Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.

PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer.

BACKGROUND: With an hypothesis that post-chemotherapy changes in serum prostate-specific antigen (PSA) levels might serve as a surrogate marker for assessing prostate cancer outcome (i.e., survival), we studied the relationship between pretherapy and post-therapy prognostic factors and survival in patients with androgen-independent prostate cancer. METHODS: A prognostic model for survival based on pretherapy and post-therapy parameters was developed from the clinical data on 254 patients with androgen-independent prostate cancer treated with 11 different protocol therapies at Memorial Sloan-Kettering Cancer Center. The model was validated by use of an independent dataset of 541 patients enrolled in two randomized phase III trials. RESULTS: In multivariate analysis, a post-therapy decline in PSA levels of 50% achieved in 12 weeks was a statistically significant factor associated with survival (two-sided P = .0012). A similar outcome was obtained with the use of an 8-week time frame. Elevated pretherapy level of serum lactate dehydrogenase (two-sided P = .0001), lower pretherapy level of hemoglobin (P = .0001), and younger age (two-sided P = .0430) had a statistically significant negative impact on outcome. Median survival times were 23, 17, and 9 months for low-, intermediate-, and high-risk groups of patients defined by the prognostic model, respectively. CONCLUSION: This study confirms the prognostic value of a post-therapy decline in PSA of 50% or greater from baseline in relation to survival in patients with androgen-independent prostate cancer treated with a variety of therapies. Two consecutive determinations at 4-week intervals can be used as an end point for efficacy in phase II trials of therapies in this disease.

Management of histologically aggressive lymphomas with a high risk of CNS disease.

The NHLs are a group of neoplasms that share a common target tissue, and are characterized by a high degree of biological and clinical heterogeneity. Adult lymphomas with a high propensity for CNS involvement comprise SNCC, lymphoma (ATLL), LL, and PCL of immunocompromised patients. Despite recently reported encouraging results, there is no standard therapy available for ATLL or PCL. In contrast, recent data from several groups suggest that the therapeutic outcome of SNCC lymphoma in adults is similar to the excellent results in children, when the same regimens are used, and the toxicity, at least for adults less than 60 years, is also similar. Although more intensive chemotherapy combined with CNS prophylaxis has extended the long-term survival of patients with LL, the treatment results in adults fall short of those for children.

Phase I/II dose-escalation study of liarozole in patients with stage D, hormone-refractory carcinoma of the prostate.

BACKGROUND: Liarozole binds to the cytochrome P-450-dependent hydroxylating enzymes involved in steroid biosynthesis and retinoic acid catabolism. This phase I study investigated the clinical/endocrine toxicity profile of liarozole and determined the maximally tolerated dose (MTD) in hormone-refractory prostate cancer patients. METHODS: Groups of five patients were treated with oral liarozole caplets, starting at 37.5 mg twice daily. The dose was doubled for each subsequent group until the MTD was reached, after which, an additional 18 patients were entered into the MTD-1 dose stratum. The long-term safety of liarozole was assessed based on treatment-emergent signs and symptoms and clinically significant laboratory results. RESULTS: Thirty-eight patients were enrolled. The MTD was determined to be 300 mg twice daily. Side effects that defined the MTD included lethargy, somnolence, body rash, and paresthesias. Two deaths occurred during the trial (pneumonia and myocardial infarction). Four patients had a > 50% decrease in prostate-specific antigen (PSA) levels (two at 150 mg, two at 300 mg). Of nine patients with measurable disease, two had partial responses. CONCLUSIONS: Liarozole was generally well tolerated with no evidence of adrenal insufficiency. Preliminary evidence of activity in this indication was observed based on dose-dependent decreases in PSA levels and improvement in soft-tissue metastasis.

The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.

We conducted a double-blind, randomized phase II study to evaluate the safety and activity of combination therapy with N-butyl-deoxynojirimycin (SC-48334) (an alpha-glucosidase I inhibitor) and zidovudine versus zidovudine alone. Patients with 200 to 500 CD4 cells/mm3 who tolerated < or = 12 weeks of prior zidovudine therapy received SC-48334 (1000 mg every 8 h) and zidovudine (100 mg every 8 h) or zidovudine and placebo. Sixty patients received combination therapy and 58, zidovudine and placebo. Twenty-three patients (38%) and 15 (26%), in the combination and zidovudine groups, respectively, discontinued therapy (p = 0.15). The mean SC-48334 steady-state trough level (4.04 +/- 0.99 micrograms/ml) was below the in vitro inhibitory concentration for human immunodeficiency virus (HIV). The mean increase in CD4 cells at week 4 was 73.8 cells/mm3 and 52.4 cells/mm3 for the combination and zidovudine groups, respectively (p > 0.36). For patients with prior zidovudine therapy, the mean change in CD4 cells in the combination and zidovudine groups was 63.7 cells/mm3 and 4.9 cells/mm3 at week 8 and 6.8 cells/mm3 and -45.1 cells/mm3 at week 16, respectively. The number of patients with suppression of HIV p24 antigenemia in the combination and zidovudine groups was six (40%) and two (11%) at week 4 (p = 0.10) and five (45%) and two (14%) at week 24 (p = 0.08), respectively. Diarrhea, flatulence, abdominal pain, and weight loss were common for combination recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

Maintenance of CD4+ cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy and safety of thymopentin in HIV-infected patients who had not yet developed AIDS. DESIGN: Patients were stratified into asymptomatic or symptomatic groups and randomized to receive either thymopentin (50 mg) or placebo, subcutaneously, double-blind for 24 or 52 weeks, three times a week. SETTING: Patients were enrolled at three sites (two hospital clinics and one private practice). PATIENTS: Of 91 HIV-seropositive patients (52 asymptomatic and 39 symptomatic) from whom HIV could be isolated from peripheral blood, 45 were enrolled for 24 weeks and 46 for 52 weeks of double-blind evaluation. MAIN OUTCOME MEASURES: Virological, immunological and clinical evaluations were performed before and during treatment. RESULTS: Thymopentin-treated asymptomatic patients had more CD4+ cells, as demonstrated by a greater area under the percentage CD4+ cells curve (P = 0.03) and a shorter median time to a 20% increase in percentage of CD4+ cells (P = 0.04) in the first 24 weeks, with similar trends in the 52-week study. By 24 weeks no asymptomatic thymopentin-treated and two placebo-treated patients (9.1%, Kaplan-Meier estimate) had progressed to constitutional symptoms (P = 0.12; two-tailed Wilcoxon-Gehan test), with only one further progression in a placebo-treated patient in the subset followed for 52 weeks. Symptomatic patients receiving thymopentin or placebo were similar in both CD4+ cell levels and disease progression (two progressions to AIDS in each group). No serious adverse effects attributable to thymopentin were observed. CONCLUSIONS: These results, if confirmed, indicate that thymopentin, by maintaining CD4+ cells, could slow or arrest immune decline and consequent disease progression at the asymptomatic stage of HIV infection.

OKT3 monoclonal antibody reversal of renal and hepatic rejection in pediatric patients.

The monoclonal antibody OKT3 was previously shown to be superior to conventional high-dose steroid therapy for reversal of acute rejection of renal allografts. Furthermore, OKT3 was effective in reversing acute renal or hepatic allograft rejection that was resistant to treatment with steroids, anti-thymocyte globulin, or both. Our analysis demonstrates that OKT3 is also effective in pediatric patients in reversing acute rejection of renal allografts (rescue treatment) or hepatic allografts (primary or rescue treatment).

Chemical consequences of incorporation of 5-fluorouracil into DNA as studied by NMR.

The cytotoxic analogue of thymine, 5-fluorouracil (Uf), is known to be incorporated into DNA in biological systems. This abnormal base has been synthetically incorporated into short DNA oligomers. The ionization of the N-3 proton of this base within DNA oligomers was measured by observation of the 19F chemical shift at varying pH values. The pKa values for the Uf ring of dTpdUfpdT and dApdUfpdA were determined to be 7.84 and 7.9, respectively. The self-complementary 12-mers d(G-C-G-C-A-A-T-Uf-G-C-G-C) and d(C-G-A-T-Uf-A-T-A-A-T-C-G) were synthesized, and 1H NMR was used to compare the helix dynamics and stability of the interstrand imino proton hydrogen bonds with those of the 12-mers d(G-C-G-C-A-A-T-T-G-C-G-C) and d(C-G-A-T-T-A-T-A-A-T-C-G). The N-3 hydrogen bond of the A-Uf base pair was less stable than the corresponding hydrogen bond in A-T base pairs in the same helix, and the A-Uf base pair was less stable than the A-T base pair in the analogous position of the control helix. The observed temperature-dependent dynamics and NMR melting temperatures of the control and dUf-containing oligomers were similar.