Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
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PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

A phase I study was conducted to characterize the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of a single dose followed by three times weekly s.c. injections of recombinant human interleukin 12 (rHuIL-12). The study encompassed 28 patients with advanced renal cell carcinoma. rHuIL-12 was administered on day 1, followed by an observation period of 7 days. Starting on day 8, repeated s.c. injections were administered 3 times a week for 2 weeks. The MTD of the initial injection was evaluated at dose levels of 0.1, 0.5, and 1.0 microg/kg. DLT was observed at 1.0 microg/kg and consisted of fever, perivasculitis of the skin, and leukopenia. The MTD of the subsequent repeated injections after 1 week of rest was studied at dose levels 0.5, 1.0, and 1.25 microg/kg. DLT at 1.25 microg/kg comprised deterioration of performance status, fever, vomiting, mental depression, and leukopenia. Other notable toxicities were oral mucositis and elevation of hepatic enzymes. Fever, leukopenia, and elevation of hepatic enzymes were more severe after the initial injection than after repeated injections at the same dose level. At dose level 0.5 microg/kg, the mean area under the plasma concentration-time curve decreased from 7.4 ng/h/ml after the first injection to 3.3 ng x h/ml (P = 0.034) after repeated administrations, and at dose level 1.0 microg/kg, it ranged from 31.8 ng/h/ml to 6.0 ng x h/ml (P = 0.041). One patient had a partial response and seven had stable disease. The MTD of a single s.c. injection of rHuIL-12 was 0.5 microg/kg, and the MTD of three subsequent administrations per week was 1.0 microg/kg. In comparison with a single administration, the three times weekly administrations at the same dose level was accompanied with a milder pattern of side effects and a reduction of the area under the plasma concentration-time curve.
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PMID:Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer. 1063 29