Phase I and pharmacological studies of the cryptophycin analogue LY355703 administered on a single intermittent or weekly schedule.

LY355703 is a synthetic derivative of the marine cryptophycins, cytotoxic agents which induce mitotic arrest by binding at the microtubule vinca binding domain. Promising preclinical features of LY355703 were the 40-400 greater potency than paclitaxel or vinca alkaloids, the broad spectrum of antitumor activity in xenografts and the antitumour activity in multidrug resistant (MDR)-expressing murine tumours. Aims of this study were to define the maximum tolerated dose (MTD) and the dose recommended for Phase II, the pattern of toxicity, the pharmacokinetic profile and to document hints of antitumour activity of LY355703 given as 2-h infusion on day 1 every 3 weeks (Study 1) or, later on, on days 1, 8 and 15 every 4 weeks (Study 2). The latter weekly regimen was selected because of the acute dose-related toxicity reported in Study 1. The dose was escalated using a modified Continual Reassessment Method. Pharmacokinetic studies were performed on day 1 of cycle 1 in both studies; LY355703 plasma concentrations were assessed by liquid chromatography with tandem mass spectrometry. A total of 35 adult patients with solid tumours entered Study 1; the dose was escalated from 0.1 to 1.92 mg/m(2); at this dose 2 of 5 patients presented grade 3 neuropathy and myalgias; 1.48 mg/m(2) was then recommended for Phase II study. A total of 8 patients were treated in Study 2 at 1 mg/m(2); cumulative long-lasting neuroconstipation and neurosensory toxicity precluded the completion of the cycle in 9 out of 15 cycles; the clinical development of the weekly regimen was then discontinued. Other toxicities included cardiac dysrhythmia and mild alopecia. Pharmacokinetics of LY355703 appeared to be linear over the dose range studied. The administration of LY355703 on a 3-week schedule is associated with an acute dose-dependent peripheral neuropathy and myalgia of high interpatient variability for which possible risk factors and pharmacokinetic correlates could not be identified.

Phase I and pharmacokinetic study of BIBX 1382 BS, an epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration.

The pyrimido-pyrimidine BIBX 1382 BS inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR), thus specifically reverting the aberrant enzymatic activity from overexpressed and constitutively activated EGFR. A phase I and pharmacokinetic study of this new specific molecule was carried out. After initially performing an accelerated titration design from the first toxicities onwards, a modified Fibonacci scheme was used to escalate the daily oral dose. The following dosages and cycles (defined as treatment during 28 days) were applied: 25 mg: 6; 50 mg: 3; 100 mg: 6; 200 mg: 7; 150 mg: 3. Over a 10 months accrual phase, 11 patients (pts) (7 females, 4 males) with a median age of 63 years (range 50-73 years), World Health Organization Performance Status (WHO PS) 0:5 pts, 1:6 pts and miscellaneous solid tumours were entered. The median number of cycles applied per pt was 2 (range 1-7). Reversible, dose-dependent increase of liver enzymes (maximal Common Toxicity Criteria (CTC) grades: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3) occurred. Oral medication yielded plasma levels far below those expected to be efficacious. In conclusion, target plasma levels could not be reached via the oral route at a reasonable dosage. Meanwhile, a preclinically unknown metabolite was identified from the urine of one patient. Subsequently, this metabolite was found to be abundant in patient plasma. The metabolite was demonstrated to be pharmacologically inactive. Due to a dose-limiting increase of liver enzymes, low bioavailability of BIBX 1382 BS and the detection of a pharmacologically inactive metabolite, this trial was discontinued.

Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomised crossover trial in advanced colorectal cancer.

The aim of this study was to determine the patient's preference for oral UFT/leucovorin (LV) or intravenous (i.v.) 5-fluorouracil (5-FU)/LV chemotherapy in metastatic colorectal cancer and to compare 5-FU exposure with these two treatment options. A total of 37 previously untreated patients with advanced colorectal cancer were randomised to start treatment with either oral UFT 300 mg/m2/day plus oral LV 90 mg/day for 28 days every 5 weeks or i.v. 5-FU 425 mg/m2/day plus LV 20 mg/m2/day for 5 days every 4 weeks. For the second treatment cycle, patients were crossed-over to the alternative treatment regimen. Prior to the first and after the second therapy cycle, patients were required to complete a therapy preference questionnaire (TPQ). The pharmacokinetics of 5-FU were determined by taking blood samples on days 8, 15 or 22 and 28 for UFT and on days 1 and 5 for i.v. 5-FU. 36 patients were eligible. 84% of the patients preferred oral UFT over i.v. 5-FU. After having experienced both treatment modalities, patients indicated taking the medication at home, less stomatitis and diarrhoea, and pill over injection as the most important reasons for their preference. The area under the plasma concentration curve (AUC) for 5-FU after UFT administration was 113 microM x min on day 8, 114 on day 15 and 98 on day 28; the peak levels (Cmax) were 1.2, 1.3 and 1.0 microM, respectively. The AUC for the 5-FU/LV courses was 3083 microM x min for day 1 and 3809 for day 5 (P=0.002). The Cmax was 170.1 and 196.2 microM (P=0.06) and the clearance 2.6 and 1.9 l/min, respectively (P=0.002). Patients with metastatic colorectal cancer clearly preferred oral over i.v. chemotherapy treatment. This choice was most importantly influenced by convenience and toxicity considerations. Although i.v. bolus 5-FU leads to higher peak 5-FU concentrations and AUC values compared with oral UFT, this pharmacokinetic advantage of i.v. 5-FU seems to translate mainly into higher toxicity as seen in large randomised studies comparing oral UFT/LV with i.v. 5-FU/LV. Oral UFT/LV compares favourably with i.v. 5-FU/LV in terms of toxicity and patient's preference and leads to prolonged 5-FU exposure, which is comparable to continuous i.v. 5-FU treatment.

Activity of the dolastatin analogue, LU103793, in malignant melanoma.

LU103793, a synthetic analogue of dolastatin 15, showed interesting pre-clinical activity in melanoma xenografts. In this phase II multicentre trial, 80 chemotherapy-naïve patients with metastatic melanoma received a total of 218 cycles of treatment. The response rate showed one complete and three partial responses of median duration six months (range 3-9.1). Toxicity was moderate, mostly haematological (neutropenia grade 4 in 16%, grade 3 in 3%). There were no significant problems with hypertension or other non-haematological toxicities.

Phase I and pharmacological study of weekly administration of the polyamine synthesis inhibitor SAM 486A (CGP 48 664) in patients with solid tumors. European Organization for Research and Treatment of Cancer Early Clinical Studies Group.

A single-agent dose-escalating Phase I and pharmacological study of the polyamine synthesis inhibitor SAM 486A was performed. A dosing regimen of four weekly infusions followed by 2 weeks off therapy was studied. Fifty patients were entered into the study. Dose levels studied were 1.25, 2.5, 5, 8, 16, 32, 48, 70, 110, 170, 270, and 325 mg/m2/week. Pharmacokinetic sampling was done on day 1, and trough samples were taken weekly during the first treatment cycle. Pharmacodynamic sampling was done on days 1 and 22. At 325 mg/m2/week, dose-limiting toxicity was seen (one patient each with grade 4 febrile neutropenia, grade 3 neurotoxicity, and grade 3 hypotension with syncope and T-wave inversions on electrocardiogram). The recommended dose for further testing was set at 270 mg/m2/week. Infusion time was increased from 10 to 180 min due to facial paresthesias and flushing and somnolence. Drug exposure increased linearly with dose. Mean +/- SD t1,2 at 70-325 mg/m2 doses was 61.4+/-26.2 h, with a large volume of distribution at steady state. In peripheral blood leukocytes, a clear relationship between dose and inhibitory effect on S-adenosylmethionine decarboxylase or changes in intracellular polyamine pools was not recorded. SAM 486A can be administered safely using a dosing regimen of four weekly infusions followed by 2 weeks off therapy. The recommended dose for Phase II studies using this regimen is 270 mg/m2/week.

[Bacterial colonization of the stomach caused by acid neutralization and inhibition of stomach emptying]. / Keimbesiedelung des Magens durch Säureneutralisation und Hemmung der Magenentleerung.

Gastric bacterial overgrowth was studied in 8 healthy volunteers. Total bacterial counts, nitrate-reducing bacteria and nitrite concentration were determined in fasting gastric juice before and after 4 weeks of treatment with a strong or with a mild antacid drug, a placebo preparation and the spasmolytic agent papaverine which is known to inhibit gastric evacuation. Placebo therapy and the mild antacid did not change any of the above parameters studied. The strong antacid caused a significant increase in the pH of gastric contents which was accompanied by an enormous increase in total bacterial counts, nitrate-reducing bacteria and nitrite concentration. Papaverine which did not cause a significant elevation of pH also definitely increased bacterial counts and nitrite concentration of gastric juice. Four weeks following termination of each treatment procedure, however, all changes outlined above had returned to pretreatment values. These results indicate that reversible gastric bacterial overgrowth under therapeutical conditions may occur when acidity of the stomach is reduced or gastric evacuation is retarded.

[Dynamics of endogenous bacterial nitrite formation in the stomach. 1. Follow-up studies in humans under natural conditions]. / Dynamik der endogenen bakteriellen Nitritbildung im Magen 1. Mitteilung: Verlaufsbeobachtung am Menschen unter natürlichen Bedingungen.

The fasting gastric secretion was analysed both bacteriologically and chemically in 15 young, voluntary test subjects with histories of a healthy stomach and physiological gastric secretion tests (Basal Acid Output, Peak Acid Output) made at regular intervals of two and 4 weeks over a period of three and six months. Two thirds of the persons studied showed during the entire period of examination the same pH values with tolerable variations and, as a result, the same order of magnitude for the total germ count, the colony count of the nitrite-forming bacteria and for the NO2- concentration. From this the conclusion can be drawn that, depending on the acidity of the individual stomach, there is an autonomous bacterial flora, which repeated examinations have shown to remain unaltered in quality and quantity. It was only in one third of the test persons that major variations of the pH values could be recorded occasionally. This, however, invariably led to corresponding changes in the bacteriological and chemical parameters. For requirements imposed by preventive medicine and hygiene, in future greater attention must be paid to the bacterial flora of the intact stomach, while making due allowance for the endogenous nitrite formation.

[Endogenous synthesis of carcinogenic N-nitroso compounds: bacterial flora and nitrite formation in the healthy human stomach]. / Die endogene Synthese kanzerogener N-Nitrosoverbindungen: Bakterienflora und Nitritbildung im gesunden menschlichen Magen.

The endogenous synthesis of cancerogenic N-nitroso compounds: Bacterial flora and nitrite formation in the human stomach. In the discussion of the endogenous nitrosamine synthesis, nitrites play a decisive role. Since in a healthy stomach the acidity important for the nitrosamine formation is present, but since this acid environment is hostile to the bacterial growth and thus counteracts bacterial endogenous nitrite formation, the oral cavity has so far been regarded as the main site of endogenous nitrite formation. An analysis of 130 gastric secretions taken from empty stomachs has demonstrated that also in a healthy stomach considerable germ counts may be obtained in part when acidity is lowered physiologically (e.g. at night). Nitrite concentrations, which are six times as high as the quantities supplied with the saliva at the same time, are also produced in the acid pH range from 4 to 6. Consequently, in a healthy stomach as well the quantity of nitrite available for an endogenous nitrosamine synthesis is by far higher than has been assumed previously. This physiological risk should be allowed for in evaluating the pathophysiological or therapeutic changes in the gastric environment.