Phase I dose-escalation study of a novel antitumor agent, SR271425, administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors.

BACKGROUND: SR271425 is a novel DNA-binding cytotoxic agent with a broad spectrum of antitumor activity in preclinical models,across a variety of the schedule of administration. In toxicological studies, it has been reported to prolong QTc proportionally to C (max). In order to circumvent this C (max)-related QTc prolongation, 5 phase I studies were initiated to investigate 1-h, 24-h, weekly, and split iv infusions. This phase I study assessed a split-dose regimen (a 1-h infusion on each of Days 1 to 3, repeated every 3 weeks) to establish the dose limiting toxicities (DLT), to recommended a phase II dose, and to characterize PK/PD. METHODS: Patient with advanced solid tumors, adequate bone marrow, hepatic, renal function and on specific cardiac criteria were eligible and "3 + 3" design was used for dose escalation. That dose escalation was guided by PK data, toxicities observed and information from other ongoing phase I studies with SR271425. SR271425 plasma levels (PK samples) were measured using a validated LC-MS/MS method. Careful monitoring of ECGs was done, and ECGs were read centrally. RESULTS: Three centers enrolled 19 heavily pretreated patients to six dose levels, from 75 to 450 mg/m(2)/day (i.e., 225-1,350 mg/m(2)/cycle): 12 males and 7 females. Median age 56. Median ECOG, PS = 1. Main tumor types were brain, breast, gynecological, and urological. Patients received a median of 2 cycles (range: 1-6). NCI-CTC Grade 1-2 toxicities included nausea, vomiting, asthenia, rash, and yellow skin discoloration. No DLTs were reported, and there were no dose-limiting prolongations of QTc. Both C (end) and AUC increased in a dose-related manner, with no evidence of accumulation between Day 1 and Day 3, consistent with the mean (+/-SD) terminal elimination half-life of 5.11 +/- 1.21 h. Stable disease was observed in five cases. CONCLUSION: Split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. MTD was not reached due to the early termination of the SR271425 program by the sponsor.

Induction of hepatic neoplastic lesions in mice with a single dose of hycanthone methanesulfonate after partial hepatectomy.

Experiments were designed to determine whether hycanthone methanesulfonate (1-([2-(diethylamino)ethyl]amino)-4-(hydroxymethyl)thioxanthen-9-one monomethanesulfonate), an antischistosomal drug, and its analog, IA-4-N-oxide (8-chloro-2-[2-(diethylamino)ethyl]-2H-[1]benzothiopyrano[4,3,2-cd]indazole 5-methanol monomethanesulfonate), will induce neoplastic lesions in the livers of mice not infected with Schistosoma mansoni. All the mice received a single i.m. injection of hycanthone methanesulfonate (76 mg/kg), IA-4-N-oxide (80 mg/kg), or an equivalent volume of the solvent, 0.9% NaCl solution, 42 hr after partial hepatectomy. Of the mice receiving hycanthone methanesulfonate and living 200 days or longer, hepatocellular carcinoma was seen in 11.5% and liver sarcoma was seen in 4.2%. This type of malignant neoplasm was not seen in the animals receiving either IA-4-N-oxide or 0.9% NaCl solution. In addition, mice receiving hycanthone methanesulfonate showed a significantly higher incidence of both type 1 (43% compared to 21% in controls) and type 2 (21% compared to 12% in controls) hepatocyte neoplasms. Mice receiving IA-4-N-oxide showed no increased incidence of neoplasms.

Phase I pharmacokinetic study of the novel antitumor agent SR233377.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

Depressive symptoms in chronic schizophrenic patients after withdrawal of long-acting neuroleptics.

A double-blind randomized investigation compared withdrawal (placebo) with continued use of long-acting neuroleptics (fluphenazine decanoate or flupenthixol decanoate) in 41 chronic schizophrenic outpatients. After 6 weeks there was a tendency toward higher depressive scores in the placebo group, a difference which became statistically significant (p less than .05) at week 24. These results do not support earlier observations that neuroleptic drugs cause depression. Further analyses of the data indicated that depressive symptomatology could be an early sign of relapse.

Neuroleptics and mortality in schizophrenia: prospective analysis of deaths in a French cohort of schizophrenic patients.

OBJECTIVE: The putative role of neuroleptics in the known excess mortality of subjects with schizophrenia remains disputed. The aim of this study was to assess the link between mortality and the class of neuroleptic. METHOD: Causes of death (suicide, cardiovascular, etc.) and exposure to neuroleptics were studied in a cohort of 3474 patients with schizophrenia followed from 1993 to 1997. RESULTS: From 1993 to 1997, 178 patients died. The risk of all-cause death (OR=1.59; 95% CI 1.02-2.50; p=0.04), and suicide (OR=2.22; 95% CI 1.24-3.97; p=0.006) were increased in users of thioxanthenes (alone or associated with other drugs), and increased risk of "other causes" of death was associated with use of atypical neuroleptics (OR=2.06; 95% CI 1.15-3.70; p=0.0016). CONCLUSION: Our findings suggest the existence of association between certain classes of neuroleptics and death, all cause or specific. This could be related to the drug itself or to patient selection.

Two-year follow-up of hycanthone-treated schistosomiasis mansoni patients in St. Lucia.

Of 433 schistosomiasis mansoni patients in St. Lucia who were treated with hycanthone (3 mg/kg of body weight), 190 were seen 2 years after treatment and 143 of these had attended all follow-up examinations at 6 weeks, 6 months, 1 year and 2 years. Viable eggs were not detected in 86% at 1 year nor in 76% at 2 years. The reinfection rate, as judged by a significant increase in egg excretion, was 15% and was related to the geographic area to which the patient returned. Extremely high total reduction in egg excretion (98%) was achieved through 1 year, and even with reinfections this fell only to 87% at 2 years. Liver and spleen enlargement was related to intensity of infection and responded to treatment in 92% and 83% of instances, respectively. Among patients with hepatosplenomegaly, those 15 years or older showed less clinical response than younger patients but were too few for statistical comparison.

Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule.

PURPOSE: SR233377 (WIN33377) is a novel 4-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered as a 2-h intravenous infusion for five consecutive days. METHODS: A group of 25 patients with a range of solid tumor diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m2 per day to 74.7 mg/m2 per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. RESULTS: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m2 dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 Cmax values increased linearly with dose, but substantial interpatient variability in SR233377 AUC, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and Cmax values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. CONCLUSIONS: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.

Early years of the Salmonella mutagen tester strains: lessons from hycanthone.

The 1960s witnessed detailed studies on the genetic properties of a large number of histidine-requiring mutants of Salmonella typhimurium. The early 1970s saw development of selected strains, the Ames strains, for use in rapid, cheap, sensitive, and manipulable tests of chemicals and chemical mixtures for genotoxic activities. Our contribution during this latter period was an investigation into the mutagenicity of hycanthone and some of its analogues. Some lessons that this study provided are enumerated. Hycanthone is definitely a liver carcinogen in rodents predisposed by hepatic hyperplasia. Between 1969 and 1975, an estimated total of 100 kg of hycanthone was injected into some 1,000,000 humans with liver hyperplasia caused by infections with parasites. It may now be possible to assess directly the long-term impacts of hycanthone in man.