A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies.

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.

A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly.

The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials.

Phase II studies of BBR3464, a novel tri-nuclear platinum complex, in patients with gastric or gastro-oesophageal adenocarcinoma.

BBR3464, a novel tri-nuclear platinum complex, forms long-range DNA adducts and is highly potent when compared with cisplatin in vitro. Preclinical studies demonstrated activity in cisplatin-resistant tumours and tumours with mutated p53 status. Phase I & II clinical studies gave preliminary indications of activity in melanoma, pancreatic, lung and ovarian cancers. The aim of this study was to determine the efficacy and confirm the toxicity of BBR3464 when given either as first- or second-line treatment for advanced disease in patients with gastric and gastro-oesphageal adenocarcinoma. Two multicentre, open label, Gehan design studies were conducted; one study used BBR3464 as first-line and the other as second-line treatment for metastatic or locally advanced disease. Nineteen first-line and 26 second-line patients were enrolled receiving a total of 74 and 53 infusions, respectively. Initially, seven patients in the second-line study received BBR3464 using the planned schedule of 1.1 mg/m2 every 4 weeks; however, 5 of these patients experienced dose-limiting grade 3 or 4 febrile neutropenia; subsequent patients in both studies were treated using the modified schedule of 0.9 mg/m2, every 21 days. In 1 of 17 evaluable, previously untreated patients, regression of multiple skin lesions was noted with stabilisation of lung metastases and maxillary sinus mass, lasting 155 days. In the first-line study, the median time to progression was 85 days [95% Confidence Interval (CI): 42, 127] (2.8 months) and in the second-line study, the median time to progression was 71 days [95% CI: 42, 109] and 38 days [95% CI: 32, 73] in the 1.1 and 0.9 mg/m2 dose level groups, respectively. Toxicity data were available for 45 patients. Neutropenia was the main toxicity seen (G3: 40%, G4: 40%). Febrile neutropenia was observed in six patients (15%) treated with 0.9 mg/m2 compared with five patients (71%) treated with 1.1 mg/m2 BBR3464. Other drug-related toxicities (G3/4) included: anaemia, thrombocytopenia, nausea, vomiting, diarrhoea, mucositis and fatigue. Diarrhoea and nausea/ vomiting were adequately controlled by the use of loperamide and antiemetics, respectively. Recruitment to the second-line study was closed early due to the poor response rate (1/17 evaluable, 6%; 95% CI: 1%, 27%) and short time to progression noted in the first-line study. Further studies with BBR3464 in this tumour type are not recommended.

Three months of octreotide treatment decreases gastric acid secretion and argyrophil cell density in patients with Zollinger-Ellison syndrome and antral G-cell hyperfunction.

METHODS: The effects of three months of treatment with octreotide on gastric acid hypersecretion induced by hypergastrinaemia were investigated in patients with Zollinger-Ellison syndrome (n = 5) or antral G-cell hyperfunction (n = 4). Gastric acid secretion, fasting plasma gastrin concentrations and clinical findings were examined, and a morphometrical analysis of oxyntic endocrine cells was performed. RESULTS: Administration of octreotide 100 mcg b.d. subcutaneously significantly decreased the volume density of argyrophil cells (P < 0.05) as well as basal and pentagastrin-stimulated acid secretion (P < 0.05). Although partial or complete loss of inhibition was found in most patients after 3 months, gastrin levels were decreased during the first 2 months of treatment (P < 0.05). Fundic D-cells were not affected by treatment. Positive correlations were observed between volume density of argyrophil cells and basal acid output (r = 0.65); plasma gastrin and basal acid output (r = 0.74); plasma gastrin concentrations and volume density of argyrophil cells (r = 0.80). CONCLUSION: These results support the important role of the enterochromaffin-like cell in maintaining acid secretion, and indicate a specific role for octreotide in the therapy of gastric acid hypersecretion associated with hypergastrinaemic diseases.

Repeatability of lactulose hydrogen breath test in subjects with normal or prolonged orocecal transit.

The within-subject repeatability of orocecal transit assessed with lactulose hydrogen breath test was evaluated in 15 healthy volunteers and 16 constipated or obese patients. The test was repeated twice in each subject. Mean (SD) transit time was 105 (63) and 103 (60) min in the first and second series of tests, respectively, showing that the first measurement did not affect the second. The within-subject repeatability of the test was related to the length of transit, the scatter of the differences between the first and second test being greater with the increase of the mean gastrointestinal transit time. The 95% coefficient of repeatability was 84 min for all measurements and 30 and 118 min, respectively, for transit times under and over 100 min. The lowest reproducibility of the test was found in constipated patients with prolonged orocecal transit.

Oral naloxone antagonizes loperamide-induced delay of orocecal transit.

Orocecal transit time was determined by the lactulose hydrogen breath test in nine healthy volunteers after administration of placebo, loperamide (16 mg per os), and loperamide (16 mg per os) followed by oral naloxone at doses of 16 and 32 mg. The four tests were performed in double-blind conditions and in random sequences. Transit time (mean, SD) after loperamide (128.8 min, 32.9) was significantly increased (P less than 0.05) compared with placebo (85.5 min, 35.7), loperamide followed by naloxone 16 mg (88.8 min, 46.2), and loperamide followed by naloxone 32 mg (84.4 min, 40.6). These results show that the peripheral opioid agonist loperamide delays orocecal transit in healthy subjects and that naloxone per os at adequate doses antagonizes this effect.

Intragastric and intraoesophageal pH monitoring in duodenal ulcerpatients: effect of the new histamine H2-receptor antagonist ramixotidine.

The effect of the new histamine H2-receptor antagonist ramixotidine 750 mg p.o., administered at 22.00 h, on intragastric and intraoesophageal pH monitored from 22.00 h to 08.00 h, was studied in a double-blind cross-over trial in 11 duodenal ulcer patients. Placebo and ramixotidine were given to each patient on 2 consecutive days in a randomized sequence. Three patients were excluded from the intragastric pH analysis as the records on the second study day were technically inadequate. No significant carry-over or sequence effect was noted. Intragastric hydrogen ion activity was significantly lower (p = 0.01) after ramixotidine than after placebo: median (range) 24 (9-100) vs 97 (27-188) mmol/l. The percentage of time with intraoesophageal pH less than 4 was less than 5% in all but three recordings, with a maximum value of 12%, and it was not significantly different after the two treatments.

Plasma prolactin, sex steroids and gastrin in human volunteers treated for 2 weeks with therapeutic doses of cimetidine or the new histamine H2-receptor antagonist ramixotidine (CM 57755A).

Three groups of eight healthy male volunteers received placebo for 2 days, then daily morning doses either of cimetidine 800 mg, ramixotidine 750 mg (CM 57755A), or placebo, for 14 days, and then were all returned to placebo for one more day. Plasma levels of prolactin, testosterone and 17 beta-estradiol were measured on Days 2, 3, 16 and 17 in blood samples taken 30 and 15 min before and 0, 60, 120, 180, 240 and 300 min after treatment. Gastrin was assayed in blood collected on the same days 180 min after treatment. Mean pre- and post-treatment areas under the time-concentration curves of the first three hormones were not significantly different in the three groups on any test day, or within the same group throughout the four test days. Mean plasma gastrin levels ranged between 27 and 42 pg/ml, respectively, in the placebo and cimetidine treated groups on test day 3, and intermediate values were found in the group receiving CM 57755A. There was no statistically significant difference in gastrin level between the groups on any test day or within the same group throughout the four test days. No subjective side-effects attributable to the treatments were reported, and there were no abnormalities in blood pressure, heart rate or standard laboratory tests.

Orocecal transit delay in obese patients.

Orocecal transit time was assessed with lactulose hydrogen breath test in 12 obese patients during intravenous infusion of placebo or naloxone 40 micrograms/kg/hr given in randomized order and in double-blind conditions. Transit time was also evaluated in 22 healthy controls. Orocecal transit was significantly (P less than 0.01) longer in the obese patients, during placebo treatment (median 130, range 100-200 min) than in the healthy controls (median 75, range 40-170 min). Compared with placebo, transit time in the obese subjects was delayed (P less than 0.05) during naloxone treatment (median 150, range 100-230 min).

Lactose malabsorption and intolerance in Italians. Clinical implications.

Lactose malabsorption was assessed by the hydrogen breath test in 40 Italian patients with irritable bowel syndrome and 42 controls without abdominal disturbances. Sixty-five percent of patients were "low milk consumers" (0-250 ml milk per day) compared with 38% of controls (P less than 0.02). Lactose loads of 25 and 50 g caused malabsorption in 82.5 and 87.5% patients and in 55 and 62% controls, respectively (patients vs controls P less than 0.02). Malabsorption was more frequent in the "low milk consumers" group (P less than 0.05). During a four-month lactose-free diet as the only treatment 7.5% of patients became symptom-free (and remained so for a further eight-month diet), 52.5% improved, and 40% showed no change.

Effect of loperamide and naloxone on mouth-to-caecum transit time evaluated by lactulose hydrogen breath test.

The effect of loperamide and naloxone on mouth-to-caecum transit time was evaluated by the lactulose hydrogen breath test in four men and four women. Each subject underwent tests during the administration of placebo, loperamide (12-16 mg po), naloxone (40 micrograms/kg/h by a three-hour intravenous infusion), and loperamide plus naloxone, carried out at intervals of one or two weeks. The transit time was significantly longer after loperamide, and this effect was antagonised by the concomitant administration of naloxone whereas naloxone administered alone had no effect on mean transit time. No clinically important side effects were reported.

Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin's lymphoma.

BACKGROUND: BBR 2778 is a novel aza-anthracenedione showing no cardiotoxicity and superior activity compared to doxorubicin and mitoxantrone in animal models. Objectives of this phase I study included the determination of the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), clinical pharmacokinetics (PK), and antitumor activity. Patients with relapsed or refractory, advanced non-Hodgkin's lymphoma were included. PATIENTS AND METHODS: Patients were treated with a q1w x 3 schedule on the basis of a modified Fibonacci dose escalation method. Seven groups with a total of twenty-six patients were treated at dosages of 5, 10, 16.5, 25, 34, 56 or 84 mg/m2/w, respectively. RESULTS: DLT was observed on the seventh dose level with neutropenia WHO grade 4 in three of six patients. Pharmacokinetic analysis showed a large volume of distribution (13.5-17.5 l/kg), a high plasma clearance (0.65-1.74 l/h/kg) and a long elimination half-life (14.7-31.9 h). Tumor response included three complete remissions and two partial remissions. CONCLUSIONS: Neutropenia is the DLT of the new aza-anthracenedione BBR 2778. The recommend dose is 84 mg/m2 in a q1w x 3 schedule. PK data are consistent with a linear kinetic of BBR 2778 comparable to mitoxantrone. This new drug shows promising activity in intensively pretreated patients with relapsed or refractory NHL. Based on this results, phase II studies with this new compound are underway.

Clinical and pharmacological phase I study with accelerated titration design of a daily times five schedule of BBR3464, a novel cationic triplatinum complex.

OBJECTIVES: To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex. PATIENTS AND METHODS: Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily x 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle. RESULTS: Dose was escalated four times up to 0.17 mg/m2/day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2. Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 were higher than on day 1, indicating drug accumulation. Approximately 10% of the equivalent dose of BBR3464 (2.2%-13.4%) was recovered in a 24-hour urine collection. CONCLUSIONS: The higher than expected incidence of neutropenia and GI toxicity might be related to the prolonged half-life and accumulation of total and free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical development.