m²). The overall disease control rate (partial response + stable disease) was 58%. Conclusion  The current study demonstrated that cetuximab PK and safety profiles are similar between Japanese and non-Japanese patient populations. It would appear that the standard dose of an initial 2-h infusion of 400 mg/m² followed thereafter by weekly 1-h infusions of 250 mg/m² for non-Japanese patients is feasible for future clinical studies in Japanese patients.     

Irinotecan in combination with thalidomide in patients with advanced solid tumors: a clinical study with pharmacodynamic and pharmacokinetic evaluation

Purpose: Recent clinical studies have demonstrated a reduction of irinotecan (CPT-11) gastrointestinal toxicities when the CPT-11 is administered in combination with thalidomide in patients with diagnosis of colorectal cancer. The main purpose of this study was to investigate possible interactions between CPT-11 pharmacokinetics and thalidomide to explain the previously described gastrointestinal toxicity reduction. Methods: In our clinical trial, advanced cancer patients were treated with CPT-11 on a dose of 350 mg/m² at day 1 every 3 weeks. Only at the first cycle, CPT-11 was administered in association with thalidomide on a dose of 400 mg/day given from day 1 to day 14. From the second cycle, the treatment was continued with irinotecan alone at the same dose. Pharmacokinetics analysis of irinotecan and its metabolites, SN-38 and SN-38-glucuronide, were performed at the first and second cycle. Results: A total of 19 patients entered the study. The pharmacokinetic analysis were performed on 16 patients. Pharmacokinetic data suggested a decreased metabolism of irinotecan into SN-38 and SN-38-glucuronide when it was administered with thalidomide. Indeed, area under the time–concentration curve (AUC) of SN-38 was significantly lower at the first cycle than the second cycle (0.99±0.45 h×μg/ml vs 1.34±0.65, respectively, P=0.027) whereas AUC of irinotecan and SN-38-glucuronide were higher at first cycle than second cycle (34.53±11.38 h×μg/ml vs. 28.42±12.23 h×μg/ml, P=0.064 and 2.39±1.21 h(μg/ml vs. 1.86±1.11 h×μg/ml, P=0.018, respectively). Conclusions: Our study demonstrates a significant decreased metabolism of CPT-11 into the active metabolite SN-38 when CPT-11 is administered in association with thalidomide. These observations strongly suggest an interaction of thalidomide with CPT-11 metabolism and, at least in part, it might explain the previously described improvement in tolerability.Grant support: The work was partially supported by Associazione Italiana Ricerca Cancro (AIRC) and Fondazione A.R.C.O.     

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Purpose  To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors. Methods  Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m²) followed by trabectedin (starting dose, 0.3 mg/m²). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses. Results  Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m² and gemcitabine 1,000 mg/m², which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration. Conclusions  Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.     

The absolute bioavailability of oral vinorelbine in patients with solid tumors

Due to advances in the methods used to quantitate vinorelbine, this study was conducted to characterize fully the bioavailability of an oral dosage form of vinorelbine. Twenty-seven eligible patients with solid tumors were enrolled onto this study and were treated in a randomized crossover design to receive either 70 mg/m² orally or 30 mg/m² intravenously followed by the alternative treatment one week later. Vinorelbine was administered orally as a soft-gelatin capsule. Pharmacokinetic sampling was carried out for 7 days following each dose. Whole blood vinorelbine concentrations were measured using a sensitive LC/MS/MS method. The data from patients were excluded if they vomited within 3 h after the oral dose. Results: Three subjects were removed from study following the first dose due to safety reasons. Of the remaining 24 subjects, five experienced vomiting within 3 h of oral dosing. Total body clearance calculated from the intravenous dose was 43.65 L/h (±10.9) and the terminal half-life was estimated to be 49 h. Using complete data from the remaining 19 subjects, the mean absolute bioavailability of the oral dosage formulation of vinorelbine was calculated to be 33% (±18%). In conclusion we have characterized the pharmacokinetics of both orally administered and intravenous vinorelbine over 7 days after administration and have determined the mean oral bioavailability of this oral formulation to be 33%.     

A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors

Purpose To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy. Patients and methods Twenty-nine patients (18M:11F) received a 2-h IV infusion of edotecarin in doses of 6, 8, 11, 13, or 15 mg/m² every 21 days (with an additional 1–2 weeks permitted for recovery) and were evaluated for safety, PK, and tumor response. Results The most common non-hematologic toxicities were grade 1–2 nausea, fatigue, anorexia, vomiting, and fever. The most common hematologic toxicities were grade 1–2 thrombocytopenia and grade 3–4 neutropenia, leukopenia, and anemia. No grade 3–4 diarrhea was reported. Dose-limiting toxicities were observed in four patients at the 15 mg/m² dose and one patient at the 13 mg/m² dose. These toxicities included grade 3 nausea, vomiting, headache, and fatigue, as well as grade 4 neutropenia and febrile neutropenia. The maximum tolerated dose was declared at 15 mg/m². One patient with bladder cancer had a confirmed partial response at a dose of 13 mg/m². There was a trend to dose-proportional increases in edotecarin peak plasma concentrations and area under the curve values. Renal excretion of edotecarin was minimal (3–8% of the dose). Conclusion The recommended Phase II dose of edotecarin is 13 mg/m² once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.Presented at the American Society of Clinical Oncology 2000 Annual Meeting, abstract #767.     

Antitumor activity of treosulfan in human lung carcinomas

Treosulfan (l-threitol 1,4-bismethanesulfonate, Ovastat) is an alkylating agent and a structural analogue of busulfan. It has been established in the clinical chemotherapy of human ovarian carcinomas for several years and has additionally been shown to be effective against xenografted human breast carcinomas. No other human carcinoma is yet known to be sensitive to treosulfan. The present study confirms the pronounced and significant antitumor activity of treosulfan against heterotransplanted human lung carcinomas of both the small-cell and the non-small-cell type. Treosulfan reduced the growth of all four small-cell lung carcinomas that were investigated in a significant manner. It was even more active than equitoxic doses of the clinically approved cytostatics ifosfamide, cisplatin, and etoposide toward three of them and induced long-lasting growth reductions (60–98% of control tumor size) corresponding to partial and nearly complete remissions. In the case of the nine non-small-cell lung carcinomas investigated, treosulfan effected significant growth inhibition of more than 50%, again in all of them, and was more active than the comparative compounds ifosfamide, mitomycin C, and cisplatin at least in one of four epidermoid lung carcinomas, one large-cell carcinoma, and one of three lung adenocarcinomas. These results are remarkable and unexpected, and the present study should be followed rapidly by phase II clinical trials of treosulfan against human lung carcinomas of both the small-cell and the non-small-cell type.     

Clinical pharmacokinetics,safety, and preliminary efficacy evaluation of icotinib in patients with advanced non-small cell lung cancer

ObjectivesTo receive pharmacokinetics, safety, and anti-tumor activity of icotinib, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), in patients with advanced non-small-cell lung cancer (NSCLC).Materials and methodsPatients (n = 40) with advanced NSCLC were enrolled to receive escalating doses of icotinib, which was administrated on Day 1 followed by 28-day continuous dosing starting from Day 4. Four dosing regimens, 100 mg b.i.d., 150 mg b.i.d., 125 mg t.i.d., and 200 mg b.i.d. were studied. Pharmacokinetics (PK), safety, and efficacy of icotinib were evaluated.ResultsIcotinib was well tolerated in Chinese patients with refractory NSCLC. No toxicity with >3 grades were reported in more than 2 patients under any dose levels. One complete response (3%) and 9 partial responses (23%) were received. Total disease control rate could reach at 73% and median progress-free survival (range) was 154 (17–462) days. PK exposure of icotinib increased with increase of dose in NSCLC patients. Food was suggested to increase PK exposure by ∼30%. Mean t_1/2β was within 5.31–8.07 h. No major metabolite (>10% plasma exposure of icotinib) was found in NSCLC patients.ConclusionsIcotinib with up to 400 mg/day exhibited good tolerance and preliminary antitumor activity in Chinese NSCLC patients. Pharmacokinetics of icotinib and 5 major metabolites were fully investigated in NSCLC patients. Optimized biologic dose (OBD) was finally recommended to be 125 mg t.i.d. for the later clinical study.