No abstract

Brequinar sodium (DUP 785, NSC 368390) is a novel quinoline-carboxylic acid derivative that has been selected for clinical evaluation because of its broad spectrum of antitumor activity in animal models and its novel chemical structure. This compound inhibits the mitochondrial enzyme dihydroorotate dehydrogenase (DHO-DH), which catalyzes the conversion of dihydroorotate to orotate, leading to a blockage in the pyrimidine de novo biosynthesis. A total of 43 patients received 110 courses of Brequinar sodium by short-term intravenous (i.v.) infusion, which was repeated every 3 weeks. Dose escalation was initially based on a modified Fibonacci scheme. After pharmacokinetic data from mice and man became available, a pharmacologically guided dose escalation was used; at toxic levels, dose escalation was applied on the basis of clinical judgement. The dose-limiting toxicities were myelosuppression, mucositis, skin rash, nausea and vomiting. The maximum tolerable doses for poor- and good-risk patients were 1,500 and 2,250 mg/m2, respectively. One mixed response was observed in a patient with papillary carcinoma of the thyroid. The recommended doses for phase II studies are 1,200 and 1,800 mg/m2 Brequinar sodium, given by a 1-h i.v. infusion every 3 weeks to poor- and good-risk patients, respectively.

No abstract

Twenty-six adult patients were entered in a phase I trial of carboplatin, a new cisplatin derivative with reduced potential for nephrotoxicity. All patients had solid tumors and the median World Health Organization performance score was 2 (0-3). Twelve patients had not received prior chemotherapy. The drug was administered as a 15-minute IV infusion, without pre- or posthydration, at daily doses of 40-125 mg/m2 for five consecutive days. Antiemetics were given only if needed. Thrombocytopenia and neutropenia were dose related and dose limiting. One patient died from septic shock at the highest dose level. Nonhemolytic anemia was also encountered. Nausea and vomiting were experienced by most patients but gastrointestinal intolerance was severe in only two patients. One patient had hypercreatininemia, which was minor and rapidly reversible. Other toxic effects consisted of negligible fatigue, paresthesia, pruritus, local pain, stomatitis, headache, and alopecia. Although none of the patients achieved a partial or complete response, antitumor effect was strongly suggested in two patients with thyroid and cervix cancer, respectively. Carboplatin is an attractive candidate for phase II trials. In good-risk patients, such trials could be initiated at a daily dose of 100 mg/m2 for five consecutive days every five to six weeks.

Thirty-three adult patients with solid tumors were treated with menogaril, a new anthracycline antibiotic. The drug was given as a two-hour infusion every 4 to 5 weeks at doses ranging from 17 to 250 mg/m2. The maximum tolerated dose was 250 mg/m2. Reversible and dose-related leukopenia was the dose-limiting toxicity. Thrombocytopenia was less frequent. Hematologic toxicity was maximal 2 weeks after treatment, and recovery usually occurred within 4 weeks. There was no dissociation between WBC and neutrophil counts, and myelosuppression did not appear to be cumulative up to 200 mg/m2. Myelosuppression was more severe for patients with heavy pretreatment and/or bone marrow involvement. Local toxicity consisting of phlebitis and/or erythema was the most common nonhematologic toxicity, especially at 250 mg/m2 (eight out of nine patients). Usually, erythema appeared within 24 hours after treatment at or near the infusion site and resolved within a few days. Occasionally, a more persistent (several weeks) orange discoloration suggesting cutaneous deposits of menogaril was observed. Nausea and vomiting were uncommon and never severe. Alopecia and mucositis were rare. Minor arrhythmias were seen in several patients during treatment, but their relationship with menogaril therapy was unclear, and in no patient did heart failure develop. Plasma concentrations were best described by a tricompartmental model with a mean terminal half-life of 29.5 hours and a mean total-body clearance of 20.2 L/h/m2. Doses of 160 and 200 mg/m2 are recommended for phase II trials in poor- and good-risk patients, respectively.

4'-Deoxydoxorubicin is a new anthracycline derivative. Experimentally, the drug shows efficacy against doxorubicin-resistant malignancies and, as compared to the parent compound, it has reduced potential for heart damage. This Phase I trial was conducted with a single dose intermittent schedule. 4'-Deoxydoxorubicin was given by rapid i.v. administration at doses of 20, 30, 35 and 40 mg/m2. A total of 25 adult patients with a variety of solid tumors received a median of two courses (1-4). Leukopenia was dose-related and dose-limiting. Occasionally severe thrombocytopenia was also encountered. Nonhematological toxic effects were mostly mild to moderate and were qualitatively similar to those commonly reported with doxorubicin. The frequency of local reactions was apparently increased but the incidence of alopecia and gastrointestinal distress was noticeably lower. There were no acute or chronic drug-induced cardiac effects. Antitumor activity was suggested in a patient with a carcinoma of the cardia. For Phase II trials, doses of 35 and 30 mg/m2 every 3-4 weeks may be recommended in good-risk and poor-risk patients, respectively.

Alizapride is a methoxy-2-benzamide derivative three times more potent than its parent compound, metoclopramide, as an antagonist of apomorphine-induced emesis in dogs. The antiemetic activity of alizapride plus dexamethasone (DXM) was compared with that of placebo plus DXM in a randomized, double-blind, crossover study in cancer patients receiving cisplatin (DDP). Alizapride, given at the maximally tolerated dose of 4 mg/kg x 5, or placebo was given in a sequence determined by randomization during two successive, identical courses of antitumor chemotherapy. The antiemetic treatment was given 30 min before and 1.5, 3.5, 5.5, and 7.5 h after starting. DXM, in a dose of 12 mg, was given IV with the first administration of alizapride or placebo. A total of 39 patients completed the two courses of chemotherapy. The severity of gastrointestinal symptoms was influenced by previous treatment but not by the treatment sequence. Although our overall results suggest that alizapride does not add to the activity of DXM against DDP-induced amesis, a statistically significant difference favoring alizapride plus DXM was found among patients with the lowest gastrointestinal tolerance to DDP: women, patients under 50 years of age, and patients pretreated with chemotherapy including DDP and non-DDP agents. Side effects consisted of orthostatic hypotension, which was symptomatic in two patients, and a single occurrence of severe extrapyramidal syndrome. We conclude that alizapride is more active than placebo when combined with DXM for DDP-induced emesis in patients at high risk of severe nausea and vomiting. The severity of the side effects in this study indicates that a dose reduction of alizapride might be appropriate for further studies.

Thirty one patients with solid tumors were entered into a phase I trial with idarubicin, a new anthracycline antibiotic with oral antitumor activity in animals. The drug was scheduled to be given for 4 consecutive weeks at doses ranging from 10 to 20 mg/m2. Leukopenia was the dose-limiting toxicity. Thrombocytopenia was occasionally seen. Since several patients could not receive the third and fourth administrations of the drug at 17.5 and 20 mg/m2, higher doses were administered only for 2 consecutive weeks. With this schedule, the maximum tolerated dose was 25 mg/m2 and leukopenia was again the dose-limiting toxicity. With both schedules, myelosuppression was highly variable and could not be related to prior therapy, bone or liver metastases, or performance status. Other toxicities were mild to moderate and were dominated by nausea and vomiting which were observed in 29% of the patients. Alopecia and mucositis were unfrequent and cardiac toxicity was not observed. Starting doses of 15 mg/m2 for 4 consecutive weeks or 20 mg/m2 for 2 consecutive weeks could be proposed for oral phase II studies with idarubicin, under careful pharmacokinetic monitoring.