Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. (1/458)

Dolastatin-10 (dola-10) is a potent antimitotic peptide, isolated from the marine mollusk Dolabela auricularia, that inhibits tubulin polymerization. Preclinical studies of dola-10 have demonstrated activity against a variety of murine and human tumors in cell cultures and mice models. The purpose of this Phase I clinical trial was to characterize the maximum tolerated dose, pharmacokinetics, and biological effects of dola-10 in patients with advanced solid tumors. Escalating doses of dola-10 were administered as an i.v. bolus every 21 days, using a modified Fibonacci dose escalation schema. Pharmacokinetic studies were performed with the first treatment cycle. Neurological testing was performed on each patient prior to treatment with dola-10, at 6 weeks and at study termination. Thirty eligible patients received a total of 94 cycles (median, 2 cycles; maximum, 14 cycles) of dola-10 at doses ranging from 65 to 455 microg/m2. Dose-limiting toxicity of granulocytopenia was seen at 455 microg/m2 for minimally pretreated patients (two or fewer prior chemotherapy regimens) and 325 microg/m2 for heavily pretreated patients (more than two prior chemotherapy regimens). Nonhematological toxicity was generally mild. Local irritation at the drug injection site was mild and not dose dependent. Nine patients developed new or increased symptoms of mild peripheral sensory neuropathy that was not dose limiting. This toxicity was more frequent in patients with preexisting peripheral neuropathies. Pharmacokinetic studies demonstrated a rapid drug distribution with a prolonged plasma elimination phase (t 1/2z = 320 min). The area under the concentration-time curve increased in proportion to administered dose, whereas the clearance remained constant over the doses studied. Correlation analysis demonstrated a strong relationship between dola-10 area under the concentration-time curve values and decrease from baseline for leukocyte counts. In conclusion, dola-10 administered every 3 weeks as a peripheral i.v. bolus is well tolerated with dose-limiting toxicity of granulocytopenia. The maximum tolerated dose (and recommended Phase II starting dose) is 400 microg/m2 for patients with minimal prior treatment (two or fewer prior chemotherapy regimens) and 325 microg/m2 for patients who are heavily pretreated (more than two prior chemotherapy regimens).  (+info)

Agranulocytosis in Bangkok, Thailand: a predominantly drug-induced disease with an unusually low incidence. Aplastic Anemia Study Group. (2/458)

Agranulocytosis, a syndrome characterized by a marked reduction in circulating granulocytes, is strongly associated with medical drug use in Europe and the United States. Unregulated use of common pharmaceutical agents in developing countries has been suspected of causing large numbers of cases of agranulocytosis and deaths, especially among children. To elucidate the incidence and etiology of agranulocytosis in Thailand, a population-based case-control study of symptomatic agranulocytosis that resulted in hospital admission was conducted in Bangkok from 1990 to 1994. An attempt was also made to study the disease in Khonkaen (in northeastern Thailand) and Songkla (in southern Thailand), but there were insufficient cases in the latter regions, and the analysis was confined to subjects from Bangkok. In that region, the overall incidence of agranulocytosis was 0.8 per million per year; there were no deaths. As expected, the incidence was higher in females (0.9 per million), and it increased with age (4.3 per million beyond age 60). Among 25 cases and 529 controls the relative risk estimate for a combined category of all suspect drugs was 9.2 (95% confidence interval = 3.9-21), and the proportion of cases that could be attributed to drug use was 68%. For individual drugs and drug classes the data were sparse; within these limitations, the strongest association appeared to be with antithyroid drugs. One case and three controls were exposed to dipyrone, a drug known to cause agranulocytosis; with such scanty data the risk could not be evaluated. Exposure to pesticides or solvents was not associated with an increased risk. This is the first formal epidemiologic study of agranulocytosis in a developing country. As in the West, most cases are attributable to medical drug use. However, the incidence of agranulocytosis in Bangkok, and apparently, in Thailand as a whole, is unusually low, and the disease does not pose a public health risk.  (+info)

Phase I study of a biweekly schedule of a fixed dose of cisplatin with increasing doses of paclitaxel in patients with advanced oesophageal cancer. (3/458)

We performed this dose-finding study with a fixed dose of cisplatin and increasing doses of paclitaxel given every 2 weeks to determine the maximum tolerable dose of this schedule. Sixty-four patients with advanced oesophageal cancer were treated with a cisplatin dose of 60 mg m(-2) and increasing doses of paclitaxel from 100 mg m(-2) up to 200 mg m(-2) both administered over 3 h for a maximum of six cycles in patients with stable disease or eight cycles in responding patients. Patients were retreated when the granulocytes were > 0.75 x 10(9) l(-1) and the platelets > 75 x 10(9) l(-1). The dose of paclitaxel could be increased to 200 mg m(-2) without encountering dose limiting haematological toxicity. At the dose levels 190 mg m(-2) and 200 mg m(-2) of paclitaxel cumulative sensory neurotoxicity became the dose-limiting toxicity. The dose intensity of paclitaxel calculated over six cycles rose from 50 mg m(-2) per week to 85 mg m(-2) per week. Only three episodes of granulocytopenic fever were encountered out of a total of 362 cycles of treatment. Of the 59 patients evaluable for response, 31 (52%) had a partial or complete response. In a biweekly schedule with a fixed dose of 60 mg m(-2) cisplatin it is possible to increase the dose of paclitaxel to 180 mg m(-2). At higher dose levels, neurotoxicity becomes the dose-limiting toxicity. The observed response rate warrants further investigation of this schedule.  (+info)

Oral versus intravenous empirical antimicrobial therapy for fever in patients with granulocytopenia who are receiving cancer chemotherapy. International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer. (4/458)

BACKGROUND: Intravenously administered antimicrobial agents have been the standard choice for the empirical management of fever in patients with cancer and granulocytopenia. If orally administered empirical therapy is as effective as intravenous therapy, it would offer advantages such as improved quality of life and lower cost. METHODS: In a prospective, open-label, multicenter trial, we randomly assigned febrile patients with cancer who had granulocytopenia that was expected to resolve within 10 days to receive empirical therapy with either oral ciprofloxacin (750 mg twice daily) plus amoxicillin-clavulanate (625 mg three times daily) or standard daily doses of intravenous ceftriaxone plus amikacin. All patients were hospitalized until their fever resolved. The primary objective of the study was to determine whether there was equivalence between the regimens, defined as an absolute difference in the rates of success of 10 percent or less. RESULTS: Equivalence was demonstrated at the second interim analysis, and the trial was terminated after the enrollment of 353 patients. In the analysis of the 312 patients who were treated according to the protocol and who could be evaluated, treatment was successful in 86 percent of the patients in the oral-therapy group (95 percent confidence interval, 80 to 91 percent) and 84 percent of those in the intravenous-therapy group (95 percent confidence interval, 78 to 90 percent; P=0.02). The results were similar in the intention-to-treat analysis (80 percent and 77 percent, respectively; P=0.03), as were the duration of fever, the time to a change in the regimen, the reasons for such a change, the duration of therapy, and survival. The types of adverse events differed slightly between the groups but were similar in frequency. CONCLUSIONS: In low-risk patients with cancer who have fever and granulocytopenia, oral therapy with ciprofloxacin plus amoxicillin-clavulanate is as effective as intravenous therapy.  (+info)

Murine neutrophil stimulation by Toxoplasma gondii antigen drives high level production of IFN-gamma-independent IL-12. (5/458)

Successful immunity to Toxoplasma gondii requires a strong cell-mediated immune response. Neutrophils possess the ability to rapidly migrate into tissues in response to microbial stimuli. Therefore, we sought to determine whether murine neutrophils could respond to T. gondii by producing immunoregulatory cytokines. We show that murine neutrophils produce high levels of IL-12 and low, but significant, levels of TNF-alpha when stimulated with T. gondii Ag. Both cytokines are produced in the absence of IFN-gamma. Production of IL-12 does not require TNFR p55, and release of TNF-alpha occurs independently of IL-12. We show that there is an influx of neutrophils into the peritoneal cavity that peaks at approximately 8 h in response to injection of live tachyzoites and that this is correlated with increased transcription of IL-12 p40. Our results establish that murine neutrophils possess the ability to produce immunoregulatory cytokines during T. gondii infection and suggest that this response may be important in early host defense and in triggering cell-mediated immunity to the parasite.  (+info)

Different effect of granulocyte colony-stimulating factor or bacterial infection on bone-marrow cells of cyclophosphamide-treated or irradiated mice. (6/458)

In the present study, the effect of treatment with granulocyte colony-stimulating factor (G-CSF) on cellular composition of the bone marrow and the number of circulating leucocytes of granulocytopenic mice, whether or not infected with Staphylococcus aureus, was assessed. With two monoclonal antibodies, six morphologically distinct cell populations in the bone marrow could be characterised and quantitated by two-dimensional flow cytometry. Granulocytopenia was induced by cyclophosphamide or sublethal irradiation. Cyclophosphamide predominantly affected the later stages of dividing cells in the bone marrow resulting in a decrease in number of granulocytic cells, monocytic cells, lymphoid cells and myeloid blasts. G-CSF administration to cyclophosphamide-treated mice increased the number of early blasts, myeloid blasts and granulocytic cells in the bone marrow, which indicates that this growth factor stimulates the proliferation of these cells in the bone marrow. During infection in cyclophosphamide-treated mice the number of myeloid blasts increased. However, when an infection was induced in cyclophosphamide and G-CSF-treated mice, the proliferation of bone-marrow cells was not changed compared to that in noninfected similarly treated mice. Sublethal irradiation affected all bone-marrow cell populations, including the early blasts. G-CSF-treatment of irradiated mice increased only the number of myeloid blasts slightly, whereas an infection in irradiated mice, whether or not treated with G-CSF, did not affect the number of bone-marrow cells. Together, these studies demonstrated that irradiation affects the early blasts and myeloid blasts in the bone marrow more severely than treatment with cyclophosphamide. Irradiation probably depletes the bone marrow from G-CSF-responsive cells, while cyclophosphamide spared G-CSF responsive cells, thus enabling the enhanced G-CSF-mediated recovery after cyclophosphamide treatment. Only in these mice, bone marrow recovery is followed by a strong mobilisation of mature granulocytes and their band forms from the bone marrow into the circulation during a bacterial infection.  (+info)

Fludarabine-based chemotherapy in untreated mantle cell lymphomas: an encouraging experience in 29 patients. (7/458)

BACKGROUND AND OBJECTIVE: A prospective study to evaluate the role of fludarabine alone or in combination with idarubicin in untreated patients with mantle cell lymphoma (MCL). DESIGN AND METHODS: Twenty-nine untreated patients with mantle cell lymphoma were stochastically treated with intravenous fludarabine at a dose of 25 mg/m(2)/day for 5 days (11 patients) or with a combination of fludarabine and idarubicin (FLU-ID) (fludarabine 25 mg/m(2) i.v. on days 1 to 3 and idarubicin 12 mg/m(2) i.v. on day 1 (18 patients). For both regimens, cycles were given at three-week intervals for a total of six courses. According to the International Prognostic Index, the most part of high-intermediate and high risk factor patients were in the FLU-ID subset: 7 (39%) patients vs. 2 (18%) in the fludarabine alone subset. RESULTS: Of the 29 patients, 8 (28%) obtained a complete response and 10 (35%) a partial response, with an overall response rate of 63%. The remaining 11 (37%) patients did not respond to the therapy. The overall response rates were 64% (7 patients) in the fludarabine group and 61% (11 patients) in the FLU-ID group. The complete response rate was 27% (3 patients) for fludarabine and 28% (5 patients) for FLU-ID. The toxicity was mild in terms of neutropenia and infections, and no fatalities occurred due to drug-induced side effects. INTERPRETATION AND CONCLUSIONS: These results suggest the efficacy of fludarabine alone or in combination with idarubicin in MCL patients. It will be important to increase this experience and to assess other fludarabine-containing regimens, in particular with cyclophosphamide plus idarubicin and with mitoxantrone and or cyclophosphamide, to test the true role of this approach in MCL.  (+info)

Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. (8/458)

PURPOSE: To evaluate the efficacy and toxicity of gemcitabine (2', 2'-difluorodeoxycytidine) plus cisplatin in previously untreated patients with advanced transitional-cell carcinoma. PATIENTS AND METHODS: Thirty-one patients with measurable advanced transitional-cell carcinoma who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 70 mg/m(2) over 1 hour on day 2 of a 28-day cycle. Prior adjuvant or neoadjuvant therapy for locally advanced disease was allowed if this was completed more than 1 year before study entry. RESULTS: There were six complete responses and 10 partial responses in 28 assessable patients, for an overall response rate of 16 of 28 (57%). The response rate on an intent-to-treat basis was 16 of 31 patients (52%). The median survival is 13.2 months, with 18 patients still alive at this time. Toxicity was primarily hematologic, with 12 of 31 patients (39%) having > or = grade 3 granulocytopenia and 17 of 31 (55%) having > or = grade 3 thrombocytopenia. Two patients had febrile neutropenia. All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. CONCLUSION: Gemcitabine plus cisplatin is an active regimen for the treatment of urothelial cancer.  (+info)

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