A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer.

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer.

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.

Development of rheumatoid arthritis after treatment of large granular lymphocyte leukemia with deoxycoformycin.

The association of T-cell large granular lymphocyte (LGL) leukemia and rheumatoid arthritis is well described and it is now recognized that these patients and patients with Felty's syndrome represent different aspects of a single disease process. Most patients have rheumatoid arthritis at the time of diagnosis of LGL leukemia. This is the first detailed report of the development of rheumatoid arthritis after the diagnosis and treatment of LGL leukemia as well as the first report of rheumatoid arthritis that occurred in association with deoxycoformycin treatment. It is likely that the beneficial sustained normalization of neutrophil counts as a result of deoxycoformycin treatment played a significant role in the development of this complication. Hematological improvement occurred despite molecular genetic evidence of persistence of the abnormal T-cell clone. The role of the clonally expanded T cells in the pathogenesis of neutropenia and rheumatoid arthritis is discussed.

An examination of lifestyle and adjustment in three community residential alternatives.

Lifestyle normalization, community integration, adjustment, social support, and personal satisfaction were examined for 133 adults with mild and moderate retardation living in small group homes, supervised apartments, and with their natural families. Results of questionnaires and structured interviews with care providers showed that the residence settings supported quite different lifestyles with respect to independence, lifestyle normalization, and integration. Persons in supervised apartments achieved the most normative lifestyles with greater personal independence and community integration while reporting levels of lifestyle satisfaction and personal well-being similar to that of persons living with their own families. Results also showed that social integration, that is, participation in activities with peers without disabilities, was extremely limited for all participants, even those living in natural families. The study exemplifies the use of a residential typology to investigate the relationship of environmental factors to community adjustment. It also exemplifies the use of multiple perspectives and multiple measures to evaluate quality of life in community living alternatives.

Hydroxamic acids as colorimetric reagents.

Thirty-three hydroxamic acids and three N-substituted hydroxamic acids or structurally similar compounds have been studied as possible colorimetric reagents for metal ions. They were tested with 78 ions under varying conditions of acidity and basicity. Aliphatic, substituted aliphatic, aromatic, substituted aromatic, and heterocyclic hydroxamic acids were represented in the compounds studied. An attempt was made to correlate the activity towards metal ions with variations in the molecular structure of the hydroxamic acids. The studies with C-substituted hydroxamic acids indicate that the preferential formation of a colour or a precipitate depends on pH, the solvent, and reagent concentration, and is not a function of the presence or absence of a substituent on the nitrogen atom. A number of the compounds offer promise of being useful colorimetric reagents under proper reaction conditions.