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1.
Charles W. Taylor Sydney E. Salmon Winston G. Satterlee Aurelia B. Robertone Thomas M. McCloskey Mark T. Holdsworth Patricia M. Plezia David S. Alberts 《Investigational new drugs》1990,8(Z1):S51-S57
The semi-synthetic vinca alkaloid vinzolidine was administered to advanced cancer patients as an intravenous bolus on a three day schedule every 21 days. Forty-two patients were treated in this phase I trial. Five partial remissions (breast-1, melanoma-2, renal cancer-2) were seen in 30 evaluable patients. The dose limiting toxicities were myelosuppression and neuropathy. Erratic myelosuppression from course to course within the same patient as seen in previous trials with oral vinzolidine, was not observed with the intravenous formulation. The measured pharmacokinetic parameters conformed best to a 2-compartment model with a mean terminal half-life of 23 hours. The anti-tumor activity observed during this phase I trial and acceptable toxicity provide the basis for initiating phase II studies in selected forms of cancer.Dr. Taylor is the recipient of a Clinical Oncology Career Development Award from the American Cancer Society. 相似文献
2.
Gladys I. Rodriguez John G. Kuhn Geoffrey Weiss Pearl De La Cruz Pamela New Suzanne M. Fields John R. Eckardt Liz Campbell Gary M. Clark Susan G. Hilsenbeck Daniel D. Von Hoff 《Investigational new drugs》1999,16(1):57-67
In this phase I study, terephthalamidine was administered as a 120-hour continuous infusion repeated every 21 days. Thirteen patients received 27 courses of terephthalamidine at four dose levels (14, 28, 46, and 70 mg/m2/day). Dose-limiting toxicity consisted of profound and intractable anorexia, weight loss and prostration in all patients. Toxicity was delayed and accompanied by hyponatremia and hypokalemia. No hematologic or other toxicity was documented. One patient with adenocarcinoma of the lung had a 40% decrease in mediastinal lymph nodes and resolution of a pleural effusion lasting 2 months. Pharmacokinetic analysis by HPLC was performed in all patients during their first course. The harmonic mean terminal half-life for terephthalamidine was 23 hours with a plasma clearance of 1.7 l/hr/m2. Both plasma concentrations achieved during infusion (r2 = 0.9) and area under the curve (AUC) (r2 = 0.8) were proportional to increase in dose (p < 0.002). Renal excretion accounted for 64% of the total cumulative dose, with an average renal clearance of 1.16 l/hr/m2. Due to the unacceptable toxicity seen at all doses with this schedule, no further studies are recommended unless the mechanism of toxicity is better understood and can be prevented. 相似文献
3.
Geoffrey R. Weiss Thomas D. Brown John G. Kuhn Daniel D. Von Hoff Robert H. Earhart Wade J. Adams J. E. Brewer J. D. Hosley Dorothy A. Kasunic 《Investigational new drugs》1993,11(1):17-27
Summary Thirty-five patients with advanced refractory cancer were enrolled on this phase I study of menogaril administered orally every 4 weeks at dosages ranging from 85 mg/m2 to 625 mg/m2. An additional 12 patients received alternating oral and IV doses of menogaril (250 mg/m2 IV; 250–500 mg/m2 oral) with accompanying blood and urine sampling for pharmacokinetics analysis. Nausea and vomiting were the dose-limiting toxicities at the 625 mg/m2 dosage level; vomiting was inadequately relieved by prophylactic antiemetics at this dosage level. Other toxicities included sporadic leukopenia at all dosage levels; at dosages of 500 mg/m2 and 625 mg/m2, leukopenia < 3000/l occurred in 7 of 24 patients. Anemia and thrombocytopenia were much less frequent toxicities. Among the patients receiving IV menogaril, peripheral vein phlebitis, leukopenia and anemia were the predominant toxicities. No antitumor responses were observed, yet one patient with nonsmall cell lung cancer experienced a 30% reduction in metastatic tumor nodules.For the patients receiving alternating oral and IV menogaril, comparative pharmacokinetic analyses were performed by HPLC. After oral administration, maximum plasma concentrations were achieved in an average of 6 hours; maximum plasma concentrations were less than one-quarter of those achieved after intravenous administration. The harmonic mean (±SD) terminal disposition half-life after oral dosing was 29.3 ±9.2 hours; mean systemic bioavailability was 33.6±10.5% after oral dosing. Forty-eight hours after an oral dose, mean cumulative urinary excretions of menogaril and the primary metabolite, N-demethylmenogaril, were 4.00±0.96% and 0.44±0.16%, respectively.Because of the poor tolerance of oral menogaril and minimal evidence of biological activity, this schedule of drug administration is not recommended for phase II evaluation. Based on this and other published studies of oral menogaril, frequent chronic low-intermediate dosages of the drug may be given orally with potentially better tolerance and antitumor activity. 相似文献
4.
Delaunoit T Burch PA Reid JM Camoriano JK Kobayash T Braich TA Kaur JS Rubin J Erlichman C 《Investigational new drugs》2006,24(4):327-333
Summary CS-682 (1-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)-N4-palmitoylcytosine) is a novel orally administered 2’-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor
activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor
activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682.
CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed
by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor
type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung
carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated
at each of the following dose levels (mg/m2/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220.
Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2,
vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3–4) were seen more
frequently with 10 patients experiencing grade 3–4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia.
Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m2/day. The maximum tolerated dose was determined to be 160 mg/m2/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable
disease after having received 34 courses of CS-682.
After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase
to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 ± 0.9 h after drug administration and
the terminal elimination half-life was 1.7 ± 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 ± 0.31 h, peak
plasma concentrations were achieved 3.1 ± 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 ± 1.7 h.
The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m2/day for 4 weeks repeated after a 2-week rest period.
Supported by Sankyo Co., Ltd, and Cyclacel Ltd. 相似文献
5.
Abraham Mittelman Carmelo Puccio Elizabeth Gafney Nancy Coombe Brinj Singh Debra Wood Paul Nadler Tauseef Ahmed Zalmen Arlin 《Investigational new drugs》1992,10(3):183-190
Nineteen patients with advanced cancer were entered into a phase I clinical trial of Tumor Necrosis Factor (TNF) which was designed to determine the pharmacokinetic profile, safety, and maximal tolerated dose (MTD) of the recombinant human cytokinein vivo. TNF was administered by continuous infusion for 24 hours followed by pharmacokinetics and a 120-hour infusion repeated every 3 weeks. The initial dose was 40g/m2 and was ultimately escalated to 200g/m2. A total of forty 5-day cycles were administered to 18 of these patients; and all were evaluable for toxicity. Toxicities in this trial included fever, chills, rigors, hypotension, headaches, seizures, lethargy, weight loss, and malaise. At all dose levels, but more significantly at the highest doses, hematological toxicities were observed and grade 3 neurotoxicity (headache and confusion), and hypotension were noted. Two patients expired during the study, and this was felt to be related to septic episodes. Because of these severe toxicities, 160g/m2 was defined as the MTD. At 160g/m2 peak serum levels occurred within 5–20 minutes of initiation and were not detectable 1 hour later. No anti-tumor responses were observed. No measurable plasma levels of TNF were observed with the administration of doses of 80g/m2. This dose level could be further studied in phase II studies alone and in combination with other agents, utilizing a continuous infusion schedule. 相似文献
6.
Schwartz GH Jones CB Garrison M Patnaik A Takimoto C McCreery H Skinner M Tolcher AW Rowinsky EK 《Investigational new drugs》2004,22(4):437-448
PURPOSE: To assess the feasibility of administering ZD9331, a thymidylate synthase (TS) inhibitor that does not undergo polyglutamation and has broad antitumor activity, in combination with docetaxel in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of the regimen and recommend appropriate doses for phase II studies, characterize the pharmacokinetics of the agents, evaluate the possibility of major drug-drug interactions, and seek preliminary evidence of anti-cancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of docetaxel as a 60-minute intravenous (IV) infusion followed 30 minutes later by ZD9331 as a 30-minute IV infusion every 3 weeks. At least three patients were treated at each dose level, and the maximum tolerated dose level was defined as the highest dose level that was not associated with an unacceptably high incidence of severe toxicity. The pharmacokinetics of both ZD9331 and docetaxel were also characterized. RESULTS: Nineteen patients were treated with 71 cycles of ZD9331 and docetaxel (ZD9331/docetaxel) at dose levels that encompassed dosing iterations of ZD9331 ranging from 65 to 260 mg/m(2) and docetaxel doses in the range of 50 to 75 mg/m(2). Neutropenia was the principal toxicity of the ZD9331/docetaxel regimen. Since five of six patients treated at the ZD9331/docetaxel dose-level of 260/60 mg/m(2) had grade 4 neutropenia that was brief and uncomplicated in the first course, a rigorous exploration of higher dose levels was not undertaken. Nonhematologic toxicities, consisting of malaise, diarrhea, rash, nausea, and vomiting, were also observed, but these effects were rarely severe. No major antitumor responses were observed. The pharmacokinetics of both ZD9331 and docetaxel were similar to those reported in previous studies of each agent administered alone, suggesting the lack of major drug-drug interactions. CONCLUSION: The combination regimen, consisting of ZD9331 and docetaxel, is feasible and well tolerated at single-agent doses that are clinically-relevant. This ZD9331/docetaxel regimen does not appear to be associated with either major pharmacokinetic or toxicologic drug-drug interactions. A ZD9331/docetaxel dose level of 260/60 mg/m(2) is recommended as an initial dose level in disease-directed studies of the regimen, with further dose escalation of docetaxel to 75 mg/m(2) if the initial treatment is well tolerated. Further studies with this regimen are warranted in tumor types that have demonstrated sensitivity to both agents. 相似文献
7.
Karl Bélanger Jacques Jolivet Jean Maroun David Stewart Antonio Grillo-Lopez Lloyd Whitfield Nancy Wainman Elizabeth Eisenhauer 《Investigational new drugs》1993,11(4):301-308
Summary DUP-937 is a new anthrapyrazole intercalator that inhibits DNA synthesis. A phase I trial was conducted in which DUP-937 was given in an intravenous bolus weekly for 3 weeks. Cycles were repeated every 5 weeks. Twenty men and 13 women with median ECOG performance status of 1 completed 74 cycles. The starting dose was 0.55 mg/m2/week and doses were escalated to 16 mg/m2/week. Non-hematological toxicity was generally mild or moderate and consisted mainly of gastro-intestinal effects, fatigue, alopecia and local-reactions. Grade 3 neutropenia was first documented at 7.36 mg/m2 and became more common at higher dose levels. Three of four patients had grade 3 neutropenia at the 16 mg/m2 dose level. Thrombocytopenia was minimal. The dose-limiting toxicity was neutropenia and the maximum tolerated dose was 16 mg/m2 weekly for 3 weeks. Mean area under the curve (AUC) values increased with dose. Linear pharmacokinetics were observed as total body clearance (CLtb), half-life (t1/2) and volume of distribution (Vss) did not change with increasing doses. One partial remission in a patient with prostate carcinoma was documented. 相似文献
8.
Tassilo Schilling Heiner H. Fiebig Sandor Kerpel-Fronius B. Winterhalter Philipp Variol Patricia Tresca Bernhard Heinrich Axel-R Hanauske 《Investigational new drugs》1996,14(4):371-378
Summary We have performed a high-dose clinical and pharmacokinetic trial with vinorelbine administered as a bolus injection every 21 days. The aim was to evaluate a schedule with longer treatment intervals than one week and to determine the toxicity pattern of such a schedule. A total of 13 patients (pts) with solid tumors (non-small-cell lung [3 pts], unknown primary [3 pts], mesothelioma [2 pts], colon/rectum, sarcoma, thyroid, head/neck and cervix [1 pt each]) were entered [9 male, 4 female, median age: 56 years (range: 37–69)]. Dose levels were 35, 40 and 45 mg/m2 with a total of 26 cycles administered. At 40 mg/m2, 2/6 pts developed grade 4 granulocytopenia. 1/1 pt at 45 mg/m2 developed a grade 4 leuko- and granulocytopenia. Non-hematological toxicities were mild to moderate. Neurologic toxicity except for constipation was mild. Constipation occurred at 35 mg/m2 in 1/6 pts WHO grade 4, at 40 mg/m2 in 2/6 pts WHO grade 3 and at 45 mg/m2 in 1/1 pt WHO grade 4 and was due to neurotoxicity. No objective antitumor response was observed. Vinorelbine pharmacokinetics were analysed in whole blood and plasma and were similar to previously published studies using 30 mg/m2. Our results confirm a high affinity of vinorelbine to corpuscular blood elements. We conclude that the MTD of vinorelbine administered once every 21 days as bolus injection is 40 mg/m2, the dose-limiting toxicities are constipation and granulocytopenia and the recommended dose for subsequent Phase II trials is 35 mg/m2. 相似文献
9.
Susan D. Huan Sewa S. Legha Martin N. Raber Irwin H. Krakoff 《Investigational new drugs》1991,9(2):199-206
Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, was shown to be more active than its analogue, Methotrexate, against murine and human tumor cell lines in vitro and in vivo. We conducted two sequential phase I studies using a single bolus injection of TMTX every 14 days (Schedule A) and a weekly × 3 schedule every 4–6 weeks (Schedule B). Twenty-seven patients were treated on Schedule A with a TMTX dose range of 5 mg/m2 to 450 mg/m2 and 23 patients were treated on Schedule B with a TMTX dose range of 50 mg/m2 to 200 mg/m2. The dose limiting toxicity was myelosuppression on both schedules. The development of hematological toxicity was highly variable at different dose levels and within the same patient at a particular dose level. The nadir of blood counts was reached by Day 8 to 10 on the single dose schedule with recovery by Day 14. On Schedule B, the nadir granulocyte count occurred on Day 14 while platelet count was generally lowest by Day 20; the blood counts usually recovered 7 to 10 days after the last dose. Other common side-effects includes skin toxicity and stomatitis which were worse on the weekly schedule. Less common toxicities included mild nausea and vomiting, diarrhea, and transient deterioration in renal and hepatic functions. The occurrence of toxicity was not related to the extent of prior treatment, liver metastases, or accumulation of third space fluids. Based on our results, we recommend a starting TMTX dose for Phase II studies of 200 mg/m2 every 2 weeks or 100 mg/m2 to 125 mg/m2 on the weekly schedule. 相似文献
10.
I. Raßmann H. Schrödel T. Schilling M. Zucchetti A. Kaeser-Fröhlich J. Rastetter A. -R. Hanauske 《Investigational new drugs》1996,14(4):379-386
Summary We have conducted a clinical and pharmacokinetic trial of the novel podophyllotoxin derivative NK611 administered orally for 21 consecutive days. The treatment was repeated every 35 days. Eighteen patients were included into the study, all of whom were eligible. Due to early progression of tumor disease in two patients, 16 patients were évaluable for toxicity [7 female, 9 male, median age 64 years (range: 44 to 73)]. Dose escalation steps were 5 mg/day [105 mg per cycle (pc)], 10 mg/day (210 mg pc), 12.5 mg/day (265 mg pc) and 15 mg/day (315 mg pc). A total of 37 courses was administered. Toxicity was evaluated using NCI-CTC criteria. Granulocytopenia was the main hematologic toxicity. Other hematologic toxicities were sporadic. Non-hematologic toxicities were mild and consisted of grade 1 nausea and grade 2 alopecia. Pharmacokinetic analyses were performed in six patients each treated with 10 mg/day and 12.5 mg per day, and in one patient treated with 15 mg/day. Using a two-compartment model, t1/2 ranged from 0.47 to 1.54 h and t1/2 from 2.0–11.6 h. Mean values for C
max
and AUC were 1.47 ± 0.331 g/ml and 13.67±3.81 g/ml·h. No objective tumor responses were observed. However, one patient with metastatic breast cancer had stable disease for twelve months. We conclude that the Maximum Tolerated Dose of NK611 administered daily for 21 consecutive days is 12.5 mg/day. The Dose-Limiting Toxicity is granulocytopenia. The recommended dose for further clinical Phase II studies is 10 mg/day. 相似文献
11.
Summary Background. Flavopiridol is a cyclin dependent kinase inhibitor. Preclinical models suggest a sequence dependent synergy between flavopiridol
and taxanes. The primary objective of this study was to determine the maximum tolerated dose (MTD) of flavopiridol and docetaxel
and the influence of flavopiridol on the pharmacokinetics of docetaxel. Methods: The major eligibility criteria included: a diagnosis of non-hematologic cancer with no conventional effective therapy, normal
organ function, and ECOG performance status of 0-2. Patients were treated with docetaxel followed 24 h later by flavopiridol
given via continuous intravenous infusion over a 24-h period. The starting doses of docetaxel and flavopiridol were 60 and
60 mg/m2, respectively. Cycles were repeated every 21 days. All patients received diarrhea prophylaxis consisting of bismuth subsalicylate.
Results: Ten patients (M:F 4:6; median age 56 years) were treated. The median number of cycles per patient was 2 (range 1–6). Two
of the three patients on dose level 1 developed dose-limiting toxicities consisting of neutropenia and fever. Seven patients
were subsequently enrolled on dose level −1 (docetaxel 60 mg/m2, flavopiridol 50 mg/m2). One episode of grade 3 diarrhea was reported at dose level −1. Conclusions: Neutropenia complicated by infection was the major dose-limiting toxicity. The recommended doses of flavopiridol and docetaxel
for phase II trials are 50 and 60 mg/m2 every three weeks, respectively. 相似文献
12.
Luc Dirix Gilles Catimel René Verdonk Ernst De Bruijn Brigitte Tranchand Claude Ardiet Allan Van Oosterom 《Investigational new drugs》1995,13(2):133-136
Summary KW-2149 is a new mitomycin C (MMC) analog, forming DNA-DNA and DNA-protein crosslinking 20-fold more effectively than MMC. Because of its equal or superiorin vitro andin vivo activity compared to MMC, a phase I study was initiated with an intravenous bolus injection every three weeks. This study was interrupted after dose escalation from 5 mg/m2 to 100 mg/m2 because of subacute and dose dependent pulmonary toxicity. Because of the lack of other end-organ toxicity, the moderate hematological toxicity and the observed antitumor effect, a second phase I study was initiated with a 24 hour continuous infusion. The starting dose was 50 mg/m2 and further escalation depended on observed pulmonary toxicity. Four patients were entered into this study and they received in total 17 courses. Toxicity was again mainly restricted to the lungs with one patient suffering grade 2 dyspnoe and another one grade 1 dyspnoe. Three patients had a substantial change in the carbon monoxide (CO) diffusion capacity. Pharmacokinetic data from these patients showed very low plasma levels both for KW-2149, as for both known metabolites M-16 and M-18.This study demonstrates that pulmonary toxicity continues to occur with KW-2149, in spite of the assurance of low plasma levels of both the parent compound and the known metabolites.The interesting activity of this compound has stimulated further in-depth research towards mechanisms of pulmonary toxicity and means of preventing them. 相似文献
13.
Susanne Danhauser-Riedl Edith Hausmann Hans-D. Schick Rita Bender Hermann Dietzfelbinger Johann Rastetter Axel-R. Hanauske 《Investigational new drugs》1993,11(2-3):187-195
Coupling of anthracyclines to high-molecular-weight carriers may alter drug disposition and improve antitumor effects. We have performed a clinical phase I trial of doxorubicin coupled to dextran (70000 m.w.). The drug was administered as single dose i.v. every 21–28 days. Thirteen patients have received a total of 24 courses (median 2; range 1–3). At the starting dose of 40 mg/m2 doxorubicin equivalent (DOXeq), WHO grade IV thrombocytopenia was noted in 2/2 patients. WHO grade IV hepatotoxicity and WHO grade III cardiotoxicity were noted in a patient with preexisting heart disease. Five patients were treated with 12.5 mg/m2 DOXeq. Maximal toxicity at this dose level was WHO grade III thrombocytopenia and local phlebitis (WHO grade II) in 1/5 patients, elevation of alkaline phosphatase (WHO grade III) and WHO grade III vomiting in another patient. Subsequently, five patients received 20 mg/m2 DOXeq. Hepatotoxicity was noted in 5/5 patients (1 × WHO grade IV, 1 × WHO grade III). Thrombocytopenia was noted in 3/5 patients (1 × WHO grade IV, 2 × WHO grade III). At 12.5 mg/m2 DOXeq, a patient diagnosed with a malignant fibrous histiocytoma had stable disease for 4 months. Pharmacokinetic analyses of total and free doxorubicin were performed in plasma and urine. The maximum peak plasma concentration (ppc) for total DOX was 12.3 g/ml at 40 mg/m2 DOXeq. The area under the plasma concentration time curve (AUC) ranged from 28.83–80.21 g/ml*h with dose-dependent elimination half lives (t1/2: 0.02–0.87 h;1/2: 2.69–11.58 h;1/2: 41.44–136.58 h). We conclude that the maximal tolerated dose (MTD) of AD-70 using this schedule is 40 mg/m2 DOXeq. The recommended dose for clinical phase II studies is 12.5 mg/m2 DOXeq.Abbreviations ALT
Alanine Aminotransferase
- AST
Aspartate Aminotransferase
- DOX
Doxorubicin
- DOXeq
Doxorubicin Equivalent
- ECG
Electrocardiogram
- HPLC
High Pressure Liquid Chromatography
- LD10
Lethal Dose for 10% of individuals
- MTD
Maximal Tolerated Dose
- ppc
Peak Plasma Concentration
- WHO
World Health Organisation 相似文献
14.
Ian R. Judson Philip J. Beale José M. Trigo Wynne Aherne Thomas Crompton David Jones Ernie Bush Bruno Reigner 《Investigational new drugs》1999,17(1):49-56
An excretion balance and pharmacokinetic study was conducted in cancer patients with solid tumors who received a single oral dose of capecitabine of 2000 mg including 50 Ci of 14C-radiolabelled capecitabine. Blood, urine and fecal samples were collected until radioactive counts had fallen to below 50 dpm/mL in urine, and levels of intact drug and its metabolites were measured in plasma and urine by LC/MS-MS (mass spectrometry) and 19F-NMR (nuclear magnetic resonance) respectively. Based on the results of the 6 eligible patients enrolled, the dose was almost completely recovered in the urine (mean 95.5%, range 86–104% based on radioactivity measurements) over a period of 7 days after drug administration. Of this, 84% (range 71–95) was recovered in the first 12 hours. Over this time period, 2.64% (0.69–7.0) was collected in the feces. Over a collection period of 24–48h, a total of 84.2% (range 80–95) was recovered in the urine as the sum of the parent drug and measured metabolites (5-DFCR, 5-DFUR, 5-FU, FUH2, FUPA, FBAL). Based on the radioactivity measurements of drug-related material, absorption is rapid (tmax 0.25–1.5 hours) followed by a rapid biphasic decline. The parent drug is rapidly converted to 5-FU, which is present in low levels due to the rapid metabolism to FBAL, which has the longest half-life. There is a good correlation between the levels of radioactivity in the plasma and the levels of intact drug and the metabolites, suggesting that these represent the most abundant metabolites of capecitabine. The absorption of capecitabine is rapid and almost complete. The excretion of the intact drug and its metabolites is rapid and almost exclusively in the urine. 相似文献
15.
Eric K. Rowinsky William A. Flood Susan E. Sartorius Kathy M. Bowling David S. Ettinger 《Investigational new drugs》1997,15(2):129-138
This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted. 相似文献
16.
Eric K. Rowinsky Louise B. Grochow Alexander Hantel David S. Ettinger Barbara L. Vito Ross C. Donehower 《Investigational new drugs》1989,7(4):317-325
Summary This phase I study was conducted to reevaluate the dose-limiting toxicities, maximum tolerated (MTD) and recommended phase II doses of oral NMF administered on a three times weekly schedule for 4 out of every 6 weeks. This schedule was based on the observation that prolonged administration of NMF was associated with the most efficacious antitumor activity in preclinical studies. Phase II trials that employed a starting dose of 800 mg/m2, determined in a previous phase I trial, were suspended because of frequent and severe toxicities. In the current study, a symptom complex characterized by nausea, vomiting, and malaise was the dose-limiting toxicity of oral NMF administered on this schedule. Other toxicities included hepatic enzyme elevations, mild myelosuppression, and worsening of preexistent toxic peripheral neuropathies. Of interest, three patients who were asymptomatic prior to treatment, rapidly developed symptoms of increased intracranial pressure after starting NMF; and, computerized tomographic brain scans revealed metastatic tumors with significant peritumoral edema. NMF was well tolerated at 600 mg/m2, however, an abrupt increase in toxicity resulted when the dose was increased to 700 mg/m2. Although NMF peak plasma concentrations (Cmax) and areas under the plasma disappearance curves (AUC) differed between the 600 and 700 mg/m2 dose levels, these differences were not striking, and similar NMF plasma concentrations and exposures were well tolerated during intravenous trials. Based on this study, the recommended phase II dose for oral NMF administered three times weekly for 4 of 6 weeks was 600 mg/m2. Cmaxs and AUCs at this dose were significantly lower than those that were demonstrated to induce cytotoxicity, and differentiating, chemosensitizing, and radiosensitizing effects in preclinical studies suggesting that further clinical evaluations of NMF may not be warranted. 相似文献
17.
A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients 总被引:6,自引:0,他引:6
Flaig TW Gustafson DL Su LJ Zirrolli JA Crighton F Harrison GS Pierson AS Agarwal R Glodé LM 《Investigational new drugs》2007,25(2):139-146
Summary Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer. Silybin-phytosome is a commercially available formulation containing silibinin.
This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose. Silybin-phytosome
was administered orally to prostate cancer patients, giving 2.5–20 g daily, in three divided doses. Each course was 4 weeks
in duration. Thirteen patients received a total of 91 courses of silybin-phytosome. Baseline patient characteristics included:
median age of 70 years, median baseline prostate specific antigen (PSA) of 4.3 ng/ml, and a median ECOG performance status
of 0. The most prominent adverse event was hyperbilirubinemia, with grade 1–2 bilirubin elevations in 9 of the 13 patients.
The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was
noted. No objective PSA responses were observed. We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses,
appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose. Asymptomatic
liver toxicity is the most commonly seen adverse event. 相似文献
18.
Summary A Phase I study of caracemide evaluating a short intravenous infusion repeated every 21 days is presented. Patients were entered at 85 mg/m2 with subsequent escalation levels of 170, 425, 595, and 795 mg/m2. Mild to moderate nausea and vomiting occurred at all dose levels. An apparent allergic reaction was observed at the 425 mg/m2 level. A burning pain originating in the mucosal areas of the head and neck, progressing to the chest and abdomen, was noted at the 425 mg/m2 level. Because of this observation, the infusion time was extended to 4 h. At the 795 mg/m2, this toxicity precluded completion of the 4 h infusion. Pharmacokinetic evaluation disclosed blood levels of 0.74–2.31 g/ml at the 425 mg/m2 during the 0.5 h infusion. At the same dose for a 4 h infusion time, blood levels were 0.15–0.18 g/ml. At 595 mg/m2 administered as a 4 h infusion, blood levels increased to 0.33 ± 0.14 g/ml. The drug was cleared rapidly from the blood compartment with a half-life of 2.5 min and a total body clearance of 11.5 1/min/m2. No partial or complete response was observed. However, an advanced colon carcinoma patient experienced subjective pain relief with a decrease in carcinoembryonic antigen. The dose-limiting toxicity of caracemide using the 4 h infusion was an intolerable burning pain with a maximum tolerated dose of 795 mg/m2. Further characterization of this dose-limiting toxicity is required prior to further clinical evaluation of caracemide. 相似文献
19.
David J. Stewart Professor of Medicine & Pharmacology Shailendra Verma Jean A. Maroun Lucille Robillard Daniele J. Perrault Vincent Young Sunil Gupta Betty Fontaine 《Investigational new drugs》1990,8(3):275-281
Summary Twenty-one adult patients with refractory solid tumors were treated on a phase I study of idarubicin (4-demethoxydaunorubicin) administered daily for 3 days every 3 weeks. Nineteen of the patients had received previous chemotherapy (including 13 with prior anthracyclines), and 12 had received prior radiotherapy. Idarubicin dose levels of 10, 15, 17.5, 20, and 25 mg/m2 were explored. Hematological toxicity was dose-related. Other toxicity was acceptable. Only one patient (treated with an idarubicin dose of 17.5 mg/m2/day) developed neutropenic fever, from which he recovered. Further dose escalations beyond 25 mg/m2 were not carried out because of the increasing length of time required for recovery from granulocytopenia at higher doses. No patient experienced a major response, but minor responses were seen in 3 patients with carcinomas of the colon, breast, and kidney respectively. Further phase II studies of oral idarubicin at a starting dose of 20–25 mg/m2 daily times 3 days in patients with good bone marrow reserves are recommended. Because of the degree of neutropenia expected, patients would have to be observed carefully.The Ontario Cancer Treatment and Research Foundation Ottawa Regional Cancer Centre, The Ottawa University Faculty of Health Sciences and Adria Laboratories Ltd.Presented in part at the 79th Annual Meeting of the American Association for Cancer Research, New Orleans, Louisianna, May 25–28, 1988 (1) 相似文献
20.
Patrick J. Creaven Raymond Perez Lakshmi Pendyala Neal J. Meropol Gregory Loewen Ellis Levine Elmer Berghorn Derek Raghavan 《Investigational new drugs》1997,15(3):227-234
The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase.These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1h i.v. infusion every 12h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search.Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t2 of 0.12h.We conclude that great caution is warranted in administering DENSPM on this schedule at doses of 83 mg/m2/day. 相似文献