Recommended Dose Level Research Articles

Phase I study of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed malignant tumors

13553 Background: New drugs are strongly needed in childhood cancers, particularly in metastatic tumors. Temozolomide (TMZ) and Topotecan (TPT) have shown activity in several pediatric cancers. Resistance to alkylating agents due to MGMT expression, MMR deficiency or microsatellite instability may be overcome through the combination with topoisomerase I inhibitors. The combination of TPT with TMZ has never been given in patients and our objective was to determine the recommended dose (RD) in children. Methods: The study was conducted in 9 centers of the SFCE Pharmacology Group. TMZ was administered orally followed by TPT as a 30 minutes intravenous infusion for 5 consecutive days every 28 days. Dose escalation was performed in a classical 3+3 methodology starting at 100 mg/m2 TMZ and 0.75 mg/m2 TPT. Dose-limiting toxicity (DLT) was evaluated after the first cycle. Pharmacokinetic parameters were studied during the 1st cycle Results: Sixteen patients, median age 8.5 years (range 3–19), were enrolled between February and October 2007. Eight had neuroblastoma, 2 osteosarcoma and 6 other tumors. All had received prior chemotherapy (median 3 lines, range1–5) of whom 5 high-dose regimens. Main toxicity was hematologic and manageable. No DLT was observed in 3 patients at the first dose level. One of 6 had G3 thrombocytopenia >7 days at 150 mg/m2 TMZ and 0.75 mg/m2 TPT (level 2). Two of 3 patients had G3 thrombocytopenia with G4 neutropenia >7 days in one at 150 mg/m2 TMZ and 1.0 mg/m2 TPT (level 3). Of 4 additional patients treated at the RD (level 2), 1 experienced G3 thrombocytopenia. Pharmacokinetic data are pending. Conclusion: TMZ-TPT combination is well tolerated with hematological toxicity being the limiting toxicity. The RD is 150 mg/m2 TMZ and 0.75 mg/m2 TPT. A phase II study in metastatic/refractory pediatric tumors is in preparation. No significant financial relationships to disclose.

Phase Ib study of ixabepilone (I) in combination with epirubicin (E) in women with metastatic breast cancer

1058 Background: Ixabepilone and anthracyclines are effective in the treatment of breast cancer. The primary objective of this phase I trial was to determine the maximum tolerated doses of the combination of epirubicin and ixabepilone. Methods: The safety, tolerability, pharmacokinetic and antitumor activity of epirubicin and ixabepilone in combination administered every 3 weeks was assessed in women with advanced breast cancer. Eligible pts with a cumulative dose of ≤ 300 mg/m2 for doxorubicin, ≤ 450 mg/m2 for epirubicin and ≥ 3 months of progression free interval after adjuvant anthracycline were enrolled. Three dose levels were explored in a 3 + 3 dose escalation design: epirubicin/ixabepilone at 75/25, 75/30 and 75/35 mg/m2. PK blood samples were collected during cycle 1 and estimated by non-compartment analysis. Results: Twenty-six pts have been enrolled to date, median age was 54 yrs (33–68). Eight pts received prior chemotherapy in adjuvant setting. Safety data are preliminary and available on 23 pts across the 3 dose levels for a total of 130 cycles (median 6 cycles, range 2–8). Neutropenia was the dose limiting toxicity, occurring in 1/6 pts at 75/25, 1/11 at 75/30 and 2/6 at 75/35 mg/m2. This included 1 pt with febrile neutropenia and 3 pts with grade 4 neutropenia of ≥ 5 days duration. Enrollment at 75/30 mg/m2 dose level is continuing. The most frequent grade 3 or 4 AE was neutropenia (4/23 and 15/23 respectively). Nonhematologic grade 3 and 4 toxicities were infrequent and included 2 pts with grade 3 neuropathy and 3 pts with grade 3 vomiting. No deaths were reported. No pharmacokinetic interaction was observed. Responses were seen at all dose levels tested. Of twelve women with measurable disease 10 achieved a partial response, one stable disease and one progressed. Six pts with non measurable disease had clinical benefit and/or no disease progression. Conclusions: Based on these preliminary data the recommended dose level of epirubicin 75 mg/m2 and ixabepilone 30 mg/m2 has a favourable toxicity and efficacy profile and warrants further investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

Microbial detoxification of metalaxyl in aquatic system

Four microorganisms, Pseudomonas sp. (ER2), Aspergillus niger (ER6), Cladosporium herbarum (ER4) and Penicilluim sp. (ER3), were isolated from cucumber leaves previously treated with metalaxyl using enrichment technique. These isolates were evaluated for detoxification of metalaxyl at the recommended dose level in aquatic system. The effect of pH and temperature on the growth ability of the tested isolates was also investigated by measuring the intracellular protein and mycelia dry weight for bacterial and fungal isolates, respectively. Moreover, the toxicity of metalaxyl after 28 d of treatment with the tested isolates was evaluated to confirm the complete removal of any toxic materials (metalaxyl and its metabolites). The results showed that the optimum degree pH for the growth of metalaxyl degrading isolates (bacterial and fungal isolates) was 7. The temperature 30°C appeared to be the optimum degree for the growth of either fungal or bacterial isolates. The results showed that Pseudomonas sp. (ER2) was the most effective isolate in metalaxyl degradation followed by Aspergillus niger (ER6), Cladosporium herbarum (ER4) and Penicilluim sp. (ER3), respectively. There is no toxicity of metalaxyl detected in the supernatant after 28 d of treatment with Pseudomonas sp. (ER2). The results suggest that bioremediation by Pseudomonas sp. (ER2) isolate was considered to be effective method for detoxification of metalaxyl in aqueous media.

Practical Application of the Continual Reassessment Method to a Phase I Dose-Finding Trial in Advanced Breast Cancer

This article presents a practical application of a new dose-finding algorithm with a continual reassessment method (CRM) to a phase I study identifying the recommended dose level of chemotherapy in patients with advanced breast cancer. First, we conducted a preliminary study to determine a prior distribution for a model parameter to be used in the CRM, based on prestudy perceptions of a panel of oncologists. During the phase I study, dose-limiting toxicity (DLT) data were continually monitored to guide decisions on dose escalation and de-escalation, based on a CRM using a Bayesian probability model. We analyzed 16 patients, 3 of whom experienced a DLT. The dose-toxicity curve was updated based on observed toxicity data. The recommended doses were very similar to those identified in a previous dose-escalation study using a conventional 3 + 3 cohort design. The main disadvantage of the CRM was the need for dedicated statistical support, but this was outweighed by more accurate estimation of recommended doses.

A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies

3594 Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median Cmax, Tmax and AUC0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose. No significant financial relationships to disclose.

A phase I study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer

5543 Background and Purpose: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. GOG are currently studying the hypoxic cytotoxin, tirapazamine (TPZ) in combination with biweekly intermediate dose cisplatin (CIS) and radiation in a large phase III trial. The aim of this phase I study was to develop a better tolerated regimen that added TPZ to the standard regimen of radiation and weekly low dose CIS. Methods: Eligible patients had previously untreated carcinoma of the cervix, Stages IB2 - IVA. The starting schedule was radiotherapy (45 to 50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly CIS 40 mg/m2 weeks 1–6 and weekly TPZ 290 mg/m2 (prior to CIS) in weeks 1–5. Results: Between 3/05 and 7/06 eleven patients were enrolled, median age (range) 52 (31–65), squamous cell carcinoma 10, adenocarcinoma 1, 1B2–5, IIA-1, IIB-3, IIIB- 1, IVA-1. The first 2 patients on dose level 1 experienced a dose limiting toxicity (DLT), one grade 3 ALT (SGPT) elevation and grade 4 pulmonary embolism and one grade 3 ototoxicity. Doses were decreased to dose level -1 CIS 30 mg/m2 and TPZ 260 mg/m2. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a, CIS 35 mg/m2 and TPZ 260 mg/m2, with 2 DLTs: grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. The sixth patient on dose level -1a withdrew from the trial in week 2 after being advised about the DLTs observed on this dose level. 3 additional patients will be accrued on dose level -1 to confirm safety of this dose level. One patient has relapsed in pelvic nodes, all other patients remain disease-free with a median followup of 10 months (range 5 - 21) Conclusions: The combination of weekly TPZ and CIS with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being TPZ 260 mg/m2, CIS 30 mg/m2. No significant financial relationships to disclose.

Adherence to insulin and its association with glycaemic control in patients with type 2 diabetes

Good glycaemic control improves outcomes in patients with type 2 diabetes, but the extent to which this depends on adherence to insulin treatment is uncertain. To investigate the association between adherence to insulin and glycaemic control in insulin-treated patients with type 2 diabetes. Observational records-based study. We studied all patients with type 2 diabetes who were resident in Tayside, Scotland from 1 January 1995 to 30 September 2001, and who were treated with insulin. Adherence to insulin treatment was measured as the annual number of days of insulin coverage on the recommended dose, calculated from the amount of drug dispensed at community pharmacies and the recommended dose level for each patient. The association between glycaemic control (HbA1c), and adherence was determined, as was the influence of covariates, including age, sex, duration of diabetes and number of injections per day. A total of 1099 people were studied: 574 (52%) males and 525 (48%) females, mean +/- SD age 62 +/- 12 years, diabetes duration 10 +/- 7 years. Median time in the study (time for which insulin was dispensed) was 1107 (range 366-2446) days. Insulin prescribed was 58.0 +/- 33.3 IU/day and insulin collected from pharmacies was 53.6 +/- 27.1 IU/day. Mean adherence to insulin was thus 70.6%+/-17.7%. Adherence to insulin (p = 0.0021), BMI (p = 0.0001) and diabetes duration (p = 0.0314) were all significant predictors of HbA1c. Adherence to insulin appears poor in these type 2 diabetes patients, and there was a significant relationship between adherence and long-term metabolic control.

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I–II study

To establish the recommended dose level (RDL) and to evaluate the efficacy and safety of gefitinib plus irinotecan in patients with advanced fluoropyrimidine-refractory colorectal cancer (CRC). Patients with advanced CRC progressing on or within 12 weeks of fluoropyrimidine-based chemotherapy, irinotecan naive and performance status of two or less were recruited. During dose-finding phase, dose-limiting toxicity (DLT) was encountered at dose level 1, therefore subsequent dose de-escalation and pharmacokinetic (PK) studies were carried out. The RDL was then expanded in a multicentre setting to further evaluate safety and efficacy. From June 2002 to February 2005, 39 patients were treated in total with 27 at the RDL. The RDL was established at irinotecan 225 mg/m(2) every 3 weeks and gefitinib 250 mg daily. The DLTs were neutropenia and diarrhoea. For the patients treated at RDL, the objective tumour response rate was 11.1% (95% confidence interval 2.4% to 29.2%) and median survival was 9.3 months. PK studies indicated that the addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib (P < 0.05), but gefitinib did not alter the PK profiles of irinotecan or SN-38. Grade 3-4 toxic effects in all patients included diarrhoea (35.9%), lethargy (15.4%), neutropenia (15.4%), febrile neutropenia (10.3%) and skin rash (7.7%). Irinotecan and gefitinib at this dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan.

A phase I study of paclitaxel, topotecan, cisplatin and Filgrastim in patients with newly diagnosed advanced ovarian epithelial malignancies: A Gynecologic Oncology Group study

Objectives. To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. Methods. Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m 2/3 h, followed 2 h later by cisplatin 50 mg/m 2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m 2 (cohort 1), or 3 days beginning at 0.5 mg/m 2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. Results. Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m 2/3 h, cisplatin 50 mg/m 2 and topotecan 0.5 mg/m 2 daily × 5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m 2/3 h, cisplatin 50 mg/m 2 and topotecan 0.75 mg/m 2 daily × 3 with Filgrastim. Conclusion. In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.

A Phase I and Pharmacokinetic Study of Pemetrexed Plus Irinotecan in Patients with Advanced Solid Malignancies

The main objectives of this phase I and pharmacokinetic, open-label study were to characterize the principal toxicities and determine the maximum tolerated dose of the multitargeted antifolate pemetrexed administered in combination with irinotecan. The study also sought to detect major pharmacokinetic drug-drug interactions between these agents and preliminary evidence of antitumor activity in patients with advanced solid malignancies. Pemetrexed was administered as a 10-min i.v. infusion followed by irinotecan given i.v. over 90 min every 3 weeks to patients with advanced solid malignancies. The study objectives were first pursued in heavily pretreated patients and then in lightly pretreated patients who also received vitamin supplementation. Twenty-three heavily pretreated patients enrolled in the first stage of the study, and the maximum tolerated dose level of pemetrexed/irinotecan without vitamin supplementation was 400/250 mg/m(2); further dose escalation was precluded by severe neutropenia that was protracted and/or associated with fever. In the second stage of the study, 28 lightly pretreated patients were administered pemetrexed/irinotecan with vitamin supplementation; these patients tolerated pemetrexed/irinotecan at a dose level of 500/350 mg/m(2), which reflected clinically relevant single-agent doses of both agents. No major pharmacokinetic interactions between the agents were evident. Four patients, two patients each with colorectal cancer refractory to fluoropyrimidines and advanced mesothelioma, had partial responses. The pemetrexed/irinotecan regimen is well tolerated in patients with advanced solid malignancies at clinically relevant single-agent doses. The recommended dose level of pemetrexed/irinotecan for subsequent disease-directed evaluations involving lightly pretreated patients is 500/350 mg/m(2) every 3 weeks with vitamin supplementation.

An evaluation of the initial and long‐term antihypertensive efficacy of zofenopril compared with enalapril in mild to moderate hypertension

Angiotensin‐converting enzyme inhibitors (ACEIs) are used in the management of a range of cardiovascular disorders and are well established in primary as well as secondary cardiovascular prevention programmes. Over the years, several second‐ and third‐generation ACEIs have been introduced into the clinic. In a comparative study in patients with mild to moderate hypertension, the efficacy and safety of zofenopril 30 mg od (with an up‐titration to 60 mg od after 4 weeks in non‐responder patients) was compared with enalapril 20 mg od (with an up‐titration to 40 mg od after 4 weeks in non‐responders) during 12 weeks of treatment. Both treatments significantly reduced systolic (SBP) and diastolic blood pressure (DBP). BP reduction was significantly greater with zofenopril (30 mg/day) during the initial 4 weeks of treatment compared with enalapril (20 mg/day). A larger proportion of patients needed dose up‐titration with enalapril compared with zofenopril to reach preset BP goals. After 12 weeks of treatment and after appropriate dose up‐titration, SBP and DBPs were lowered to similar extent in the two treatment groups, resulting in no differences between the groups in terms of response and control rates. A similar number of patients reported adverse events in the two study groups. However, the severity of adverse events were significantly milder with zofenopril compared with enalapril. In mild to moderate hypertensive patients, zofenopril treatment results in a more pronounced lowering of BP compared with enalapril at recommended dose levels. Additionally, at clinical and comparative antihypertensive doses, zofenopril presents a more beneficial adverse event profile compared with enalapril.

Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid tumors

Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administered once daily for 14 days every 3 weeks in patients with solid tumors. In the pilot food effect part, patients received a single dose of 20 mg indibulin on day-8 and -4, fasted or fed, in a randomized crossover design. In the dose-escalation part, patients received a single dose of indibulin on day-4. Three dose levels were evaluated: 20, 40 and 80 mg. After a washout period, patients received indibulin once daily for 14 days every 3 weeks (multiple dose part). Blood samples were collected in the pilot food effect- and in the dose escalation study. A total of 14 patients entered, of which 6 completed the food effect study. The ratio of indibulin (fed/fasted) in the food effect study for AUC(0-72) was estimated as 1.24 (P=0.082, 95%CI 0.96-1.41) and C(max) ratio was 0.89 (P=0.54, 95%CI 0.55-1.44). Interpatient variability was high. Higher peak plasma concentrations were reached under fasting conditions which was undesired regarding tolerability. Therefore the dose escalation study was continued under fed conditions. Dose limiting toxicities, nausea and vomiting, appeared to be related to the increased volume of the solvent lactic acid. This study is continued, evaluating indibulin administered as capsules on the recommended dose level of 60 mg daily for 14 days.

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory irinotecan-naïve advanced colorectal cancer (CRC): dose-finding, pharmacokinetics, safety and efficacy

13520 Background: Gefitinib (IRESSA) is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has shown supra-additive activity in human CRC xenografts when combined with irinotecan. We have previously established that the recommended dose level (RDL) to be irinotecan 225mg/m2 q3 weeks and gefitinib 250mg daily (Chau et al ASCO 2004). The dose limiting toxicities were neutropenia and diarrhoea. The continuation phase of this study aimed to evaluate the efficacy and safety of this combination. Patients and Methods: Between Jun 2002 and Feb 2005, patients (pts) with advanced CRC progressing on or within 12 weeks of fluoropyrimidines-based chemotherapy, irinotecan-naïve and performance status ≤2 were recruited. Thirty-nine pts were treated with irinotecan and gefitinib in total with 27 treated at the RDL. Results: Median age was 61 years (range: 31–79) and 13 (33.3%) pts were females. All pts were Caucasians (94.9%) and non-oriental Asians (5.1%). Thirteen (33.3%) pts had received (neo)adjuvant chemotherapy and 16 (41.0%) pts had prior oxaliplatin-based chemotherapy for metastatic disease. Grades 3–4 toxicities were anaemia 2.6%, neutropenia 15.4%, febrile neutropenia 10.3%, diarrhoea 35.9%, nausea 2.6%, vomiting 5.1%, lethargy 15.4% and skin rash 7.7%. For the pts treated at RDL, the objective tumour response rate was 11.1% (3 partial responses [PRs]; 95% confidence interval [CI]: 2.4–29.2%) and the disease control rate was 40.7% (3PRs, 8 stable diseases lasting for ≥12 weeks). The median time to progression was 4.2 months and median survival was 9.3 months. Six-month progression free survival was 22.2% (95% CI: 6.5–37.9%) and 6-month overall survival was 73.4% (95% CI: 56.5–90.3%). Preliminary pharmacokinetic data suggested that the addition of irinotecan to gefitinib resulted in an average of 14–33% increase in exposure to gefitinib (p&lt;0.05). Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable. Gefitinib did not appear to add substantial efficacy to irinotecan. The relative low dose of irinotecan at the RDL and the rarity of EGFR somatic mutation in CRC may be contributory to the modest activity of irinotecan and gefitinib combination. [Table: see text]

Phase I, safety, pharmacokinetic and biomarker study of BAY 57–9352, an oral VEGFR-2 inhibitor, in a continuous schedule in patients with advanced solid tumors

3040 Background: BAY 57–9352 is a potent competitive inhibitor of the VEGFR-2 (IC50: 6 nM), VEGFR-3 (IC50: 4 nM), PDGFR-β and c-KIT tyrosine kinases. BAY 57–9352 showed tumor efficacy in colon, breast, pancreatic and NSCLC models. Methods: Patients with advanced solid tumors received oral BAY 57–9352 on a continuous basis, in escalating doses. One cycle was defined as 21 days of treatment. Extensive PK and PD (dynamic contrast-enhanced MRI [DCE-MRI]) evaluations were performed. Plasma biomarkers (e.g. VEGF)were also evaluated. Results: Forty patients (median 54 yrs) were enrolled at seven dose levels from 20 mg solution once daily to1500 mg twice daily (bid; 150 mg tablets) for a total of 169 cycles (range 1–17). The most frequent drug-related adverse events were nausea, hypertension, headache, vomiting, hoarseness, rash, dry skin and anorexia. One patient treated at 600 mg bid had a dose-limiting toxicity defined by an increase from grade 2 to 3 hypertension, despite the addition of an ACE-inhibitor and Ca-antagonist on day 8 of cycle 2. Another patient at that same dose level and also on day 8 cycle 2, had grade 3 AST/ALT increase, however this was not assessed as dose-limiting. Both patients continued treatment after dose reductions. Treatment was well tolerated, even at the highest dose levels. One patient with a hemangio-endothelioma (600 mg bid) had a clinical response and one desmoid tumor patient (900 mg bid) had a 53% reduction in tumor volume. BAY 57–9352 AUC increased dose proportionally up to 900 mg bid. The target AUC, based on animal models (5 mg × h/L) was reached in all patients at 900 mg bid. Dose levels exceeding 900 mg bid had similar plasma VEGF biomarker levels. Conclusions: BAY 57–9352 was well tolerated in doses up to 1500 mg bid. Based on safety, PK, PD and biomarker assessments, the recommended dose level is 900 mg bid. A 300 mg tablet is being tested for patient convenience. Combination chemotherapy studies have been started. [Table: see text]

Application of pharmacokinetic-pharmacodynamic modelling in management of QT abnormalities after citalopram overdose

To develop guidelines for the management of QT prolongation after citalopram overdose, including decontamination with single-dose activated charcoal (SDAC) and cardiac monitoring. Simulation study using a previously developed pharmacokinetic-pharmacodynamic (PKPD) model which predicted the time-course of QT prolongation and the effect of citalopram dose and use of SDAC on QT prolongation. The previously developed PKPD model was used to address the following in patients following citalopram overdose: (1) Above what dose should patients be decontaminated? (2) Above what dose should patients have cardiac monitoring? (3) For what period of time should patients be monitored? The primary outcome was QT,RR combinations above an abnormal threshold as a surrogate predictor of torsades de pointes. Simulations were performed using MATLAB for an overdose patient with typical demographics: 30-year-old female with a heart rate of 79 bpm taking citalopram therapeutically. The simulations showed: (1) There was significant benefit associated with the administration of SDAC to patients following citalopram overdose ingesting >600 mg; (2) With citalopram overdoses >1,000mg it was advisable to give SDAC and cardiac monitor the patient; (3) The risk of developing future abnormal QT,RR combinations was less than 1% in patients with normal QT,RR combinations up to 13 h post-dose, so the minimum monitoring time for citalopram overdoses >1,000mg should be 13h. Recommended dose levels for intervention should be lowered in older patients and patients with tachycardia, while men are less sensitive to QT prolongation. Guidelines for the management of QT prolongation after citalopram overdose were developed. We believe the model will help clinicians to decide which patients to decontaminate and monitor.

A phase I/II study of nedaplatin and 5-fluorouracil with concurrent radiotherapy in patients with esophageal cancer

To determine the recommended dose (RD) of cis-diammine-glycolatoplatinum (nedaplatin) when given concurrently with 5-FU and high dose radiation therapy in the treatment of esophageal cancer. The purpose of the phase II trial is to determine efficacy and further define the side effect profile. Twenty-six patients with clinical stage I to IVA squamous cell carcinoma of the esophagus were enrolled in a non-surgical treatment comprised of a fixed dose of fluorouracil (400 mg/m2 administered as continuous intravenous infusion on days 1-5 and days 8-12) plus escalating doses of nedaplatin (40 mg/m2 in level 1, 50 mg/m2 in level 2, or 60 mg/m2 in level 3 on days 1 and 8), repeated twice every 3 weeks with concurrent radiotherapy (60 Gy). Between July 1998 and February 2004, a total of 26 patients entered this trial, all of whom were considered evaluable for toxicity assessment. In phase I of the study, 12 patients were treated in sequential cohorts of three to six patients per dose level. The maximum tolerated dose was reached at level 3 with two grade 4 neutropenia and one grade 4 thrombocytopenia. Thus, the recommended dosing schedule is level 2. Of the 20 patients treated at the RD level 2, including 6 patients of the RD phase I portion, 8 out of 20 patients (40%) had grade 3-4 neutropenia, 5 patients (25.0%) had grade 3-4 thrombocytopenia, 4 patients (20.0%) had grade 3 anemia and 4 patients (20.0%) had grade 3-4 esophagitis. Other toxicities were relatively mild and usually of grade 2 or less. Objective responses were noted in the 26 patients (overall response rate, 88.5%) including 11 (42.3%) complete remissions. The 1- and 3-year survival rates were 65.1 and 37.2%, respectively, with a median survival time of 21.2 months. The combination of nedaplatin and 5-FU with radiation is a feasible regimen that shows promising antitumor activity with an acceptable safety profile in patients with esophageal cancer.

Phase 1 Trial of Gefitinib Plus Sirolimus in Adults with Recurrent Malignant Glioma

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

Gemcitabine and paclitaxel in metastatic or recurrent squamous cell carcinoma of the head and neck: a phase I???II study

The purpose of this study was to determine the maximum tolerated dose, toxicity profile and anti-tumor activity of paclitaxel in combination with gemcitabine when administered to patients with unresectable locally recurrent or metastatic squamous cell carcinoma of the head and the neck (SCCHN). Twenty-seven patients were treated in a phase I-II study with gemcitabine at a dose of 800 mg/m on days 1 and 8, escalating to a dose of 1,000 mg/m, plus escalating doses of paclitaxel (100, 135 and 175 mg/m) on day 2. Treatment consisted of 6 cycles repeated every 3 weeks. The main toxicity was myelosuppression. Other toxicities were mild and manageable. Due to grade 4 neutropenia at higher doses the recommended dose level of the gemcitabine/paclitaxel combination was 1,000/135 mg/m. Four patients achieved a partial response and no patient had a complete remission, giving an overall response rate of 14.8%. The median time of survival was 24 weeks. We conclude that the combination of paclitaxel and gemcitabine is tolerated, but shows insufficient clinical activity in patients with recurrent and/or metastatic SCCHN to warrant further testing.

Estimation of Zinc and Copper Balance in Japanese Farmland Soil Associated with the Application of Chemical Fertilizers and Livestock Excreta

We estimated the zinc (Zn) and copper (Cu) balance in Japanese farmland soil in 1997. Zinc and Cu uptake by crops amounted to 563 Mg and 108 Mg, respectively, while Zn and Cu doses from chemical fertilizer were 297 Mg and 63 Mg, respectively. Zinc and Cu contents of livestock excreta were estimated to be 2,863 Mg and 713 Mg, and 1,551 Mg and 337 Mg of this was applied to farmland soil. As a result, there was an excess of 1,285 Mg of Zn and 292 Mg of Cu in farmland soil. This excess corresponded to 0.379% of the amount of total Zn and 0.270% of the amount of total Cu in farmland soil. Even if all excess Zn and Cu was accumulated in farmland soil, it would take more than 190 years to reach the permissible upper level of Zn, based on the average Zn concentration in non-polluted farmland soil. However, the promotion of the use of livestock excreta, especially pig excreta that contain high levels of Zn and Cu, may shorten the time required to reach the level. Although there are some guidelines, the recommended dose level has not clearly determined. Conventional dose of Zn applied through chemical fertilizer and manure is lower than the recommended Zn application level. Doses may depend on plant diagnosis and we should monitor the contamination of soils and crops with Zn and Cu, or the application might depend on other indicators like the Zn/cadmium ratio.

Phase I/II study of docetaxel (DOC) and S-1 for patients (pts) with advanced gastric cancer (AGC)

4064 Background: New combination chemotherapy with DOC and oral DPD-inhibitory fluoropyrimidine, S-1 for pts with AGC was investigated in the multicenter phase I/II study as; 1) agents are active for AGC, 2) different modes of action, and 3) down-regulation of thymidylate synthase by DOC. Methods: Eligibility criteria included; pathologically confirmed AGC, measurable lesions, PS 0–1, ≤1 prior chemotherapy, ≥20 years old, adequate organ functions and written IC. DOC was administered (60–120 min., i.v.) on day 1 and the dose was escalated by 10 mg/m2 from the starting dose of 50mg/m2 in phase I part. S-1 was fixed at the conventional daily dose of 80 mg/m2 on days 1–14. The treatment was repeated every 4 weeks. The recommended dose (RD) of combined DOC+S-1 was studied in every 3–6 pts cohort and determined according to the pre-defined DLTs. 45 pts were planned to enroll at the RD level in phase II part. Results: 50 eligible pts were enrolled in this study from 9/02 to 6/04. In phase I part, all 3 pts enrolled in the starting dose level showed intolerable toxicities (grade 3 neutropenia with infection in one pt and grade 4 neutropenia on day 8 during S-1 administration in 2 pts). Then the dose of DOC was de-escalated to 40 mg/m2 and this dose level was determined as RD for phase II part. 46 out of 47 pts enrolled were evaluable for safety and 44 pts for efficacy, respectively. Pt characteristics were as follows; median age 65 (range 42–79), M/F 31/15, PS0/1 26/20, histological type differentiated/undifferentiated 29/17 and chemonaïve/pre-treated 25/21 pts. 9 pre-treated pts (45%) and 12 chemonaïve pts (50%) showed response (RECIST). Overall response rate was 48% (95%CI: 33–63%). Pts received a median of 3 courses (range 1–6). Common grade 3+ toxicities were neutropenia (70%), leucopenia (39%), anemia (22%), and anorexia (20%). These toxicities were tolerable and manageable. No treatment-related death was observed. Preliminary survival analyses showed an estimated median survival of 377 days (95%CI: 266–488 days). Matured survival data will be presented at the meeting. Conclusions: This new regimen with DOC and S-1 showed promising activity and manageable toxicity, thereby leading to a further phase III study with this regimen in pts with AGC. No significant financial relationships to disclose.