Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:009512 (tumor necrosis factor)
 58,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A total of 22 patients with metastatic renal cell carcinoma or malignant melanoma were treated in a phase II study to assess the safety and efficacy of combination therapy of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). 3 x 10(6) U/m2/day recombinant human (rh)IL-2 was given in repetitive cycles by continuous 24-h infusion from day 1 to day 4; 6 x 10(6) U/m2/day rhIFN-alpha was given subcutaneously on days 1 and 4. There was one complete remission and two partial remissions in the renal cell carcinoma group and two partial remissions in the malignant melanoma group, giving an overall response rate of 24% in 21 evaluable patients with a median response duration of 5+ months. Toxicity was moderate, with hypotension, fever, chills, nausea, neurotoxicity, and dermatitis as prominent side effects. Measurement of circulating cytokine levels showed increased serum tumor necrosis factor-alpha (TNF), interferon-tau, and soluble interleukin-2 receptor levels during each cycle with a tendency to higher concentrations of TNF in responders as compared to nonresponders. With regard to therapeutic efficacy and tolerance, our approach might represent an alternative to the high-dose protocols and the labor- and cost-intensive strategies of adoptive immunotherapy.
 ...
PMID:Combination of interleukin-2 and interferon-alpha in renal cell carcinoma and malignant melanoma: a phase II clinical trial. 130 89

Twenty-two evaluable patients with advanced adenocarcinoma of the pancreas, but without prior chemotherapy or immunotherapy, received recombinant tumor necrosis factor (rTNF). rTNF was given as an intravenous infusion over 30 min daily x 5, every 14 days, at a starting dose of 150 micrograms/m2/day. Toxicities included fevers/rigors, nausea/vomiting/anorexia, flu-like symptoms, hypotension, hyperglycemia, anemia, coagulopathy, hepatotoxicity, and hypertriglyceridemia. Laboratory evidence of disseminated intravascular coagulopathy occurred in 11 patients, with only 3 of these patients having clinical manifestations. Two patients suffered from pulmonary emboli. The high incidence of coagulopathy was felt to be, at least in part, disease related. No objective responses were observed with a 95% confidence interval of 0-15%.
 ...
PMID:A phase II trial of recombinant tumor necrosis factor in patients with adenocarcinoma of the pancreas: a Southwest Oncology Group study. 179 Jan 46

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.
 ...
PMID:A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer. 191 10

Sixteen previously treated (with only one prior regimen) patients with histologically proven metastatic or locally recurrent colorectal carcinoma were treated with recombinant tumor necrosis factor (rTNF) administered by 30-minute i.v. infusions twice daily for 5 consecutive days every other week for 8 weeks. Patients received 100 micrograms/m2 twice daily on day 1 of cycle 1 with escalation to 150 micrograms/m2 twice daily thereafter. Patients were concomitantly treated with indomethacin 25 mg every 6 hours and acetaminophen 650 mg every 4 hours to obviate fever and chills. Toxicities included: nausea/vomiting (69%), headache (25%), chills (69%), pain at tumor sites (63%), hypotension (31%), and hypertension (38%). Hematologic toxicity included leukopenia less than 2000 cells/mm3 (38%) and thrombocytopenia less than 100,000 cells/mm3 (13%). Liver function abnormalities occurred independently of the site or extent of metastatic disease and inconsistently in each treatment cycle. Four patients developed bilirubinemia greater than 2.5 x baseline values (range, 2.5 to 10.3 U/L); five patients had greater than 2.5 x elevations in alkaline phosphatase (range, 624 to 1663 U/L). Two patients developed retinal vein thrombosis in the absence of hemostatic abnormalities. In both instances, this complication occurred several weeks after completion of therapy. No objective responses were noted in 14 evaluable patients (95% confidence interval: 0 to 0.23). Three patients had stable disease for a median duration of 4.5 months. In conclusion, i.v. rTNF at this dose and schedule has no demonstrable antitumor efficacy. Twice-daily i.v. administration of this agent is associated with more hepatotoxicity than previously reported in trials using subcutaneous or once daily i.v. administration. Retinal vein thrombosis may be a late complication of i.v. rTNF at this dose and schedule.
 ...
PMID:A phase II trial of recombinant tumor necrosis factor in patients with advanced colorectal carcinoma. 238 95

A principal side effect of biological response modifiers (BRMs) is a constellation of constitutional symptoms often referred to as a "flu-like syndrome" (FLS). Precisely what this syndrome encompasses is frequently unclear, but its major components appear to be fever, chills, rigors, myalgias, and headache. Other components variously included are anorexia, nausea, upper respiratory symptoms such as nasal congestion and cough, and the ill-defined symptom, malaise. The manner in which the "flu-like" syndrome manifests itself during treatment with interferon (IFN), interleukin-2 (IL-2), tumor necrosis factor (TNF), monoclonal antibodies (MoAbs), and colony stimulating factors (CSFs) will be described with attention to frequency, duration and severity. The common mechanisms underlying the appearance of a flu-like syndrome during biotherapy will be elucidated with emphasis on the role of endogenous pyrogens and prostaglandins and on the physiology of the process. Methods to prevent or alleviate these uncomfortable side effects, including medical interventions such as alterations in schedule/route/dose of BRM administration and premedication with a variety of agents, as well as nursing measures such as patient education will be discussed.
 ...
PMID:Recent advances in the management of biotherapy-related side effects: flu-like syndrome. 268 12

Based on a phase I study in 1986, 22 patients have been entered in a phase II study of high-dose human tumor necrosis factor (rH-TNF) since May 1987. Of these patients, 18 are evaluable at present, 2 are still under investigation, and 2 have dropped out. All had advanced stages of cancer (9 soft-tissue sarcomas, 3 melanomas, 5 hypernephromas) and inclusion in the study was ethically acceptable (informed consent). The daily dose of rH-TNF was 15 x 10(5) units/m2, escalated to 21 x 10(5) units/m2 (683-956 micrograms/m2 every week; range 1-6 cycles). Additional prophylactic ketoprofen administration was carried out. Of the 18 evaluable patients, 4 responded with no change (2/4, clinical improvement) and 14 showed progressive disease. The main toxicities observed were hypotension (decrease in systolic blood pressure, 21-60 Torr), leukocytosis, increases in ALAT/ASAT (WHO grade 0-4), fever (WHO grade 1-2), chills (mild to moderate), neurotoxicity (WHO grade 0-2), and nausea/vomiting (WHO grade 0-3).
 ...
PMID:Phase II clinical trial of high-dose recombinant human tumor necrosis factor. 279 Nov 93

Nineteen patients with advanced cancer for which there was no effective standard therapy or whose disease was refractory to standard therapy were treated with recombinant tumor necrosis factor (rTNF). The rTNF was administered subcutaneously for 5 consecutive days every other week for 3 treatment weeks. The doses administered ranged from 5 micrograms/m2/day to 150 micrograms/m2/day. There was no intrapatient dose escalation. Systemic side effects of chills, fever, hypotension, nausea, vomiting, and headache were mild and self-limiting. At the maximum tolerated dose of 150 micrograms/m2/day, five of seven patients experienced moderate to severe thrombocytopenia. Mild rapid declines in total leukocyte count occurred within 60-90 min of administration of the drug, followed by a rise in the total leukocyte count by 120 min. When the total daily dose was administered in a single subcutaneous site, skin ulceration and necrosis occurred at the 100 micrograms/m2/day dose. By giving the total daily dose in two subcutaneous sites, the maximum tolerated dose increased to 150 micrograms/m2/day, and there was no further skin ulceration or necrosis. Skin necrosis occurred in the abdomen and thigh but not on the upper extremity at the 100 micrograms/m2/day dose given in a single site. There was no other significant organ toxicity. No rTNF was detectable in the serum even at the highest doses. No antibodies to TNF developed in any of the patients. The recommended dose of rTNF for Phase II trials given for 5 days subcutaneously is 150 micrograms/m2/day divided into two or more sites.
 ...
PMID:A phase I trial of subcutaneously administered recombination tumor necrosis factor to patients with advanced malignancy. 279 95

A phase I trial of intramuscularly administered recombinant human tumor necrosis factor (rTNF) was conducted in 19 adult patients with advanced solid tumors. The agent was administered daily for up to five consecutive days every other week for two to four courses. Doses of rTNF ranged from 5 to 200 micrograms/m2/d. Dose-limiting toxicities were encountered at doses greater than 100 micrograms/m2/d. Toxicities included tenderness, erythema and induration at the site of injection, fatigue, fever, chills, headache, anorexia, nausea, vomiting, and diarrhea. Moderate to marked reductions in WBC and platelet counts were observed regularly at the highest dose levels, but none were clinically significant. Hepatic enzyme elevation was seen frequently, and two patients developed hyperbilirubinemia. Only one of seven patients treated with doses greater than 100 micrograms/m2/d completed the planned course of therapy. Even at the highest dose levels, serum concentrations of rTNF could only rarely be detected in the serum. No therapeutic responses were observed. The maximal tolerated dose (MTD) of rTNF in this trial was 150 micrograms/m2/d, administered for two courses.
 ...
PMID:Phase I trial of intramuscularly administered tumor necrosis factor in patients with advanced cancer. 291 29

A phase I study of recombinant human tumor necrosis factor (rHu-TNF:PT-050) given by intravenous infusion over 30 min or by intratumoral administration was performed in 53 patients with various types of malignant tumors. The dose of rHu-TNF was started with 0.1 x 10(6) U/body for both intravenous infusion and intratumoral administration and increased to 5 x 10(6) U/body for intravenous infusion and 2 x 10(6) U/body for intratumoral administration. The side effects of rHu-TNF given by intravenous infusion included fever, shaking chills, hypotension, general malaise, nausea, and vomiting, and clinical laboratory tests showed elevations of GOT, GPT, and ALP, etc. Among these, only hypotension was dose-related and was considered to be a dose-limiting factor. The maximum tolerable dose estimated was 1 x 10(6) U/body. The plasma concentration of rHu-TNF after completion of a 30-min infusion was dose-dependent, and the elimination half-life was 0.5-2.4 hr. When the rHu-TNF was administered intratumorally, the frequency of side effects was low compared with intravenous infusion.
 ...
PMID:Phase I study of recombinant human tumor necrosis factor (rHu-TNF:PT-050). 318 Jan 46

2B1 is a bispecific murine monoclonal antibody (BsMAb) with specificity for the c-erbB-2 and Fc gamma RIII extracellular domains. This BsMAb promotes the targeted lysis of malignant cells overexpressing the c-erbB-2 gene product of the HER2/neu proto-oncogene by human natural killer cells and mononuclear phagocytes expressing the Fc gamma RIII A isoform. In a Phase I clinical trial of 2B1, 15 patients with c-erbB-2-overexpressing tumors were treated with 1 h i.v. infusions of 2B1 on days 1, 4, 5, 6, 7, and 8 of a single course of treatment. Three patients were treated with daily doses of 1.0 mg/m2, while six patients each were treated with 2.5 mg/m2 and 5.0 mg/m2, respectively. The principal non-dose-limiting transient toxicities were fevers, rigors, nausea, vomiting, and leukopenia. Thrombocytopenia was dose limiting at the 5.0 mg/m2 dose level in two patients who had received extensive prior myelosuppressive chemotherapy. Murine antibody was detectable in serum following 2B1 administration, and its bispecific binding properties were retained. The pharmacokinetics of this murine antibody were variable and best described by nonlinear kinetics with an average t 1/2 of 20 h. Murine antibody bound extensively to all neutrophils and to a proportion of monocytes and lymphocytes. The initial 2B1 treatment induced more than 100-fold increases in circulating levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 8 and lesser rises in granulocyte-monocyte colony-stimulating factor and IFN-gamma. Brisk human anti-mouse antibody responses were induced in 14 of 15 patients. Several minor clinical responses were observed, with reductions in the thickness of chest wall disease in one patient with disseminated breast cancer. Resolution of pleural effusions and ascites, respectively, were noted in two patients with metastatic colon cancer, and one of two liver metastases resolved in a patient with metastatic colon cancer. Treatment with 2B1 BsMAb has potent immunological consequences. The maximum tolerated dose and Phase II daily dose for patients with extensive prior myelosuppressive chemotherapy was 2.5 mg/m2. Continued dose escalation is required to identify the maximally tolerated dose for patients who have been less heavily pretreated.
 ...
PMID:Phase I trial of 2B1, a bispecific monoclonal antibody targeting c-erbB-2 and Fc gamma RIII. 755 34


1 2 3 4 5 6 Next >>