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1.
Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. 总被引:7,自引:0,他引:7
David B Agus Michael S Gordon Charles Taylor Ronald B Natale Beth Karlan David S Mendelson Michael F Press David E Allison Mark X Sliwkowski Gracie Lieberman Stephen M Kelsey Gwen Fyfe 《Journal of clinical oncology》2005,23(11):2534-2543
PURPOSE: Pertuzumab, a recombinant humanized monoclonal antibody (2C4), binds to extracellular domain II of the HER-2 receptor and blocks its ability to dimerize with other HER receptors. Pertuzumab represents a new class of targeted therapeutics known as HER dimerization inhibitors. A clinical study was conducted to investigate safety and pharmacokinetics of pertuzumab and to perform a preliminary assessment of HER dimerization inhibition as a treatment strategy. PATIENTS AND METHODS: Patients with incurable, locally advanced, recurrent or metastatic solid tumors that had progressed during or after standard therapy were recruited to a dose-escalation study of pertuzumab (0.5 to 15 mg/kg) given intravenously every 3 weeks. Results: Twenty-one patients received pertuzumab and 19 completed at least two cycles. Pertuzumab was well tolerated. Overall, 365 adverse events were reported and 122 considered to be possibly drug related. Of these, 116 were of grade 1 to 2 intensity. The pharmacokinetics of pertuzumab were similar to other humanized immunoglobulin G antibodies, supporting a 3-week dosing regimen. Trough plasma concentrations were in excess of target concentrations at doses greater than 5 mg/kg. Two patients, one with ovarian cancer (5.0 mg/kg) and one with pancreatic islet cell carcinoma (15.0 mg/kg), achieved a partial response. Responses were documented by Response Evaluation Criteria in Solid Tumors after 1.5 and 6 months of pertuzumab therapy, and lasted for 11 and 10 months, respectively. Stable disease lasting for more than 2.5 months (range, 2.6 to 5.5 months) was observed in six patients. CONCLUSION: These results demonstrate that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active, suggesting that inhibition of dimerization may be an effective anticancer strategy. 相似文献
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Canney PA Machin MA Curto J 《European journal of cancer (Oxford, England : 1990)》2006,42(16):2751-2756
BackgroundThis was a feasibility study of the combination of Exemestane and the cyclooxygenase-2 (COX-2) inhibitor Celecoxib in advanced breast cancer.Patients and methodsPost-menopausal women with histologically proven, hormone receptor positive, advanced breast cancer who had progressive disease, normal blood counts, liver and renal function were eligible. Exemestane was given at a dose of 25 mg daily and Celecoxib at a dose of 400 mg bd. Responses were assessed according to RECIST criteria and toxicity was accessed according to CTC. The primary end-point was the percentage of patients who had neither discontinued therapy nor progressed at 6 months (‘treatment successes’).ResultsFifty-three eligible patients were enrolled. Of 30 patients with target lesions, 4 (13%) had a complete response (CR), 12 (40%) a partial response (PR) and 5 (17%) stable disease (SD). The best response in 18 of the 23 patients with no target lesions at baseline was stable disease. The clinical benefit (CR, PR + SD) for the whole group was therefore 39/53 (74%). The ‘treatment success’ rate was 60%. There were two non-malignant deaths which may have been associated with treatment.ConclusionThe combination of Exemestane and Celecoxib shows promising activity and tolerability and these results support the use of this combination in phase III clinical trials of short duration treatments. 相似文献
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Toby A. Eyre MD Graham P. Collins PhD Avinash Gupta MD Nicholas Coupe MD Semira Sheikh PhD John Whittaker Lai Mun Wang MD Leticia Campo Elizabeth Soilleux PhD Finn Tysoe Richard Cousins Nick La Thangue PhD Lisa K. Folkes PhD Michael R. L. Stratford PhD David Kerr PhD Mark R. Middleton PhD 《Cancer》2019,125(1):99-108
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BackgroundNotch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009.MethodsDose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity.ResultsThirty-five patients received LY900009 at dose levels ranging from 2–60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1–4 h post-dose. LY900009 inhibited plasma levels of amyloid-β peptide in a dose-dependent manner with 80–90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway.ConclusionsThe recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans. 相似文献
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Amita Patnaik S Gail Eckhardt Elzbieta Izbicka Anthony A Tolcher Lisa A Hammond Chris H Takimoto Garry Schwartz Heather McCreery Andrew Goetz Masataka Mori Kazutoyo Terada Lou Gentner Mary-Ellen Rybak Henry Richards Steven Zhang Eric K Rowinsky 《Clinical cancer research》2003,9(13):4761-4771
PURPOSE: To assess the feasibility of administering tipifarnib, an oral nonpeptidomimetic competitive inhibitor of farnesyltransferase, in combination with gemcitabine and recommend doses for disease-directed clinical trials. The study also sought to identify drug-drug pharmacokinetic interactions, evaluate effects on protein farnesylation, and seek preliminary evidence for clinical activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with tipifarnib at doses of 100, 200, and 300 mg twice daily continuously and 1000 mg/m(2) gemcitabine i.v. on days 1, 8, and 15 every 4 weeks. To identify pharmacokinetic interactions, the treatment and plasma sampling schemes were designed to permit comparisons of the pharmacokinetic behavior of each agent administered alone and together. The proportions of unfarnesylated and farnesylated HDJ2, a chaperone protein that undergoes farnesylation, were measured in peripheral blood mononuclear cells. RESULTS: Nineteen evaluable patients were treated with 74 courses of tipifarnib/gemcitabine (mg/mg/m(2)). Myelosuppression was the principal toxicity. Dose-limiting myelosuppression occurred in 2 of 5 patients at the 300/1000 dose level, whereas 2 of 11 evaluable patients at the 200/1000 dose level experienced dose-limiting toxicity. There was no evidence of clinically relevant pharmacokinetic interactions between tipifarnib and gemcitabine. Inhibition of farnesylation of HDJ2, a potential surrogate for Ras and/or other potentially relevant farnesylated proteins, was demonstrated in peripheral blood mononuclear cells at all dose levels. Partial responses were noted in patients with advanced pancreatic and nasopharyngeal carcinomas. CONCLUSIONS: On the basis of the results of this study, the tipifarnib/gemcitabine dose level of 200/1000 is recommended for disease-directed studies. At this dose level, biologically relevant plasma concentrations of tipifarnib that consistently inhibit protein farnesylation in vitro are achieved and drug-induced inhibition of protein farnesylation is measured in most patients. 相似文献
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Trumper M Ross PJ Cunningham D Norman AR Hawkins R Seymour M Harper P Iveson T Nicolson M Hickish T 《European journal of cancer (Oxford, England : 1990)》2006,42(7):827-834
The aim of this study was to determine the benefits of chemotherapy for oesophago-gastric cancer (OGC) in patients 70 years and above (> or =70) in comparison to younger patients. 1080 patients were enrolled into three randomised controlled trials assessing fluorouracil-based combination chemotherapy. Patients received either a platinum-containing regimen (ECF, MCF), PVI 5-FU (protracted venous infusion of 5-fluorouracil)+/-mitomycin C (MMC), or FAMTX. Of the 1080 patients randomised, 257 (23.8%) were aged > or =70 years. There were no significant differences in the incidence of grades 3/4 toxicity between the two cohorts. Objective and symptomatic response rates, failure-free and overall survival were not significantly different. In a multivariate analysis, independent prognostic factors for survival were performance status and locally advanced disease, not age. Patients > or =70 years with OGC obtained similar benefits from palliative chemotherapy with respect to symptomatic response, tumour regression and survival, without increased toxicities. 相似文献
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Roger B. Cohen Steinar Aamdal Marta Nyakas Maria Cavallin Darron Green Maria Learoyd Ian Smith Razelle Kurzrock 《European journal of cancer (Oxford, England : 1990)》2013,49(7):1521-1529
ObjectiveThis is the first clinical study of the MEK1/2 inhibitor AZD8330 (ARRY-424704). This phase I study defined the maximum tolerated dose (MTD) and assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8330 in patients with advanced malignancies.MethodsPatients with refractory cancer or cancer with no standard therapy received either once-daily (OD) or twice-daily (BID) oral AZD8330 on day 1 followed by a 7-day washout period and continuous dosing from day 8. The starting dose was 0.5 mg with dose escalations in subsequent cohorts until a non-tolerated dose was reached.ResultsEighty-two patients received AZD8330 across 11 cohorts. The most frequent AZD8330-related adverse events were acneiform dermatitis (13/82, 16%), fatigue (11/82, 13%), diarrhoea (11/82, 13%) and vomiting (9/82, 11%). Four patients experienced dose-limiting toxicities: mental status changes (40 mg OD; 2/9 patients and 60 mg OD; 1/3) and rash (20 mg BID; 1/9). The MTD was defined as 20 mg BID. AZD8330 exposure increased approximately proportionally with dose across the dose range 0.5–60 mg OD. Dose-dependent modulation of phosphorylated ERK in peripheral blood mononuclear cells (PBMCs) was observed at doses ?3 mg. One patient had a partial response and thirty-two (39%) had stable disease, with a duration >3 months in 22 patients, assessed by Response Evaluation Criteria in Solid Tumors.ConclusionAZD8330 has a manageable toxicity profile at the MTD of 20 mg BID, and target inhibition was confirmed in PBMCs. One patient with malignant melanoma had a partial response. 相似文献
11.
Bisagni G.; Cocconi G.; Scaglione F.; Fraschini F.; Pfister Ch.; Trunet P. F. 《Annals of oncology》1996,7(1):99-102
PURPOSE: To evaluate the endocrine effects as well as the pharmacokineticparameters, efficacy and safety of letrozole, a new fourth-generationnon-steroidal aromatase in hibitor. Patients and methods: Fourteen postrnenopausal women with progressivemetastatic breast cancer, previously treated with endocrinetherapy and/or chemotherapy for advanced disease, were treatedwith 0.5 mg daily doses of letrozole, orally. Endocrine andpharmacokinetic measurements were made before treatment andon days 14, 28, 56, and 84 of therapy. RESULTS: Letrozole induced a >86% decrease in plasma estrone and a=67% reduction in circulating estradiol from day 14 on. Therewas a statistically significant decrease in plasma cortisol,which appeared clinically irrelevant since all values remainedwithin the normal range. No significant changes in aldosteroneconcentration were noted. One patient achieved a complete response(CR) and 4 patients a partial response (PR), with an objectiveresponse rate of 36% (95% CI 13% to 6 5%). Median duration ofresponse was 24 months, ranging from 4 to 44 months. No toxiceffects attributable to letrozole were noted in any patient. CONCLUSION: Letrozole appears to be a very promising new antiaromatase drug.The characteristics of the patients more likely to respond,taking into account prior systemic treatment, should be definedby future studies. Further phase II and phase III studies comparingletrozole to other available second or even first-line endocrine-therapyagents, are war ranted. aromatase inhibitors, breast carconoma, endocrine therapy, letrozole 相似文献
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Christopher M. Stephenson Robert D. Levin Thomas Spector Christopher G. Lis 《Cancer chemotherapy and pharmacology》2013,72(1):139-146
Purpose
This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy.Methods
Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m2 in the first cohort. For subsequent cohorts, dose was increased by 20 g/m2 until a maximum tolerated dose was found.Results
Ascorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m2, respectively). C max and AUC values increased proportionately with dose between 0 and 70 g/m2, but appeared to reach maximal values at 70 g/m2 (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m2 maintained levels at or above 10–20 mM for 5–6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response.Conclusions
Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient’s blood and was well tolerated. The recommended dose for future studies is 70–80 g/m2. 相似文献13.
A. H. Honkoop P. J. van Diest J. S. de Jong S. C. Linn G. Giaccone K. Hoekman J. Wagstaff H. M. Pinedo 《British journal of cancer》1998,77(4):621-626
Forty-two patients with clinical stage IIIA or IIIB breast cancer were treated with neoadjuvant chemotherapy followed by mastectomy and radiotherapy. The median follow-up was 32 months (range 10-72 months) and the median time to progression was 17 months (range 10-30 months). A multivariate analysis showed that a longer disease-free survival (DFS) was related to more chemotherapy cycles given (P = 0.003), a better pathological response to chemotherapy (P = 0.04) and fewer positive axillary lymph nodes (P = 0.05). A better overall survival (OS) was related to more chemotherapy cycles given (P = 0.03) and better pathological response to chemotherapy (P = 0.04). In patients with residual tumour after neoadjuvant chemotherapy, high levels of staining for Ki-67 was correlated with a worse DFS (P = 0.008). Other biological characteristics, including oestrogen receptor status, microvessel density (CD31 staining), P-glycoprotein (P-gp) staining and nuclear accumulation of p53, were not independent prognostic factors for either DFS or OS. If both P-gp and p53 were expressed, DFS and OS were worse in the uni- and multivariate analysis. The preliminary results of this phase II study suggest that coexpression of P-gp/p53 and a high level of staining for Ki-67 after chemotherapy are associated with a worse prognosis, and that prolonged neoadjuvant chemotherapy and the attainment of a pathological complete remission are important factors in determining outcome for patients with this disease. 相似文献
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Infante JR Kurzrock R Spratlin J Burris HA Eckhardt SG Li J Wu K Skolnik JM Hylander-Gans L Osmukhina A Huszar D Herbst RS 《Cancer chemotherapy and pharmacology》2012,69(1):165-172
Purpose
Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5.Methods
This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated.Results
In part A, 29 patients received at least one dose of AZD4877 (5?mg, n?=?4; 7.5?mg, n?=?4; 10?mg, n?=?3; 15?mg, n?=?3; 20?mg, n?=?3; 30?mg, n?=?6; 36?mg, n?=?3; 45?mg, n?=?3). The MTD was defined as 30?mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30?mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25?mg, was evaluated in part B (n?=?14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure.Conclusion
The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30?mg. At the selected 25?mg dose, AZD4877 had an acceptable safety profile. 相似文献15.
A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors. 总被引:4,自引:0,他引:4
Michele Basche Daniel L Gustafson Scott N Holden Cindy L O'Bryant Lia Gore Samir Witta Mary Kay Schultz Mark Morrow Adrah Levin Brian R Creese Michael Kangas Kaye Roberts Thu Nguyen Kat Davis Russell S Addison Jane C Moore S Gail Eckhardt 《Clinical cancer research》2006,12(18):5471-5480
PURPOSE: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. EXPERIMENTAL DESIGN: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). RESULTS: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months. CONCLUSION: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials. 相似文献
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Desar IM Timmer-Bonte JN Burger DM van der Graaf WT van Herpen CM 《British journal of cancer》2010,103(11):1637-1643
Background:
The combination of sorafenib (vascular endothelial growth factor receptor 2 inhibitor) and sirolimus (mammalian target of rapamycin inhibitor) might work synergistically.Methods:
A phase I dose-escalation study with sorafenib twice a day (b.i.d.) and sirolimus once daily (q.d.) was performed to determine the recommended dose of the combination in patients with solid tumours. Secondary objectives were to determine the safety profile and maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK) of the combination.Results:
Dose-limiting toxicities were transaminitis and cutaneous toxicity. The most frequently reported adverse events were elevated transaminases, hypophosphatemia, fatigue, anorexia, diarrhoea, nausea, rash and palmar–plantar erythrodysaesthesia. Sirolimus did not change the PK of sorafenib; in contrast, sorafenib reduced the AUC(0−96) and Cmax of sirolimus. No objective responses were observed; eight patients showed stable disease for a median of 16.3 weeks (range 8–24). The MTD of the combination was sorafenib 200 mg b.i.d. with sirolimus 1 mg q.d.Conclusion:
The combination of sorafenib and sirolimus showed enhanced toxicity, which could not be explained by the PK of both drugs. The relative low doses at the MTD, in combination with the PK results, do not warrant further development of this combination. 相似文献17.
J L Mansi A de Graeff D R Newell J Glaholm D Button M O Leach G Payne I E Smith 《British journal of cancer》1991,64(3):593-597
Lonidamine is a substituted indazole carboxylic acid with a unique mechanism of action and early clinical studies have reported anti-tumour activity. In a phase II study 32 patients with previously treated advanced breast cancer were given Lonidamine in a daily divided oral dose of 600 mg. Of 28 patients evaluable for response, three (11%) achieved a partial response (4-24+ months) and three (11%) a minor response. Two patients have stable disease (greater than 3 months) and 20 progressed. Toxicity was very mild. Sixteen (53%) of 31 patients had myalgia which lasted a median of 2 weeks. This was investigated with nuclear magnetic resonance spectroscopy in four patients but the changes were unrelated to the degree of myalgia. No other major side-effect was seen, and no dose reduction was required. Lonidamine pharmacokinetics have been investigated in 17 patients 1 month after the start of therapy. Lonidamine was detected in the plasma of all patients, but there was no clear relationship between Lonidamine levels and clinical response or toxicity. Lonidamine appears to be active against advanced breast cancer and its low toxicity would allow combination studies with chemotherapy. 相似文献
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Berardi R Saladino T Mari D Silva RR Scartozzi M Verdecchia L Onofri A Cascinu S 《Tumori》2005,91(6):463-466
AIMS AND BACKGROUND: Colorectal cancer is the most common gastrointestinal tumor in Western countries and is increasing in elderly patients. In recent years, new treatments based on the use of 5-fluorouracil associated with oxaliplatin or CPT-11 have shown promising activity. The aim of the present study was to analyze the tolerability and activity of chemotherapy with 5-fluorouracil plus oxaliplatin or CPT-11 in elderly patients with advanced colorectal cancer. METHODS: Patients aged 70 years or older with advanced colorectal cancer were treated with 5-fluorouracil (400 mg/m2 in bolus and 600 mg/m2 in a 22-hr continuous infusion on days 1-2) plus folinic acid (100 mg/m2) associated to oxaliplatin (85 mg/m2 on day 1, FOLFOX regimen) or CPT-11 (180 mg/m2 on day 1, FOLFIRI regimen), every 14 days. RESULTS: Twenty-nine patients with a median age of 76 years (range, 70-82) were treated with FOLFOX or FOLFIRI as first-line chemotherapy for metastatic disease. We observed a partial response in 8/29 (27.6%), stable disease in 11/29 (37.9%) and progressive disease in 10/29 (34.5%). Median survival was 21 months; 1-year survival probability was 89.8%. Grade III leukopenia was observed in 2/29 (7%) patients and grade III diarrhea in 1/29 patients. No other grade III-IV toxicity was observed. CONCLUSIONS: FOLFOX and FOLFIRI appear to be active and well tolerated regimens for elderly patients with advanced colorectal cancer. 相似文献
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O'Connor R O'Leary M Ballot J Collins CD Kinsella P Mager DE Arnold RD O'Driscoll L Larkin A Kennedy S Fennelly D Clynes M Crown J 《Cancer chemotherapy and pharmacology》2007,59(1):79-87
Purpose: Multi-drug resistance mediated by ATP-binding cassette trans-membrane protein pumps is an important cause of cancer treatment failure. Sulindac has been shown to be a competitive substrate for the clinically important resistance protein, multi-drug resistance protein-1 (MRP-1), and thus might enhance the anti-cancer activity of substrate chemotherapeutic agents, e.g. anthracyclines. Methods: We conducted a dose-escalating, single arm, prospective, open label, non-randomised phase I trial of epirubicin (75 mg/m2) in combination with escalating oral doses of sulindac (0–800 mg) in patients with advanced cancer to identify an appropriate dose of sulindac to use in future resistance studies. Anthracycline and sulindac pharmacokinetics were studied in cycles 1 and 3. Results: Seventeen patients (8 breast, 3 lung, 2 bowel, 1 melanoma, 1 renal, 1 ovarian and 1 of unknown primary origin, 16/17 having had prior chemotherapy) were enrolled. Eight patients received a full six cycles of treatment; 14 patients received three or more cycles. Dose-limiting toxicity was observed in two patients at 800 mg sulindac (1 renal impairment, 1 fatal haemoptysis in a patient with advanced lung cancer), and sulindac 600 mg was deemed to be the maximum tolerated dose. Sulindac had no effect on epirubicin pharmacokinetics. Among 15 patients with evaluable tumour, two partial responses were seen (malignant melanoma and breast cancer). Four others had prolonged stable disease. Conclusion: Epirubicin 75 mg/m2 and sulindac 600 mg are the recommended doses for phase II studies for these agents in combination.R. O’Connor, M. O’Leary, M. Clynes and J. Crown contributed equally to the study 相似文献
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PURPOSE: The study investigated the therapeutic effects of fadrozole (CGS 16949A), a new aromatase inhibitor, in women who had received prior treatment for metastatic breast cancer. MATERIALS AND METHODS: Eighty postmenopausal women who had received prior treatment for metastatic breast cancer were randomized to receive fadrozole 1 mg/d or 4 mg/d per day orally. Seventy-eight patients were assessable for toxicity and response. RESULTS: Toxicity was limited to mild (grade 1) to moderate (grade 2) hot flashes in 28%, nausea and vomiting in 13%, fatigue in 8%, and mild loss of appetite in 5% of patients. No electrolyte or unanticipated hormonal changes occurred. The overall response was 23% (complete response, 10%; partial response, 13%). In addition, 45% of the patients had a no change status. There was no difference in response rate between the patients randomized to the two different doses of fadrozole. Only dominant site of metastases significantly affected response. The median time to treatment failure (TTF) was 4.4 months (4.7 months on 1 mg/d and 3.7 months on 4 mg/d). The median survival was 22.6 months (17.5 months on 1 mg/d; median survival has not been reached in patients on 4 mg/d). The response and survival in patients with estrogen receptor (ER)-positive and ER-unknown disease were not significantly different. CONCLUSIONS: Fadrozole has good therapeutic effect as a second-line treatment in postmenopausal women with metastatic breast cancer. In this study there was no significant difference in toxicity or response between 1 mg/d and 4 mg/d. Further trials comparing fadrozole to other hormone treatment are indicated. 相似文献