Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deferiprone, also known as L1, is an orally active iron chelator that has been studied extensively in clinical trials. The sporadic occurrence of agranulocytosis in association with deferiprone and the highly variable frequency of other possible side effects such as arthralgia have created uncertainty about the true incidence of deferiprone-related complications. A multi-center, 1-year trial was initiated to determine the safety profile of deferiprone. Using the Apotex formulation of deferiprone, 187 patients with thalassemia who were unable or unwilling to use deferoxamine were enrolled in four centers; 162 patients completed one year of therapy. Agranulocytosis (ANC < 500/mm3) occurred in one patient after 15 weeks of treatment, was not accompanied by infection and resolved following treatment with G-CSF. Nine other subjects developed less severe neutropenia (ANC 500-1500/mm3) with the lowest absolute neutrophil count reaching 500-1250/mm3. The neutropenia in these patients developed after 1-50 weeks of therapy, frequently accompanied febrile illnesses, and occurred predominantly in non-splenectomized patients. Reasons other than neutropenia for discontinuing use of deferiprone included nausea (4), voluntary withdrawal (3), high ALT (2), platelet count < 100,000/mm3 (2), low but unconfirmed ANC (1), protocol violation (1) fatigue (1), and depression (1). Mean ALT levels rose within three months of therapy and stabilized thereafter. Arthralgia and nausea and/or vomiting occurred in 6% and 24% of subjects, respectively. In this multi-center trial with weekly monitoring of blood counts, the incidence of agranulocytosis was 0.58 per 100 patient-years, and the frequency of agranulocytosis after one year was 0.5%. These findings support the safety of this formulation of deferiprone, using the careful monitoring system employed in this trial.
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PMID:A multi-center safety trial of the oral iron chelator deferiprone. 966 43

The purpose of this study was to assess the safety and feasibility of using standard and escalated doses of cyclophosphamide with doxorubicin, vincristine and prednisone (CHOP) plus granulocyte colony stimulating factor (G-CSF) to treat elderly patients who have advanced stage intermediate grade lymphoma. Consenting patients age > or = 65 years who had an acceptable performance status and adequate cardiac, renal and liver function were eligible for this Phase I study. G-CSF, 5 ug per kg, was given daily with each cycle from day 2 until neutrophil recovery of > or = 10 x 10(9)/L. Ten patients received standard CHOP; sequential cohorts of 5 patients were then to be given CHOP with cyclophosphamide doses of 900, 1050, 1200, and 1350 mg/m2. If 2 patients had dose limiting toxicity, cohorts were expanded to 10 patients; if 3 patients within a cohort had dose limiting toxicity, the previous dose level was considered the maximum tolerated dose of cyclophosphamide. Secondary outcomes were average relative received dose intensity, response, progression-free and overall survival, toxicity, hospitalizations and transfusions. Eight patients (80%) completed 6 cycles of standard CHOP plus G-CSF. Therapy was stopped prematurely in 2 patients due to pneumonia (1) and disease progression (1). Six of 11 patients (55%) given CHOP with cyclophosphamide 900 mg/m2 (CHOP-900) completed treatment. Therapy was stopped in 5 patients due to a toxic death from infection (1), cumulative fatigue (3), and pneumonitis (1). Further dose escalations were not attempted due to the inability to complete 6 treatment cycles in 45% of CHOP-900 cases. The received dose intensities of cyclophosphamide relative to standard CHOP measured over the actual time on therapy were 96% with standard CHOP and 115% with CHOP-900. At 3 years, progression free survival is 40% with standard CHOP and 82% with CHOP-900; overall survivals are 40% and 91% respectively. Neutropenia of < 1.0 x 10(9)/L occurred in 47% of treatment cycles with standard CHOP and in 77% with CHOP-900. In both groups, the mean duration of neutropenia was < 2 days. From these studies we conclude that, standard CHOP with G-CSF can be safely given to elderly patients. Escalating the dose of cyclophos
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PMID:A phase I trial of standard and cyclophosphamide dose-escalated CHOP with granulocyte colony stimulating factor in elderly patients with non-Hodgkin's lymphoma. 971 21

The duocarmycins represent a new group of antitumor antibiotics produced by Streptomyces that bind to the minor groove of DNA. KW-2189 is a water-soluble semisynthetic derivative of duocarmycin B2, with significant activity in murine and human tumor models. We conducted a Phase I trial of KW-2189 in patients who had solid tumors that were refractory to standard chemotherapy or for whom no more effective therapy existed. KW-2189 was administered as a rapid i.v. bolus daily for 5 days every 6 weeks. Twenty-two patients were enrolled and received a total of 31 cycles of KW-2189. Leukopenia, neutropenia, and thrombocytopenia were the dose-limiting toxicities, with nadirs occurring at medians of 36, 38, and 29 days, respectively, at the 0.04 mg/m2/day dose level. Nonhematological toxicities were mild, although one patient developed grade 3 fatigue. Four patients had stable disease over two to four cycles of treatment and showed no cumulative toxicity. The mean t1/2, plasma clearance, and steady-state volume of distribution were 13.5 min, 1,287 ml/min/m2, and 10,638 ml/m2, respectively. Pharmacokinetics were similar on days 1 and 5, with no drug accumulation in plasma. The active metabolite DU-86 was not consistently found in patient plasma. For Phase II trials, when the 5 days every 6 weeks schedule was used, 0.04 mg/m2/day KW-2189 appears to be the maximal tolerated dose, especially for patients who have received prior chemotherapy. At this dose level, the drug was well tolerated, and the toxicities were acceptable.
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PMID:Phase I study of the duocarmycin semisynthetic derivative KW-2189 given daily for five days every six weeks. 974 27

Docetaxel has been shown to have significant antitumor activity. The mechanism of action is through stabilization of tubulin, arresting cells in the G2M phase of the cell cycle. The maximum tolerated dose of docetaxel is 100 mg/m2 every 21 days. Short-lasting neutropenia is the dose-limiting toxicity. Other significant toxicities include alopecia, mucositis, fatigue, sensory neuropathy, fluid retention, rash, and hypersensitivity reactions. Phase II studies of docetaxel as a single agent in patients with squamous cell carcinoma of the head and neck (SCCHN) have documented response rates of 27% to 43%. Studies of docetaxel combined with cisplatin, and docetaxel, cisplatin, and 5-fluorouracil (TPF) as induction therapy for patients with SCCHN demonstrate that these regimens are highly active. An early trial of induction TPF with leucovorin (TPFL) has yielded an overall response rate of 100% and complete response rate of 61%. In vitro studies have shown docetaxel to be a potent radiation sensitizer for squamous cell carcinoma cell lines, and phase I trials using concurrent docetaxel and radiotherapy are ongoing.
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PMID:Docetaxel in head and neck cancer: a review. 978 5

The combination of paclitaxel 135 mg/m2 (24-hour infusion) and cisplatin 75 mg/m2 is now considered the standard treatment in first-line chemotherapy for stage III suboptimally debulked and stage IV ovarian cancer. Interest is focused on the possibility of evaluating the combination of paclitaxel with carboplatin, because it was found to be less nefrotoxic and less neurotoxic than cisplatin. This study seeks to determine the maximum tolerated dose and to assess the antitumor activity of the combination of a 3-hour paclitaxel infusion followed by carboplatin. Thirty-three chemotherapy-naive patients with stage III-IV epithelial ovarian cancer entered this open, nonrandomized dose-finding study. The first dose level investigated was paclitaxel 125 mg/m2 and carboplatin 250 mg/m2: the dose level progression was performed by alternatively increasing paclitaxel 25 mg/m2 and carboplatin 50 mg/m2. Cycles were repeated every 28 days. At least three patients were treated at each dose level. Overall, 233 and 224 cycles, respectively, are evaluable for nonhematologic and hematologic toxicity. Dose-limiting toxicities (febrile neutropenia and severe fatigue) were observed in two of six patients at level VIII (paclitaxel 225 mg/m2 and carboplatin 400 mg/m2) and therefore the previous dose-level (paclitaxel 200 mg/m2 and carboplatin 400 mg/m2) was considered as the maximum tolerated dose. Neutropenia (grade 3-4 in 63% of cycles), neurotoxicity (grade 2 in 37.5% and grade 3 in 9% of patients), arthromyalgias (grade 2 in 53% of patients and grade 3 in 3% of patients), and grade 3 alopecia were the most common toxicities observed. The incidence of thrombocytopenia was low (grade 3 in 4% of cycles) and no renal toxicity was observed. An objective remission was documented in 74% of 31 evaluated patients, including eight complete remissions (26%) confirmed by second-look surgery. The combination of paclitaxel 200 mg/m2 3-hour infusion followed by carboplatin 400 mg/m2 (30-minute infusion) is a safe and active regimen as first-line chemotherapy for advanced ovarian cancer.
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PMID:The combination of paclitaxel and carboplatin as first-line chemotherapy in patients with stage III and stage IV ovarian cancer: a phase I-II study. 978 7

A late phase II clinical study of RP56976 (docetaxel) was conducted in patients with advanced/recurrent gastric cancer as a multicenter cooperative trial. Docetaxel was administered intravenously at a dose of 60 mg/m2 every 3-4 weeks. Of the 76 patients enrolled, 66 patients were eligible and 59 patients were evaluable for response. One patient showed complete response (CR), 13 patients partial response (PR), 1 patient minor response (MR), 19 patients no change (NC) and 25 patients had progressive disease (PD). The overall response rate in 59 evaluable patients was 23.7% (95% CI = 13.6-36.6%). The primary tumor showed a 4.3% (1/23) response, while the metastatic lesions in the abdomen, pelvic mass, lung, liver, and lymph nodes showed response rates of 62.5% (5/8), 33.3% (1/3), 33.3% (1/3), 14.8% (4/27), and 13.9% (5/26), respectively. About hematological toxicity, severe (Grade 3 or more) leukopenia was observed in 36 patients (56.3%) and neutropenia in 52 patients (81.3%). Other major toxicity (Grade 3 or more) included nausea/vomiting in 11 patients (17.2%), anorexia in 9 patients (14.1%), fatigue in 5 patients (7.8%), and alopecia in 7 patients (10.9%), all which were tolerable. The results show that docetaxel is an effective anticancer agent for advanced/recurrent gastric cancer.
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PMID:[Late phase II clinical study of RP56976 (docetaxel) in patients with advanced/recurrent gastric cancer: a Japanese Cooperative Study Group trial (group A)]. 979 14

This study was aimed to determine the activity and toxicity of combination paclitaxel and carboplatin in stage III B and IV NSCLC. Eligibililty required performance status. Paclitaxel was administered at a dose of 200 mg/m2, 3-hour infusion, followed by carboplatin at a tartgeted area under the concentration-time curve (AUC) of 6. Treatment was repeated at 3-week intervals for 6 courses. G-CSF 5 micrograms/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leukopenia or granulocytopenia in the previous course. From August 1996 through June 1997, 15 patients were enrolled. The median age was 47 years (range 20-68 years), 60 per cent were female. 73.3 per cent had adenocarcinoma, and 66.7 per cent had stage III B disease. Eighty three courses were administered; 13 patients (86.7%) completed all six cycles. The objective response rate was 53.3 per cent, with 1 (6.7%) complete response and 7 (46.7%) partial responses. Pleural effusion, lung lesion and lymph node were the three most common sites that responded to chemotherapy. The major toxicity was myelosuppression. Grade 3 or 4 granulocytopenia, anemia and thrombocytopenia were observed in 18 per cent, 7.2 per cent and 1.2 per cent, respectively, of 83 courses administered. Four episodes of febrile neutropenia (4.8%) occurred in 3 patients. There was one episode of anaphylaxis during Paclitaxel infusion. Other common toxicities were mild myalgia, paresthesias, alopecia and fatigue. Most of the toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.
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PMID:Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): a preliminary study. 980 67

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

Recombinant human interleukin 3 (rhIL-3, expressed in Escherichia coli) is a hematopoietic growth factor with protean biological effects on bone marrow in animal models, including enhanced granulocyte and platelet production and the capacity to ameliorate chemotherapy-induced bone marrow toxicity. We, therefore, undertook a Phase I trial in patients with advanced solid tumors and normal bone marrow function. Cohorts of four to six patients each received daily s.c. doses of rhIL-3 (SDZ-ILE-964; Sandoz) at dose levels of 1. 0, 2.5, 5.0, and 10.0 microgram/kg according to the following schedule: cycle 1, rhIL-3 days 1-14; cycle 2, carboplatin (350 mg/m2) on day 1 and etoposide (100 mg/m2) on days 1-3; and cycle 3, carboplatin (350 mg/m2) on day 1, etoposide (100 mg/m2) on days 1-3, and rhIL-3 on days 4-17. Each cycle was a total of 28 days. An analysis of 20 patients entered into all four escalating dose levels revealed that, during cycle 1, absolute neutrophil count (ANC) increased from a median baseline of 6,643/mm3 to a median of 12,692/mm3, and platelets increased from a median baseline of 314,000/mm3 to a median of 465,000/mm3. When cycle 2 was compared with cycle 3, the median ANC nadir increased from 192/mm3 to 988/mm3, and the mean ANC nadir increased from 458/mm3 to 1,297/mm3. Median platelet count nadirs increased from 29,000/mm3 to 84,000/mm3, and the mean nadir platelet counts increased from 72,000/mm3 to 129,000/mm3. Total days on which platelets were <50,000/mm3 was 52 for cycle 2 and 19 for cycle 3. The maximum tolerated dose of rhIL-3 was 5.0 microgram/kg/day; dose-limiting toxicities included fatigue, chills, fever, and headache. These data suggest a clear but variable biological activity observed with IL-3, as measured by the reduction in the depth and duration of thrombocytopenia and/or neutropenia when cycle 2 was compared with cycle 3. rhIL-3 is a promising cytokine that may help to ameliorate the bone marrow toxicity observed with the use of chemotherapeutic agents.
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PMID:Phase I trial of recombinant interleukin 3 before and after carboplatin/etoposide chemotherapy in patients with solid tumors: a southwest oncology group study. 981 5

GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.
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PMID:A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion. 982 74


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