Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer.

The immunoconjugate XMMCO-791/RTA consists of ricin A chain bound to a murine monoclonal antibody MoAb 791T. This monoclonal antibody (MoAb) binds to a glycoprotein of 72 kD, which is expressed on human colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma. XMMCO-791/RTA was tested in a Phase I trial with proposed dose escalation steps of 0.02, 0.04, 0.15, and 0.2 mg/kg per day. Twelve patients with metastatic colorectal carcinoma were treated at 0.02, 0.03, and 0.04 mg/kg per day dose levels administered over 1 hour on days 1-5. Study-related toxicities were hypotension (6 patients); greater than 10% weight gain (6 patients); peripheral edema (9 patients); fever (4 patients); confusion (3 patients); diarrhea (3 patients); proteinuria, as identified by dipstick (3 patients), greater than 0.6 mg/dl decrease in serum albumin (11 patients); greater than 25% decrease in oncotic pressure (10 patients), and a decrease in ionized calcium (8 patients). Six patients received a second course of treatment. HAMA levels developed in 9 patients and titers increased with number of courses administered. Decreased overall toxicity, in comparison to the first course, was noted, but one patient had an allergic-type response (hypotension, crushing chest pain, diaphoresis) after the test dose of the second course (HAMA level > 10,000 IgG). Life-threatening toxicity in the form of fluid shift, resulting in noncardiac pulmonary edema and third-spacing occurred after course 1 in 1 of 3 patients at the 0.04 mg/kg per day level. No further dose escalation was attempted and no antitumor activity was seen.

Treatment of acute shoulder syndrome with flurbiprofen.

A multi-dose, double-blind, randomized, placebo-controlled, multicenter study was conducted to evaluate 68 patients with acute bursitis or tendinitis following treatment with flurbiprofen (Ansaid, Upjohn) or placebo. Flurbiprofen was administered in a total daily dosage of 200 to 300 mg four times daily. Based on efficacy rating scales, flurbiprofen-treated patients had the greatest proportion of improvement at almost all time periods. They also showed statistically significant improvement compared with placebo-treated patients, according to investigators' overall assessments at all time periods. Most patients showed improvement within three to four days of treatment. Flurbiprofen was both well tolerated and effective for the relief of pain caused by bursitis or tendinitis of the shoulder.

Flurbiprofen for the treatment of bone pain in patients with metastatic breast cancer.

Two investigators enrolled 26 women with metastatic breast carcinoma in a six-week, double-blind, placebo-controlled, crossover study of flurbiprofen (Ansaid, Upjohn) and placebo. The study was designed to determine the efficacy of flurbiprofen in reducing bone pain due to metastatic breast cancer. Pain score, overall performance, and concomitant use of narcotics were evaluated. The overall mean differences in pain scores between flurbiprofen and placebo showed better control of pain during treatment with flurbiprofen. None of these differences approached statistical significance. Evaluation of overall performance status reached statistical significance in one investigator's group. Three out of four patients reported decreased consumption of acetaminophen/aspirin plus codeine combinations while receiving flurbiprofen.

Pharmacokinetics of flurbiprofen.

Both radiolabeled and nonlabeled drug have been used to study the pharmacokinetics of flurbiprofen (Ansaid, Upjohn). Drug absorption is rapid, drug disappearance half-life is independent of oral dose, and the area under the plasma drug concentration versus time curve increases with increasing oral dose. Elimination of intact drug from the peripheral circulation is biphasic and rapid. Following a single oral dose of 100 mg of flurbiprofen, drug bioavailability is equivalent using regimens of four 25-mg tablets, two 50-mg tablets, or one 100-mg tablet once daily. Long-term administration of flurbiprofen appears neither to inhibit nor induce the drug's metabolism.

Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with phenylbutazone.

Flurbiprofen (Ansaid, Upjohn), a potent new analgesic and anti-inflammatory agent, was compared with phenylbutazone in 90 patients with ankylosing spondylitis. In this double-blind, randomized, 26-week study, a total daily dose of 200 mg of flurbiprofen, administered three times daily, was as effective as 300 mg of phenylbutazone in controlling the pain and other symptoms of ankylosing spondylitis. In some patients, symptoms were adequately controlled by 150 mg of flurbiprofen per day, administered twice daily. There were no statistically significant differences between flurbiprofen and phenylbutazone in the investigators' and patients' assessments of improvement at all key follow-up periods. In addition, there were no consistently significant differences between drugs in the efficacy pain scales and quantitative measurements studied. Flurbiprofen was well tolerated in doses of up to 300 mg per day, and no clinically significant laboratory abnormalities were detected. Flurbiprofen appears to be an excellent alternative to phenylbutazone in the management of patients with ankylosing spondylitis.

Flurbiprofen in the treatment of ankylosing spondylitis. A comparison with indomethacin.

In this randomized, double-blind study, 57 patients with ankylosing spondylitis were evaluated after 26 weeks of treatment with either flurbiprofen (Ansaid, Upjohn) or indomethacin. Flurbiprofen administered four times a day in a total daily dose of 200 mg was effective in controlling the pain and associated symptoms of ankylosing spondylitis. Pain was adequately controlled in some patients following a total daily dose of 100 mg of flurbiprofen administered twice a day. Flurbiprofen was as effective as indomethacin in most key efficacy measurements analyzed. The drug was well tolerated in doses of up to 300 mg per day, and no clinically significant laboratory abnormalities were detected. Flurbiprofen is an excellent treatment for the control of pain and inflammation in patients with ankylosing spondylitis.

Flurbiprofen in the treatment of acute gout. A comparison with indomethacin.

The relative efficacy and safety of flurbiprofen (Ansaid, Upjohn) and indomethacin were compared in 29 patients with monoarticular gouty arthritis of less than 48 hours' duration. A loading dose of 400 mg of flurbiprofen or 200 mg of indomethacin was administered for 24 hours, followed by 200 mg of flurbiprofen per day or 100 mg of indomethacin per day for a maximum of five days. Based on global assessment of improvement, at least 50 percent of patients in both treatment groups showed improvement within 24 hours. There were statistically significant improvements in pain, swelling, erythema, and skin temperature in both groups of patients within 48 hours of treatment. By 72 hours, the proportion of patients with improvement in the flurbiprofen group was equal to or greater than the proportion in the indomethacin group for all clinical efficacy parameters. At the end of treatment, eight of 15 patients in the indomethacin group and five of 14 patients in the flurbiprofen group were asymptomatic. There were no statistically significant differences between indomethacin and flurbiprofen in the percentage of asymptomatic patients at the end of treatment. Side effects were mild in both groups. No clinically significant between-treatment differences were noted in vital signs or in the results of laboratory assays.

Safety of flurbiprofen in the treatment of ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis. A summary of liver and kidney assay data.

The safety of flurbiprofen (Ansaid, Upjohn) was assessed after pooling data on kidney and liver function collected from nine separate phase III clinical trials involving 1,677 patients (941 receiving flurbiprofen and 736 receiving comparison drugs) with ankylosing spondylitis, osteoarthritis, or rheumatoid arthritis. Multiple categories were created to discern the effects of treatment, disease, age (under 60 and 60 years or older), and duration of exposure to flurbiprofen. No clinically significant trends in kidney or liver function were detected in any category following the administration of flurbiprofen.

Flurbiprofen in the treatment of rheumatoid arthritis. A comparison with aspirin.

This large-scale, double-blind study compared 200 mg per day of flurbiprofen (Ansaid, Upjohn) with 4,000 mg per day of aspirin in 822 patients with definite or classical rheumatoid arthritis who were evaluated for up to 52 weeks. Overall response to therapy was similar in both groups. By the end of the study, however, significantly more patients remained in the flurbiprofen (54 percent) than in the aspirin group (40 percent). Significant differences were also found in the incidence and severity of adverse reactions: 36 percent of flurbiprofen-treated and 63 percent of aspirin-treated patients reported side effects. Severe adverse reactions occurred in 6.7 percent of the flurbiprofen-treated patients compared with 16.5 percent of the aspirin-treated patients. Withdrawals that were due at least in part to adverse reactions were more than twice as frequent in the aspirin group (21.4 percent) than in the flurbiprofen group (10.2 percent). Laboratory data collected throughout the study showed no clinically significant abnormalities in either group. This study suggests that flurbiprofen effectively controls the pain and other symptoms of rheumatoid arthritis, and is superior in safety to aspirin in the treatment of patients with acute and chronic disease.

Treatment of osteoarthritis of the knee. A comparison of flurbiprofen and aspirin.

The analgesic efficacy of flurbiprofen (Ansaid, Upjohn) and aspirin were compared in a 12-week, double-blind, randomized, parallel, multicenter study of 147 patients with osteoarthritis of the knee. Flurbiprofen (73 patients) was administered two, three, or four times a day in total daily doses of 100, 150, or 200 mg; aspirin (74 patients) was also given two, three, or four times a day in total daily doses of 2,000, 3,000, or 4,000 mg. Flurbiprofen was found effective in controlling pain and other symptoms of osteoarthritis. In general, the flurbiprofen group showed greater improvement in efficacy variables than did the aspirin group. Statistically significant improvements were noted in the flurbiprofen-treated patients for disability at week 12, and in the clinicians' assessment of response to therapy and disability at the final evaluation. Many flurbiprofen-treated patients (46 percent) completing the trial followed a relatively low dosage regimen of 50 mg twice daily for more than half the study. Flurbiprofen was well tolerated, and no significant laboratory abnormalities were detected.

Phase I study using combination of hydroxyurea and 5-azacytidine (NSC-102816).

Thirteen patients were treated with a hydroxyurea -- 5-azacytidine combination in an attempt to show an increase in therapeutic efficacy of 5-azacytidine without increased bone marrow toxicity. Leukemic and nonleukemic patients were selected in order to compare the effect of a combination therapy on bone marrow. There was no clear-cut tumor response observed in evaluable patients. Overall activity of the combination, as judged by the onset of myelosuppression, appears to be higher than that of 5-azacytidine given alone.

Variation of levels of plasma guanosine diphosphate L-fucose:beta-D-galactosyl alpha-2-L-fucosyltransferase in acute adult leukemia.

We have measured plasma levels of an alpha-2-L-fucosyltransferase in 18 patients with acute adult leukemia at various clinical stages along with simultaneous bone marrow aspirations and biopsies. Patients in remission had significantly lower levels of this enzyme than did nonresponding or relapsing patients. Furthermore, plasma levels were correlated with percentage of marrow blast cells. This enzyme may serve as a biological marker for monitoring patients with acute leukemia receiving chemotherapy. It is particularly helpful as a guide to chemotherapy in patients on whom bone marrow aspirates are technically difficult to obtain.

Phase I study of 5-azacytidine (NSC-102816) using 24-hour continuous infusion for 5 days.

The biologic and antitumor activity of 5-azacytidine has been well demonstrated in the past. The drug at present is thought to be primarily cell cycle phase specific. This study was designed to eliminate undesirable side effects (mainly nausea and vomiting) occurring with a bolus dose and to confirm the recent findings of the relative stability of 5-azacytidine's solution with preserved biologic and antitumor activity. In the study we determined that a dose of 150 mg/m2/day given as a 120-hour continuous iv infusion and repeated at 28-day intervals produced safe, manageable, and reproducible toxicity. The drug was freshly prepared at 4-hour intervals. Eleven courses were administered to seven patients at this dose level and no patient experienced nausea or vomiting. Leukopenia was the major toxic effect. Antitumor activity was shown in one patient with colon cancer and another with American Burkitt's lymphoma.