Pharmacokinetics of an etoposide infused over three days: concomitant infusion with cisplatin.

The pharmacokinetics of a 72-hour infusion of 240 mg/m2 etoposide administered concurrently with 90 mg/m2 cisplatin was studied in 12 lung cancer patients. The area under the curve (AUC), elimination half-life, steady state concentration, systemic clearance, renal clearance of etoposide and distribution volume at steady state were 225.4 +/- 39.2 micrograms x h/ml, 8.1 +/- 3.4 h, 3.1 +/- 0.6 micrograms/ml, 18.8 +/- 3.1 ml/min/m2, 3.1 +/- 1.4 ml/min/m2, 9.6 +/- 3.8 l/m2, respectively, which were in accordance with those reported previously in patients treated with etoposide alone. Although concentration at 24 hours, total bilirubin level and total protein level were correlated with the AUC which in turn correlated with hematologic toxicity, the variables were not predictive of hematologic toxicity. We conclude that the concomitant administration of cisplatin at a dose level of 30 mg/m2/day might not affect the pharmacokinetics of prolonged etoposide infusion.     

Clinical pharmacodynamics of continuous-infusion etoposide

Summary Continuous-infusion etoposide was given to 15 patients with newly diagnosed small-cell lung cancer (extensive disease) and 10 patients with various refractory malignancies. The untreated patients with lung cancer received 200 mg/m² etoposide over 24 h in combination with 100 mg/m² cisplatin, and the pretreated patients received 400 mg/m² etoposide over 36 h as monotherapy. Pharmacokinetic studies of etoposide were carried out in all patients. High-performance liquid chromatography (HPLC) was used to measure etoposide. All patients had normal hepatic and renal function tests and were followed weekly for hematologic toxicity after therapy. In all, 14 untreated and 9 pretreated patients were evaluable. Biostatistical analysis was done to correlate pharmacokinetic results to hematologic effects. Pearson correlation coefficients were calculated for continuous variables (i.e., blood counts), and Spearman correlation coefficients were calculated for ranked variables (i. e., toxicity grades). The values for the area under the plasma concentration vs time curve (AUC) and systemic clearance varied widely among patients. However, the AUC and clearance were significantly correlated (P<0.05) with the WBC and platelet nadirs and the decrease in hemoglobin. The grade of leukopenia and total grade of hematologic toxicity were also correlated with AUC and clearance. Because the interpatient variability in etoposide pharmacokinetics correlates with the variable degree of hematologic toxicity, pharmacokinetic drug monitoring is suggested.     

Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide phosphate (BMY-40481)

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25–110 mg/m²/day for 5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110 mg/m²/day for 5 days every 3 weeks and the dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensitivity reactions. The etoposide phosphate:etoposide area under the plasma concentration versus time curve (AUC) ratio was <1% and the pharmacokinetic parameters for etoposide were within previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide AUC and baseline white blood cell count were significant determinants of leucopenia (model r² = 0.51).     

A Phase I-II study of sequential administration of topotecan and oral etoposide (toposiomerase I and II inhibitors) in the treatment of patients with small cell lung carcinoma

BACKGROUND: Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC. METHODS: Patients with histologically confirmed, limited or extensive stage SCLC were eligible. The dose escalation scheme of three cohorts (six patients per cohort) started at intravenous topotecan 0.5 mg/m(2) per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). Subsequent dose levels involved escalation of topotecan to 0.75 mg/m(2) per day and 1.0 mg/m(2) per day for 5 days. A Phase II study was conducted at one dose level below the maximum tolerated dose. The authors alternated the drug sequence with each consecutive cycle and compared the hematologic toxicity between the two sequences. RESULTS: Thirty-six patients (21 patients with limited disease and 15 patients with extensive disease) received a total of 173 courses of sequential combination chemotherapy (topotecan --> etoposide, 88 courses; etoposide --> topotecan, 85 courses). The authors identified dose levels for the Phase II study as follows: topotecan, 0.75 mg/m(2) per day for 5 days; and etoposide, 50 mg twice daily for 7 days. The dose-limiting toxicity was neutropenia. At this dose level, the incidence of Grade 3-4 neutropenia and the incidence of Grade 3-4 thrombocytopenia were 25% and 10.9%, respectively. Two patients died from neutropenic sepsis. There was no significant difference in hematologic toxicities between the two sequences. Complete and partial response rates were 5.6% and 55.6%, respectively (limited disease, 9.5% and 66.75%; extensive disease, 0% and 40%, respectively). The median progression free survival was 31.9 weeks (limited disease, 36.1 weeks; extensive disease, 28.9 weeks; 95% confidence interval, 25.6-36.0 weeks), and the median overall survival was 52.4 weeks (limited disease, 54.9 weeks; extensive disease, 30.1 weeks; 95% confidence interval, 39.6-57.7 weeks). CONCLUSIONS: Combination therapy with topoisomerase I and II inhibitors is a safe and effective regimen for patients with SCLC. Future research on this combination should focus on an oral regimen for patients with extensive disease and poor tolerance to cisplatin. The authors recommend an oral dosage of topotecan at 1.2 mg/m(2) per day (equivalent to intravenous topotecan at 0.75 mg/m(2) per day) for 5 days followed by etoposide 50 mg twice daily for 7 days.     

Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose of paclitaxel with carboplatin with and without filgrastim support in patients with metastatic non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of paclitaxel and carboplatin and correlate these with the pharmacodynamic effects. PATIENTS AND METHODS: Thirty-six chemotherapy-naive patients with metastatic NSCLC were entered into this phase I dose-escalation and pharmacokinetic study. Paclitaxel was initially administered as a 24-hour infusion at a fixed dose of 135 mg/m2, and the carboplatin dose was escalated in cohorts of three patients, using Calvert's formula [dose(mg) = area under the concentration time curve (glomerular filtration rate + 25)], to target areas under the concentration time curve (AUCs) of 5, 7, 9, and 11 mg/mL x minute. A measured 24-hour urinary creatinine clearance was substituted for the glomerular filtration rate. Once the maximum-tolerated AUC (MTAUC) of carboplatin was reached, the paclitaxel dose was escalated to 175, 200, and 225 mg/m2. When the paclitaxel dose escalation began, the AUC of carboplatin was reduced to one level below the MTAUC. RESULTS: Myelosuppression was the major dose-limiting toxicity. Thrombocytopenia was observed at a carboplatin AUC of 11 mg/mL x minute after course 2 and thereafter. End-of-infusion plasma paclitaxel concentrations and median duration of time above 0.05 microM were similar in course 1 versus course 2 at the 135 and 175 mg/m2 dose levels. The neutropenia experienced by patients was consistent with that observed in patients who had received paclitaxel alone. Measured carboplatin AUCs were approximately 12% (20% v 3% with course 1 v course 2, respectively) below the desired target, with a standard deviation of 34% at all dose levels. A sigmoid-maximum effect model describing the relationship between relative thrombocytopenia and measured free platinum exposure indicated that patients who received the combination of carboplatin with paclitaxel experienced less severe thrombocytopenia than would be expected from carboplatin alone. Of the 36 patients entered onto the study, one experienced a complete response and 17 had partial responses, for an overall response rate of 50%. The recommended doses of paclitaxel (24-hour infusion) and carboplatin for future phase II studies of this combination are (1) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute without filgrastim support; (2) paclitaxel 135 mg/m2 with a carboplatin dose targeted to achieve an AUC of 9 mg/mL x minute with filgrastim support; and (3) paclitaxel 225 mg/m2 with a carboplatin dose targeted to achieve an AUC of 7 mg/mL x minute with filgrastim support. CONCLUSION: The regimen of paclitaxel and carboplatin is well-tolerated and has promising activity in the treatment of NSCLC. There is no pharmacokinetic interaction between paclitaxel and carboplatin, but there is a pharmacodynamic, platelet-sparing effect on this dose-limiting toxicity of carboplatin.     

A phase I trial defining the maximum tolerated systemic exposure of topotecan in combination with Carboplatin and Etoposide in extensive stage small cell lung cancer

PURPOSE: Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. METHODS: Thirty-four chemotherapy-na?ve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. RESULTS: The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. CONCLUSION: It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.     

Phase I and pharmacological study of the new topoisomerase I inhibitor GI147211, using a daily x 5 intravenous administration.

Topoisomerase I inhibitors are interesting anti-cancer agents with a novel mechanism of action. We performed a phase I study with intravenous GI147211, a new semisynthetic camptothecin analogue, using a daily x 5 schedule administered every 3 weeks, to evaluate the side-effects and pharmacokinetics of the agent. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard froms of therapy were eligible for the study. GI147211 was given as a 30 min intravenous infusion daily for 5 consecutive days, repeated every 3 weeks. In subsequent patient cohorts the dose was escalated from 0.3 to 1.5 mg m-2 day-1. Pharmacokinetics analysis was performed on days 1 and 4 of the first course using a validated high-performance liquid chromatographic assay and non-compartmental methods. A total of 19 patients were entered into the study, one patient was not evaluable for toxicity because only one drug administration was given. Eighteen patients received a total of 67 courses through four dose levels. The dose-limiting toxicities were neutropenia and thrombocytopenia at the dose of 1.5 mg m-2 day-1. Nadirs occurred on day 15 and day 15 respectively. Other toxicities were mild and infrequent and included nausea/vomiting, headache and alopecia. The maximal tolerated dose was 1.2 mg m-2 day-1. One partial response was observed in a patient with colorectal cancer. The total plasma clearance was 999+/-184 ml min-1 (range 640-1329). The volume of distribution was 190+/-461 m-2 and the terminal half-life was 3.7+/-1.2 h. The AUC increased linearly with the administered dose. A steep and significant sigmoid relationship was established between the AUC and the percent decrease of ANC. GI147211 is a new topoisomerase I inhibitor that induced dose-limiting neutropenia and thrombocytopenia in this phase I study. The recommended dose for phase II studies with this schedule is 1.2 mg m-2 x 5 every 3 weeks.     

Population pharmacokinetics of melphalan,infused over a 24-hour period,in patients with advanced malignancies

Purpose The objective of the present study was to characterize the population pharmacokinetics of melphalan infused over a 24-h period in patients with advanced malignancies.Methods Enrolled in the study were 64 patients (144 courses). The population pharmacokinetic analysis was performed using NONMEM through the graphical interface Visual-NM. Population characteristics were computed from an initial group of 43 patients (99 courses), and 21 additional patients (45 courses) were used for model validation. With the use of a one-compartment model, the influence of demographic and biological characteristics was examined. The basic parameters were total clearance (CL) and volume of distribution (V). The interoccasion variability was taken into account in the model. The drug exposure was estimated for each patient and correlated with markers of efficacy and toxicity.Results Data analysis was performed using a three-step approach. In step 2, a close relationship was found between creatinine clearance, gender and melphalan CL. The inclusion of this second stage model significantly improved the fit. Melphalan CL was higher in male patients (14.3±4.5 l/h per m²) than in female patients (12.3±4.5 l/h per m²). CL was also reduced somewhat in patients with decreased creatinine clearance. Large interindividual variability in pharmacokinetic parameters occurred (CL varied from 4.4 to 30.6 l/h per m²). The percentage intrapatient variability in clearance between courses was 25.4%. For determining melphalan AUC in clinical routine from one sample drawn at steady state, Bayesian methodology allowed a more accurate estimation of CL than the classical formula. Neutropenia and thrombocytopenia were the main haematological toxicities encountered; grade 4 was observed in 34 and 22 courses over a total of 144 courses, respectively. No significant relationship between AUC and haematological toxicity was found. In patients with prostatic cancer a weak relationship was observed between the decrease in PSA levels and AUC (P=0.0457), while in patients with ovarian cancer no relationship was found between AUC and CA125 levels.Conclusion The population pharmacokinetic approach developed in this study should allow dosage to be individualized in order to decrease toxicity while maintaining good efficacy.     

Long-term survival in SCLC after treatment with paclitaxel,carboplatin and etoposide--a phase II study

PURPOSE: We evaluated the toxicity and feasibility of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Eighty-nine patients with limited disease (LD) or extensive disease without distant metastases (ED I) were treated in this multi-centered phase II trial between April 1996 and June 1997. Paclitaxel administration (175 mg/m(2) by a 1 h intravenous infusion) was immediately followed by a 30 min infusion of carboplatin at an area under the concentration time curve (AUC) of 5 on day 1 and etoposide 50 mg orally twice daily (bid) was given on days 2-8. Courses were repeated every 21 days. Patients who had an objective response continued treatment for a maximum of 6 courses. RESULTS: Eighty-four patients were assessable for response. Overall response rate (RR) was 82.1% with 17.8% complete remissions and 64.3% partial remissions. Median survival for LD patients was 20.5 months with a 1 year survival rate of 71.4% and a 3 year survival rate of 21.4%. Median survival of ED I patients was 11 months with a 1 year survival rate of 31.3% and a 3 year survival rate of 3.1%. Overall median survival was 18.1 months with a 1 year survival rate of 56.8% and a 3 year survival rate of 14.8%. Median progression-free intervals were 12.3 months for patients with LD stage of the disease and 8 months with ED I stage. Grade 3/4 toxicity was primarily hematologic. Grade 3/4 leucopenia occurred in 16.0% of courses and febrile episodes were detected in 0.3% of courses. Non-hematologic toxicities were uncommon. Grade 3 GI-tract toxicities or peripheral neuropathy appeared in less than 1% of the courses. Toxicities were detected according to WHO toxicity criteria. CONCLUSION: Paclitaxel can be added at full dose (175 mg/m(2)) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Efficacy data, RR, progression-free interval and survival in both, extensive and limited stage patients compare favorably with other reported data. This new regimen will be further evaluated in comparison to standard regimens in a phase III trial.     

局限期小细胞肺癌加速超分割放疗同步EP方案化疗的剂量递增I期研究

背景与目的加速超分割放疗（每日两次方案）联合EP方案同步化疗是美国国立综合癌症网络（Na-tional Comprehensive Cancer Network, NCCN）指南推荐的局限期小细胞肺癌的标准治疗方式,但国人对EP方案标准化疗剂量耐受性尚不明确。本研究旨在探讨局限期小细胞肺癌同步放化疗EP方案的最大耐受剂量。方法研究纳入病理证实的局限期小细胞肺癌患者,进行加速超分割放疗同步EP方案（依托泊苷+顺铂）化疗,放疗处方剂量为45 Gy/30 f,1.5 Gy/f,每日两次,同一日两次放疗间隔时间≥6 h,5天/周,共3周完成。化疗方案采用依托泊苷联合顺铂,每21天为1周期,具体依托泊苷100 mg/m2,d1-d3,顺铂采用剂量递增的方式（第1组为70 mg/m2 d1,第2组为75 mg/m2 d1）。主要观察指标为治疗期间的血液学毒性。次要观察指标为非血液学毒性和1年总生存期（overall sur-vival, OS）、无进展生存期（progression free survival, PFS）。根据不良事件常用术语评定标准（Common Terminology Criteria for Adverse Events, NCI-CTCAE）4.0,最大耐受剂量设定为6例患者中不超过1例患者出现剂量限制毒性（4级血液学毒性）的剂量,同时下一剂量组6例患者至少2例出现剂量限制性毒性。结果研究共纳入20例局限期小细胞肺癌患者,平均年龄49.50（30-68）岁。第1组入组6例患者,1例患者出现4度中性粒细胞减少;后第2组入组14例患者,1例患者出现4度中性粒细胞减少。其中,第1组有4例患者出现≥3度血液学毒性,1例患者出现3度以上放射性食管炎;第2组有10例患者出现≥3度血液学毒性,无患者出现3度以上放射性食管炎。中位随访9.0个月（3.2个月-36.2个月）,1年OS、PFS分别为91%、62%。结论局限期小细胞肺癌患者采用加速超分割放疗联合EP方案化疗将顺铂剂量递增至75 mg/m2是安全的,其有效性还需要进一步扩大样本量和随访更长的时间来证实。     

Intermediate dose etoposide plus G-CSF 16 g/kg is more effective than cyclophosphamide 4 g/m(2) plus G-CSF 10 g/kg in PBSC mobilization of lymphoma patients

We designed intermediate dose etoposide + G-CSF 16 microg/kg as a Peripheral Blood Stem Cell (PBSC) mobilization schedule suitable for outpatient administration. Forty-one Lymphoma patients received intermediate dose etoposide (200 mg/m(2) i.v. day +1, +2, +3) +G-CSF 16 microg/kg/day. Results of PBSC mobilization in these patients were compared with those of a group of 37 lymphoma patients mobilized using cyclophosphamide (CTX) at dosage of 4 g/m(2) + G-CSF 10 microg/kg/die. Mean peak of CD34+ cells achieved in P.B. and total CD34+ cells harvested were higher in patients mobilized with intermediate dose etoposide (p = 0.003 and p = 0.004, respectively). After transplantation recovery of polymorphonucleate neutrophils (PMN) > 0.5 x 10(9)/L did not differ significantly between groups: 11.7 days in intermediate dose etoposide group and 11.5 days in CTX group (p = 0.7). Intermediate dose etoposide + G-CSF 16 microg/kg resulted in a maximum length of neutropenia (PMN < 0.5 x 10(9)/L) of 2 days and neutropenic fever was registered during only 3/41 courses (7.3%). Intermediate dose etoposide + G-CSF 16 microg/kg is a highly effective mobilizing therapy, further, it has the advantage of low hematologic toxicity and can be easily administered as outpatient treatment.     

Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose intravenous etoposide in elderly patients with small-cell lung cancer.

PURPOSE: The target area under the plasma-concentration-versus-time curve (AUC)-based dosing of carboplatin using Calvert's formula is expected to result in more acceptable toxicity and greater efficacy in elderly patients with small-cell lung cancer (SCLC) than the body surface area-based dosing strategy. This phase II study was designed to determine the toxicity and efficacy of carboplatin based on Calvert's formula plus the standard dose of intravenous etoposide for elderly patients with SCLC. PATIENTS AND METHODS: Carboplatin, dosed to a target AUC of 5 x (24-hour creatinine clearance + 25), was given intravenously on day 1 and etoposide 100 mg/m(2) was given intravenously on days 1, 2, and 3. Patients aged >/= 70 years old with a performance status of 0 to 2 were eligible. RESULTS: Thirty-six patients were enrolled onto the study. The patient characteristics were as follows: median age, 73 years; limited disease (LD), 16 patients; and extensive disease (ED), 20 patients. Grades 3 and 4 leukopenia occurred in 57% and 3% of patients, and grades 3 and 4 thrombocytopenia occurred in 40% and 11% of patients, respectively. There was one treatment-related death due to hemoptysis. Other toxicities were relatively mild. There were two complete responses and 25 partial responses, for a response rate of 75%. The median survival time was 10.8 months (LD, 11.6 months; ED, 10.1 months), and the 1-year survival rate was 47%. CONCLUSION: This carboplatin/etoposide combination chemotherapy is an active and relatively nontoxic regimen in elderly patients with SCLC, which suggests that the combination may be suitable for randomized controlled trials.     

Teniposide and cisplatin given by intraperitoneal administration: preclinical and phase I/pharmacokinetic studies

Cisplatin and teniposide given by intraperitoneal (IP) route exert a synergistic therapeutic effect against ascitic P388 leukemia in mice. As single agents, they display different dose-limiting toxicities and favourable pharmacokinetic characteristics in IP phase I trials. We administered cisplatin (fixed dose: 200 mg/m2) and teniposide (escalating doses) by IP route without dwell-time to investigate the toxicity, pharmacokinetics and clinical activity of this 2-drug combination. Nine patients received a total of 14 courses. Myelosuppression, nausea and vomiting were the most frequent toxicities. Leukopenia was the dose-limiting toxicity. The maximum tolerated dose of teniposide was 100 mg/m2 when administered with a fixed dose of 200 mg/m2 cisplatin. Pharmacokinetic analysis showed that the main parameters of both cisplatin and teniposide in the peritoneum and in the plasma were not modified when the drugs were combined. It appears that a pharmacodynamic interaction exists between cisplatin and teniposide which results in increased hematologic toxicity. Although an objective response has been observed in one patient with refractory ovarian cancer, such association should not be applicable for further clinical development due to marked toxicity and the low dose of teniposide recommended.     

Phase I clinical and pharmacokinetic study of flavopiridol in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors. PATIENTS AND METHODS: Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3. RESULTS: Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 micromol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2). CONCLUSION: The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.     

Phase I and pharmacokinetic study of a daily times 5 short intravenous infusion schedule of 9-aminocamptothecin in a colloidal dispersion formulation in patients with advanced solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography. RESULTS: Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer. CONCLUSION: 9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.     

The prognostic value of etoposide area under the curve (AUC) at first chemotherapy cycle in small cell lung cancer patients: a multicenter study of the groupe Lyon-Saint-Etienne d'Oncologie Thoracique (GLOT)

PURPOSE: To assess the potential relationships between systemic exposure to doxorubicin, etoposide and ifosfamide at first chemotherapy cycle and therapeutic effect, tumor response, toxicity, and survival, in small cell lung cancer (SCLC) patients. PATIENTS AND METHODS: Twenty-four patients referred to five different centers with either thorax-limited or metastatic SCLC entered the study. All but one received two induction courses of the 3 day-AVI (doxorubicin 50 mg/m(2) day 1, etoposide 120 mg/m(2) day 1, 2, 3, ifosfamide 2000 mg/m(2) day 1, 2) regimen. Individual plasma samples were collected at the first course and complete concentration data on 24 courses were available. Drugs exposures were estimated using a population pharmacokinetic method and expressed as clearance (Cl), area under the curve (AUC), and AUC-intensity (AUC/cycle duration). Responding patients received thoracic irradiation+concomitant cisplatinum-etoposide (limited disease) or four more courses of AVI (extensive disease). The impact of exposure parameters on haematological toxicity, tumor response and overall survival was assessed using linear regression, the Mann-Whitney U-test and the log-rank test/Kaplan-Meier estimation, respectively. RESULTS: Twenty-three patients could be evaluated for response and survival. We found no relationship between drug exposure and haematological toxicity but all patients had received Granulocyte-Colony Stimulating Factor support. Tumor response was marginally influenced by ifosfamide AUC. In patients with etoposide AUC>254.8 mg h/l, 1-year survival was 50.0 vs. 9.1% in the other group (median 11.4 vs. 7.1 months, P=0.02), with respect to established prognostic factors. In patients with extensive disease only (n=15), 1-year survival was 42.9 vs. 0% (median 11.3 vs. 5.3 months, P=0.01). CONCLUSION: This study strongly suggests that SCLC patients should benefit from sufficient etoposide exposure at first cycle to improve survival. Adaptative control based on plasma concentration measurements should be tested in further studies assessing various polychemotherapy regimens.     

Phase I Study and Clinical Pharmacological Evaluation of Daily Oral Etoposide Combined with Carboplatin in Patients with Lung Cancer

Twenty-eight patients with inoperable or relapsed lung cancer were given a combination of oral etoposide, administered once a day at doses ranging from 40 to 60 mg/m²/day (d) for 21 consecutive days, and carboplatin, administered intravenously over 1 h at doses ranging from 300 to 400 mg/m² on day 1 to determine the appropriate doses of this combination. In addition, pharmacokinetic and pharmacodynamic analyses were performed. All the patients had a performance status of 0 to 1. Serum etoposide and free platinum (Pt) concentrations were measured using high-performance liquid chromatography and atomic absorption, respectively. Myelosuppression, nausea and vomiting were the dose-limiting toxicities of this schedule. The maximum tolerated dose (MTD) was 50 mg/m²/d oral etoposide for 21 days and 400 mg/m² i.v. carboplatin on day 1. For heavily pretreated patients, the MTD was 40 mg/m²/d oral etoposide for 21 days and 350 mg/m² i.v. carboplatin on day 1. No cumulative increase in the area under the concentration-time curve (AUC) for oral etoposide over time was observed. There were significant correlations between the free Pt serum level (6, 8, 12, 24 h post-dose) and etoposide AUC level (days 1, 10 and 21) for graded hematological toxicity, and the percentage decreases and nadir counts of hemoglobin, leukocytes, neutrophils and platelets. Several pharmacodynamic models were developed to predict the hematological toxicity. In order to facilitate pharmacodynamic evaluations in future studies, a limited sampling model for oral etoposide was also developed and validated.     

Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma.

PURPOSE: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated. PATIENTS AND METHODS: Twenty-seven patients (23 male, four female) with MPM were treated on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL.min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10). RESULTS: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days. CONCLUSION: The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration.     

Phase I and pharmacokinetic study of exatecan mesylate (DX-8951f): a novel camptothecin analog.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic (PK) profile, and recommended phase II dose of Exatecan mesylate (DX-8951f) when administered as a 24-hour continuous infusion every 3 weeks to patients with solid tumors. PATIENTS AND METHODS: Twenty-two patients with advanced solid tumors, all previously treated, and with performance status < or = 2, were entered. The starting dose of DX-8951f was 0.15 mg/m(2); the dose was escalated according to the modified continual reassessment method. The drug was administered until disease progression or until unacceptable toxic effects occurred. RESULTS: Seven dose escalations were completed, and a total of 53 courses were delivered (median, two courses; range, one to eight courses) during the study. At doses 1.2 mg/m(2) and lower, toxicities were mostly grade 1, primarily hematologic. In the initial cohort of three patients treated at 2.4 mg/m(2), grade 2 hematologic toxicity was observed. Of the six additional patients entered at 2.4 mg/m(2), three had grade 3 or 4 granulocytopenia. At doses higher than 2.4 mg/m(2), DLT granulocytopenia was observed. Nonhematologic toxicities, including nausea, vomiting, diarrhea, fatigue, and alopecia, were mild to moderate. Neither complete nor partial responses were observed, but four patients had stable disease. The PK profile of DX-8951f seemed linear at the doses administered. The plasma clearance, total volume of distribution, and terminal elimination half-life were approximately 3 L/h, 40 L, and 14 hours, respectively. CONCLUSION: The DLT of this DX-8951f schedule was granulocytopenia for minimally pretreated patients, and both granulocytopenia and thrombocytopenia for heavily pretreated patients. The MTD for both minimally and heavily pretreated patients was 2.4 mg/m(2). DX-8951f seems to have a linear PK profile on the basis of single-dose administration. The recommended phase II dose with this schedule is 2.4 mg/m(2) for minimally pretreated patients. A lower dose should be used for heavily pretreated patients.     

Phase I trial of a twice-daily regimen of amifostine with ifosfamide, carboplatin, and etoposide chemotherapy in children with refractory carcinoma

BACKGROUND: Amifostine protects normal tissues against chemotherapy and radiation-induced toxicity without loss of antitumor effects. Evidence suggests that multiple daily doses of amifostine may improve its cytoprotective effects. The purpose of this study was to assess the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of twice-daily doses of amifostine with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy for children with refractory malignancies and to determine the pharmacokinetic properties of amifostine, WR-1065, and the disulfide metabolites of amifostine. METHODS: Patients with refractory malignancies were treated with amifostine 15 minutes before and 2 hours after chemotherapy with ifosfamide (3 g/m(2) per dose on Days 1 and 2) and carboplatin (635 mg/m(2) on Day 3). Etoposide was administered on Days 1 and 2 (150 mg/m(2)). The starting dose of amifostine was 740 mg/m(2). Pharmacokinetic studies were performed after the first dose of amifostine. RESULTS: Twelve patients received 23 courses of ICE and amifostine. Dose-limiting toxicities for amifostine at 740 mg/m(2) were somnolence and anxiety. The other Grade 3 and 4 toxicities included asymptomatic, reversible hypocalcemia, vomiting, and reversible hypotension. At a dose of 600 mg/m(2), amifostine was well tolerated. Hypocalcemia, due to rapid, transient suppression of parathyroid hormone production, required close monitoring and aggressive intravenous calcium supplementation. Pharmacokinetic studies revealed high interpatient variability with rapid plasma clearance of amifostine and WR-1065. The median elimination half-life of amifostine (9.3 minutes) and WR-1065 (15 minutes) was much shorter than the disulfide metabolites (74.4 minutes). CONCLUSIONS: The recommended pediatric dose of amifostine for a twice-daily regimen is 600 mg/m(2) per dose (1200 mg/m(2)/day) with DLTs of anxiety and somnolence, lower than the previously recommended single dose of 1650 mg/m(2).