Population pharmacokinetic/pharmacodynamic modeling of drug-induced adverse effects of a novel homocamptothecin analog, elomotecan (BN80927), in a Phase I dose finding study in patients with advanced solid tumors.

PURPOSE: To characterize the pharmacokinetic profile of elomotecan, a novel homocamptothecin analog, evaluate the dose-limiting toxicities, and establish the relationship between exposure and toxicity in the first Phase I study in patients with advanced malignant solid tumors. Preliminary antitumor efficacy results are also provided. DESIGN: Elomotecan was administered as a 30-min intravenous infusion at doses ranging from 1.5 to 75 mg once every 3 weeks to 56 patients with advanced solid tumors. Plasma concentration data and adverse effects were modeled using the population approach. RESULTS: Elomotecan showed linear pharmacokinetics, and clearance was decreased with age. The model predicts a 47 and 61 % reduction in CL for patients aged 60 and 80 years, respectively, when compared with younger patients (30 years). Neutropenia represented the dose-limiting toxicity. The maximum tolerated dose and the recommended dose (RD) were 75 and 60 mg, respectively. Elomotecan elicited a 20, 5, 2, and 2 % severe (grade 4) neutropenia, asthenia, nausea, and vomiting at the RD, respectively. Of the subjects in the RD cohort, 41.7 % had a stable disease mean duration of 123.6 ± 43.4 days. CONCLUSIONS: The pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60 mg administered as a 30-min intravenous infusion, once every 3 weeks.

Steroid sulfatase: a new target for the endocrine therapy of breast cancer.

Inhibitors of steroid sulfatase are being developed as a novel therapy for hormone-dependent breast cancer in postmenopausal women. Data suggest that steroid sulfatase (STS) activity is much higher than aromatase activity in breast tumors and high levels of STS mRNA expression in tumors are associated with a poor prognosis. STS hydrolyzes steroid sulfates, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to estrone and DHEA, which can be converted to steroids with potent estrogenic properties, that is, estradiol and androstenediol, respectively. Several potent irreversible STS inhibitors have now been identified, including STX64 (BN83495), a tricyclic sulfamate ester. This drug recently completed the first-ever trial of this new type of therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. STX64, tested at 5-mg and 20-mg doses, was able to almost completely block STS activity in peripheral blood lymphocytes and tumor tissues. Inhibition of STS activity was associated with significant reductions in serum concentrations of androstenediol and estrogens. Unexpectedly, serum androstenedione concentrations also decreased by up to 86%, showing that this steroid, which is the main substrate for the aromatase in postmenopausal women, is derived mainly from the peripheral conversion of DHEAS. Of eight patients who completed therapy, five showed evidence of stable disease for up to 7.0 months. This new endocrine therapy offers considerable potential for the treatment of hormone-dependent breast cancer in postmenopausal women.

Luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer: a review of their discovery, development, and place in therapy.

BACKGROUND: Early identification of the biological activity of luteinizing hormone-releasing hormone (LHRH) paved the way for the synthesis of analogues with enhanced potency and biological properties. Early testing in animal models and humans provided insight into the potential clinical uses of these substances, and, within 10 years, LHRH-agonist therapy had become available for use in patients with advanced prostate cancer (PC). Over time, the role of LHRH-agonist therapy has expanded to include use as part of multimodal treatment regimens throughout the course of the disease. OBJECTIVES: This article reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PC. METHODS: Relevant clinical studies were identified through searches of the English-language literature indexed on MEDLINE through May 2006. The main search terms were prostate cancer and LHRH agonist. RESULTS: Results of the initial therapeutic trials of sustained-release depot formulations of LHRH agonists in patients with PC were reported in the mid-1980s, indicating that these agents were effective and well tolerated in improving clinical symptoms and producing medical castration. Longer-term studies and subsequent meta-analyses of randomized controlled trials in patients with advanced PC found no significant differences in overall survival when single-therapy androgen suppression was achieved through the use of LHRH-agonist therapy or orchiectomy. Randomized trials have reported significant improvements in disease-free and overall survival in patients with locally advanced or high-grade PC treated with LHRH agonists in addition to radiotherapy. Several prospective randomized trials have reported decreases in rates of positive surgical margins with short-term (6 weeks to 4 months) neoadjuvant LHRH-agonist therapy in patients with stage T1 to T3a PC undergoing prostatectomy. Definitive comparisons of immediate and delayed treatment in patients with biochemical relapse have not been reported. However, the results of several studies suggest that immediate LHRH-agonist therapy (or orchiectomy) may improve the course of disease progression and survival. The risks of long-term treatment (eg, osteoporosis; fracture; anabolic loss of muscle mass, with a tendency toward weight gain) must be considered carefully in patients who are likely to receive chronic LHRH-agonist therapy. Intermittent schedules have been developed to reduce the adverse effects associated with LHRH-agonist therapy; some reports support sparing effects on bone and muscle mass and relative improvements in toxicities during off-therapy periods, whereas others have documented continuing decreases in bone mineral density (BMD), with the rate of bone loss highest during the early cycles of therapy. Bisphosphonate therapy has been shown to increase BMD in patients with PC and may therefore be beneficial when overt symptoms of osteopenia or osteoporosis are present. CONCLUSIONS: LHRH-agonist therapy has been the mainstay of treatment for advanced PC for >20 years. Clinical evidence supports expanding use of these agents at an earlier stage of disease and as part of multimodal regimens that include radiotherapy. There is a need for further study of the efficacy of adjuvant LHRH-agonist therapy along with prostatectomy, in patients with biochemical failure, in intermittent regimens, and in conjunction with cytotoxic therapies in late-stage disease.

The novel sequence-specific DNA cross-linking agent SJG-136 (NSC 694501) has potent and selective in vitro cytotoxicity in human B-cell chronic lymphocytic leukemia cells with evidence of a p53-independent mechanism of cell kill.

SJG-136 (NSC 694501) is a novel DNA cross-linking agent that binds in a sequence-selective manner in the minor groove of the DNA helix. It is structurally novel compared with other clinically used DNA cross-linking agents and has exhibited a unique multilog differential pattern of activity in the NCI 60-cell line screen (i.e., is COMPARE negative to other cross-linking agents). Given this profile, we undertook a preclinical evaluation of SJG-136 in primary tumor cells derived from 34 B-cell chronic lymphocytic leukemia (B-CLL) patients. SJG-136 induced apoptosis in all of the B-CLL samples tested with a mean LD50 value (the concentration of drug required to kill 50% of the cells) of 9.06 nmol/L. Its cytotoxicity was undiminished in B-CLL cells derived from patients treated previously, those with unmutated VH genes, and those with p53 mutations (P=0.17; P=0.63; P=0.42, respectively). SJG-136-induced apoptosis was associated with the activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor Z-LEHD-FMK. Furthermore, SJG-136 did not trigger the phosphorylation of p53 or the up-regulation of GADD45 expression in B-CLL cells whereas the cross-linking agent chlorambucil elicited both of these effects. This suggests that SJG-136 cross-linking adducts are not subject to p53-mediated DNA excision repair mechanisms in B-CLL cells. Taken together, these data demonstrate a novel mechanism of action for SJG-136 that appears to circumvent the effects of poor prognostic markers. This unique cytotoxicity profile warrants further investigation and supports the evaluation of this agent in Phase I clinical trials for patients with B-CLL.

A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma.

A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P