Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.
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PMID:Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours. 1064 11

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.
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PMID:Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study. 953 8

The aim of this phase II trial was to examine the efficacy of a new nitrosourea, cystemustine, in soft tissue sarcoma. Between January 1990 and March 1991, 32 pretreated patients with advanced soft tissue sarcoma were enrolled. Cystemustine was given every 2 weeks at 60 mg/m2 via a 15-min i.v. infusion. All eligible patients were considered evaluable for response and toxicity (WHO criteria). Of the 32 enrolled patients, 4 were ineligible, leaving 28 evaluable patients. All but 1 had been pretreated: 6 with adjuvant chemotherapy, 18 patients with first-line palliative chemotherapy without nitrosourea, 3 with both treatments, and 18 had received radiotherapy. Median age was 54 years (range 20-73) and median performance status was 1 (0-2). One partial response (PR, duration 12 weeks), 2 stable disease and 25 progressions were observed, giving an overall response rate of 3.57% (confidence interval: 0.1-18.4%). Toxicity was mild, and was mainly neutropenia (no grade 3 or 4), thrombocytopenia (3.57% grade 3 and grade 4) and nausea-vomiting (no grade 3 or 4). It should be noted that the treatment for the patient who obtained a PR was third line with no previous response. Cystemustine with this schedule appears to have a low clinical activity and toxicity in advanced soft tissue sarcoma.
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PMID:Results of a phase II trial with second-line cystemustine at 60 mg/m2 in advanced soft tissue sarcoma: a trial of the EORTC Early Clinical Studies Group. 964 Feb 34

This phase II study investigated the activity of continuously administered oral trofosfamide in chemotherapy-pretreated patients with metastatic soft-tissue sarcoma (STS). Trosfosfamide is an oxazaphosphorine with ifosfamide as the predominant metabolite. Eighteen patients with a median age of 60 years were treated with trofosfamide given as continuous oral treatment. Starting dose was 300 mg/day for 7 days and subsequently 150 mg/day. All patients had previously received at least one chemotherapy regimen including doxorubicin and ifosfamide. Three patients achieved partial responses (18%) and nine a disease stabilization (53%) for an overall response rate of 18% (95% CI: 0.5-35%). Median progression-free interval was 4 months (0-17 months) and median overall survival was 10 months (4-39+) months. Toxicity was generally mild. Only one WHO grade III nausea, but no other non-hematologic WHO grade III/IV toxicity occurred. Leukopenia WHO grade III/IV was observed in four patients (22%). No thrombocytopenia <50,000/microl and no neutropenic infection was seen. Continuously administered oral trofosfamide is a well-tolerated palliative treatment in anthracycline/oxazaphosphorin-pretreated patients with advanced STS achieving responses and/or disease stabilization in up to 70% of patients.
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PMID:Phase II study of oral trofosfamide as palliative therapy in pretreated patients with metastatic soft-tissue sarcoma. 1047 64

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
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PMID:DX-8951f: summary of phase I clinical trials. 1119 1

Primary sarcoma of the gallbladder is a rare disease. The tumor occurs more frequently in women. Usually gallstones are present. Symptoms resemble those of cholelithiasis or cholecystitis. The diagnosis is rarely made preoperatively. The patient was a 51-year-old woman with a 2-month history of right upper quadrant pain, nausea, vomiting, and a 10-pound weight loss. Ultrasound showed cholelithiasis and cholecystitis. Laparoscopic cholecystectomy was converted to open as a result of dense tissue in the middle to distal gallbladder. Exploration by a right subcostal incision revealed multiple implants on the surface of the liver and the peritoneum of the upper abdomen. The wall of the gallbladder was very thick and inflamed. Cholecystectomy with liver biopsy was performed. Pathology revealed poorly differentiated epithelioid leiomyosarcoma of the gallbladder with extension to the liver. The disease followed a very aggressive course and the patient died 3 weeks after the procedure. Recommended treatment is extensive surgical resection that can be followed by radiotherapy or chemotherapy. The tumor follows a very aggressive course, which often lasts a few weeks. Prognosis is poor with rare reported 5-year survivals.
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PMID:Leiomyosarcoma of the gallbladder: a case report. 1156 67

Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside analog with antitumor activity against a variety of malignancies. The critical enzyme cytidine kinase is saturated at plasma concentrations achieved after a 30-min infusion at conventional doses. Prolonged infusion time may yield higher intracellular dFdCTP concentrations. A phase I study was designed to determine the maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck cancer, seven sarcoma, three esophageal cancer, three non-small-cell lung cancer and one ovarian cancer) were enrolled. Twenty patients were defined as refractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m(2)) were evaluated for gemcitabine administered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 mg/m(2), with granulocytopenia, thrombocytopenia and asthenia being dose limiting. The maximum grade III/IV patient toxicities for hemoglobin, leukocytes, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respectively. Non-hematological toxicities included asthenia, nausea/vomiting and diarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well tolerated up to 450 mg/m(2) in heavily pretreated patients. Myelosupression and asthenia were dose-limiting toxicities.
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PMID:Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors. 1159 51

ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.
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PMID:ET-743. 1201 79

SU5416 is a small molecule antiangiogenic agent that inhibits vascular endothelial growth factor (VEGF) stimulation of the KDR tyrosine kinase receptor. In this Phase I dose escalation trial, a weekly dose schedule of SU5416 was tested whereby an initial 5-day loading dose was followed by weekly maintenance infusions. The start dose was 20 mg/m(2) for the loading dose followed by 65 mg/m(2) for the weekly infusions. Dose escalations occurred at 33% until a final dose of 65 mg/m(2) (loading dose) and 190 mg/m(2) (weekly infusion) was obtained. Twenty-two patients were treated at five dose levels; tumor types included gastrointestinal (8), breast (3), lung (4), sarcoma (2), and other (5). The most common serious drug-related toxicity was headache, often associated with nausea and vomiting. Grade 1 and 2 toxicities included headache, nausea, vomiting, asthenia, pain at the infusion site, phlebitis, change in voice, and fevers. Of 19 evaluable patients, 4 obtained clinical benefit as defined by tumor regression (1) or disease stabilization for at least 12 weeks (3). Pharmacokinetic data revealed that the weekly infusion schedule prevented the reported 50-60% induction in SU5416 clearance observed with either daily or twice weekly dosing. Higher baseline levels of urine VEGF were observed in the 4 patients who gained clinical benefit, suggesting this may be a useful marker for predicting response to anti-VEGF therapies. Our results suggest that a weekly schedule of SU5416 shows signs of biological activity and is well tolerated at doses up to 145 mg/m(2).
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PMID:Results of a Phase I dose-escalating study of the antiangiogenic agent, SU5416, in patients with advanced malignancies. 1223 19

In primates, little has been reported about malignant mesenchymal uterine tumours. A case of a spontaneous metastasising uterine sarcoma in a 17-year-old rhesus monkey is presented. Clinically, transient abdominal pain, spasms, nausea, anaemia, a firm uterus and bloody vaginal discharge were noted. In a diagnostic laparoscopy, both massive adhesions in the lesser pelvis and 10 ml of ascites fluid were detected. In necropsy, in addition to peritonitis with massive adhesions, a cauliflower-shaped, irregular, tough, greyish-white uterine tumour was seen. Two cherry-sized tumour metastases were noticed in the greater omentum. In histology, both in the uterus and the metastases, a sarcoma with a low amount of connective tissue and well-differentiated cell nuclei was identified.
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PMID:A spontaneous uterine sarcoma in a rhesus monkey (Macaca mulatta). 1245 Jan 92


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