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H A Burris

Publications and source records attributed to H A Burris.

At least 55 records · Page 3Linked to original sources
PubMed1998

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Adult↗
PubMed1998

A phase II study of docetaxel in patients with paclitaxel-resistant metastatic breast cancer.

PURPOSE: To evaluate the efficacy and safety of docetaxel in patients with paclitaxel-resistant metastatic breast cancer (MBC). PATIENTS AND METHODS: Docetaxel (100 mg/m2) was administered every 3 weeks to 46 patients registered at four centers. Patients had previously received < or = two chemotherapy regimens for MBC. All patients had progressive disease while receiving paclitaxel therapy. Treatment was repeated until there was evidence of disease progression or for a maximum of three cycles after best response. RESULTS: Objective responses were seen in eight of 44 assessable patients (18.1%; 95% confidence interval [CI], 6.7% to 29.5%). Seven patients had partial responses and one patient responded completely. Response rates were not significantly different by previously received paclitaxel dose or resistance. No responses were seen in 12 patients who had previously received paclitaxel by 24-hour infusion, but the response rate in 32 patients who had received paclitaxel by 1- to 3-hour infusion was 25%. The median response duration was 29 weeks and the median time to disease progression was 10 weeks. Median survival was 10.5 months. Clinically significant (severe) adverse events included neutropenic fever (24% of patients), asthenia (22%), infection (13%), stomatitis (9%), neurosensory changes (7%), myalgia (7%), and diarrhea (7%). CONCLUSION: Docetaxel is active in patients with paclitaxel-resistant breast cancer, particularly in those who failed to respond to brief infusions of paclitaxel. Response rates were comparable to or better than those seen with other therapies for patients with paclitaxel-resistant MBC. This confirms preclinical studies, which indicated only partial cross-resistance between paclitaxel and docetaxel.

Adult↗
PubMed1998

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

PURPOSE: To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS: Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS: Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION: 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Adult↗
PubMed1998

Phase I trial of docetaxel administered by weekly infusion in patients with advanced refractory cancer.

PURPOSE: Docetaxel is a highly active antineoplastic agent; however, grade IV leukopenia occurs in the large majority of patients treated with a dose of 100 mg/m2 every 3 weeks. Recent experience with weekly paclitaxel has demonstrated a bone marrow-sparing effect when a weekly administration schedule is used. We investigated a weekly schedule of docetaxel in an attempt to alter the toxicity profile and improve the therapeutic index. PATIENTS AND METHODS: Thirty-eight patients with advanced, refractory malignancy entered this phase I trial between October 1996 and June 1997. Docetaxel was administered weekly for 6 consecutive weeks, followed by 2 weeks without treatment. Sequential cohorts of patients were treated at the following dose levels: 20, 25, 30, 36, 43, and 52 mg/m2. Patients were reevaluated after one course (8 weeks); patients with objective response or stable disease continued treatment for a maximum of four courses or until disease progression. RESULTS: Thirty-five patients completed at least one course of therapy. Myelosuppression was not a dose-limiting toxicity (DLT) at any of the doses tested. Only five episodes of grade III leukopenia occurred (14% of patients, 2% of doses), and no grade IV leukopenia was produced. No grade III or IV thrombocytopenia or anemia was observed. Grade III fatigue and asthenia were observed in all three patients treated at 52 mg/m2/wk and in two of 10 at 43 mg/m2/wk. Other grade III toxicity included acral erythema (n = 1), neuropathy (n = 1), peripheral edema (n = 1), and diarrhea (n = 1). The DLTs of this docetaxel schedule are fatigue and asthenia. Although the maximum-tolerated dose by definition of this study was 43 mg/m2/wk, we selected 36 mg/m2/wk for ongoing phase II studies. CONCLUSION: The toxicity profile of docetaxel is markedly altered when the drug is administered by a weekly schedule. Myelosuppression is mild and uncommon. Fatigue and asthenia are the DLTs; other nonhematologic toxicities, which included peripheral edema and neuropathy, are uncommon, and the arthralgia/myalgia syndrome was not observed. Weekly administration of docetaxel may provide a better tolerated, efficacious use of this drug; further investigation of weekly docetaxel as a single agent and in combination regimens is warranted.

Adult↗
PubMed1998

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.

Adult↗
PubMed1998

A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide.

Because topoisomerase (topo) I- and topo II-targeting agents exert their principal effects on the two major classes of enzymes involved in regulating DNA topology in the cell, there has been considerable interest in evaluating combinations of these classes of agents. In preclinical studies of inhibitors of topo I and topo II in combination, drug scheduling and sequencing have been critical determinants of antitumor activity, with a greater magnitude of cytotoxicity generally occurring when treatment with the topo I inhibitor precedes treatment with the topo II-targeting agent. The underlying mechanism that has been proposed to explain this schedule dependency is compensatory up-regulation of topo II and, therefore, enhanced cytotoxicity of topo II inhibitors in cells treated initially with topo I inhibitors. The feasibility of sequentially administering the topo I inhibitor topotecan (TPT) followed by the topo II inhibitor etoposide to patients with advanced solid malignancies was evaluated in this Phase I and translational laboratory study. Fifty patients with solid neoplasms were treated with TPT doses ranging from 0.17 to 1.05 mg/m2/day as a 72-h continuous (i.v.) infusion on days 1-3 followed by etoposide, 75 or 100 mg/m2/day as a 2-h i.v. infusion daily on days 8-10. The combined rate of severe neutropenia and thrombocytopenia was unacceptably high above the TPT (mg/m2/day)/etoposide (mg/m2/day) dose levels of 0.68/100 and 0.68/75 in minimally and heavily pretreated patients, respectively, and these dose levels are recommended for further disease-directed evaluations of TPT/etoposide on this administration schedule. Successive biopsies of accessible tumors were obtained for quantitation of topo I and II levels prior to and immediately after treatment with TPT and prior to and immediately after treatment with etoposide in seven patients. The results of these limited studies in tumors did not fully support the proposed mechanistic rationale favoring the development of this particular sequential TPT/etoposide regimen, because only two of the six patients' tumors in whom topo I was successively measured had either modest or substantial decrements in topo I levels following treatment with TPT, and the principal effect of interest, up-regulation of topo II following treatment with TPT, was clearly documented in the tumors of only one of six subjects in whom successive measurements of topo I were performed. Even in view of the notable objective antitumor activity in three subjects, including a complete response in a patient with colorectal carcinoma and partial responses in one patient each with non-small cell lung and gastric carcinomas, the toxicity and ancillary laboratory results do not provide substantial evidence that sequential treatment with TPT and etoposide might be more advantageous than either TPT or etoposide administered as a single agent.

Adult↗
PubMed1997

Phase II trial of topotecan in advanced gastric cancer: a Southwest Oncology Group study.

Topotecan (NSC 609099) is a camptothecin analogue that demonstrated activity against a variety of human tumors in preclinical studies. A phase II trial was performed with topotecan given to patients with locally advanced or metastatic adenocarcinoma of the stomach. Topotecan was administered IV Bolus over 30 minutes on a daily X 5 schedule, every three weeks, with a starting dose of 1.5 mg/m2. Twenty patients were entered onto the study, all of whom were eligible. All patients were evaluable for toxicities. Half of these patients experienced at least one Grade 4 hematologic toxicity, comprised of either granulocytopenia or leukopenia (4 patients with both, 3 patients with grade 4 granulocytopenia, and 2 patients with only grade 4 leukopenia). Other non-life threatening (Grade 3) toxicities included nausea (2 patients), weakness (2 patients), weight loss (1 patient), blurred vision (1 patient), diarrhea (1 patient) and malaise/fatigue/lethargy (1 patient). Two patients achieved a partial response, for an overall response rate of 10% (95% confidence interval of 1.2 to 31.7%). The median survival for the 20 patients was five months.

Adenocarcinoma↗
PubMed1997

Phase I study of daily times five topotecan and single injection of cisplatin in patients with previously untreated non-small-cell lung carcinoma.

BACKGROUND: The objectives were to determine the dose-limiting toxicity of topotecan in combination with cisplatin, to describe the principal toxicities, and to define the maximally-tolerated doses of the drugs in previously untreated patients with advanced non-small-cell lung carcinoma. PATIENTS AND METHODS: The study was designed to evaluate escalated doses of topotecan (starting at 0.75 mg/m2/day) as a 30-minute infusion daily for five consecutive days with a fixed clinically-relevant dose of 75 mg/m2 cisplatin given on day 1, every three weeks. RESULTS: Fifteen chemotherapy-naive patients entered the study and 14 were evaluable for toxicity. All 11 patients treated at the first topotecan/cisplatin dose level of 0.75/75 mg/m2, experienced at least one episode of grade 4 neutropenia. For six patients, absolute neutrophil counts were below 500/ml for more than five days, and two of them developed a grade 4 thrombocytopenia. At the next higher topotecan/cisplatin dose level (1.0/75 mg/m2), grade 4 neutropenia lasting longer than five days occurred in all three evaluable patients, including one patient who expired due to a severe neutropenia associated with sepsis. Non-hematologic toxicities, predominantly nausea and vomiting, were mild to moderate in severity and manageable. Four patients had partial responses (30.7%; 95% confidence interval (9%-61%) of relatively short duration. CONCLUSION: Both severe neutropenia and thrombocytopenia precluded dose escalation of topotecan and cisplatin administered on this schedule. In previously untreated patients, the first topotecan/cisplatin dose level (0.75/75 mg/m2), was associated with intolerable myelosuppression, and, therefore, the dose levels evaluated in this study cannot be recommended for subsequent phase II investigations. The high toxicity of this schedule and the recent understanding of the pharmacokinetic interaction between those drugs may encourage the investigation of the alternate sequence of cisplatin after TPT in phase II studies.

Aged↗
PubMed1997

Phase I study with the DNA sequence-specific agent adozelesin.

Adozelesin, a synthetic analog of the antitumor antibiotic CC-1065, is a novel cytotoxic agent which inhibits DNA synthesis by binding to the minor groove of the DNA helix. Preclinical studies have shown a broad spectrum of activity against a variety of murine and human tumor xenograft models. We conducted a phase I study of adozelesin to (i) determine a recommended dose for phase II testing using a 10 min i.v. infusion, (ii) characterize the toxic effects of the drug using this schedule and (iii) document any antitumor activity observed. Adozelesin was administered as an i.v. infusion every 6 weeks. CBC and biological parameters were performed weekly. The starting dose of 10 microg/m2, corresponding to 1/30 the mouse equivalent lethal dose, was escalated, according to a modified Fibonacci scheme, until dose-limiting toxicity was encountered. Forty-seven adult patients with solid malignancies were entered in the study. Successive dose levels used were 10, 20, 33, 50, 70, 105, 120, 150 and 180 microg/m2. The main toxic effect was myelosuppression, which was dose limiting. The maximally tolerated dose was defined as 180 microg/m2. A minor response with a 4 month duration was reported in one previously treated patient with melanoma. We conclude that the recommended phase II dose of adozelesin given as a 10 min infusion is 150 microg/m2, repeated every 4 weeks.

Adult↗
PubMed1997

Phase I and pharmacologic study of oral topotecan administered twice daily for 21 days to adult patients with solid tumors.

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Recently bioavailability of an oral formulation of approximately 30% with limited variability was reported. We conducted a phase I and pharmacokinetic study of the oral formulation of topotecan to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: Patients were treated with oral topotecan given twice daily for 21 days, with cycles repeated every 28 days. In subsequent cohorts, the dose was escalated from 0.15 to 0.6 mg/m2 twice daily. Pharmacokinetics were performed on day 1 and 8 of the first course using a validated high-performance liquid chromatographic assay and noncompartmental pharmacokinetic methods. RESULTS: Thirty-one patients entered the study; one patient was not assessable for toxicity and response as therapy was prematurely interrupted on request of the patient who had not experienced toxicity. Thirty patients received a total of 59 courses. The dose-limiting toxicity (DLT) was reached at a dose of 0.6 mg/m2 twice daily and consisted of diarrhea, which started subacutely at a median onset on day 15 (range, 12 to 20) and resolved after a median of 8 days (range, 7 to 16). Other toxicities were mild, including leukocytopenia, thrombocytopenia, nausea, and vomiting. The MTD was 0.5 mg/m2 twice daily. No responses were observed. Pharmacokinetics showed a substantial variation of the area under the plasma concentration-time curve at time point "t" [AUC(t)] of topotecan and ring-opened product hydroxyacid. A significant correlation was observed between the percentage of decrease in WBC count versus the AUC(t) of topotecan (r = .75), which was modeled by a sigmoidal maximal effect concentration (Emax) function. CONCLUSION: The DLT in this phase I study for chronic oral topotecan for 21 days was diarrhea. The recommended dose for phase II studies is 0.5 mg/m2 twice daily.

Administration, Oral↗
PubMed1997

Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Adult↗
PubMed1997

Docetaxel in combination with fluorouracil for advanced solid tumors.

The results from preclinical studies using murine tumor models show that the combination of docetaxel (Taxotere) and fluorouracil (5-FU) is highly synergistic. Phase I studies in patients with advanced solid tumors indicate that 60 mg/m2 of docetaxel administered as a 1-hour intravenous infusion followed by a daily intravenous bolus of 300 mg/m2 of 5-FU on days 1 through 5 is the recommended dose for phase II studies. Preliminary results from another phase I study using a continuous infusion regimen for 5-FU suggest that 85 mg/m2 of docetaxel administered as a 1-hour intravenous infusion followed by continuous infusion of 750 mg/m2 per day of 5-FU on days 1 through 5 may be the recommended dose for phase II studies. As expected, dose-limiting toxicities included neutropenia and mucositis. Ongoing phase I/II and II studies are investigating the combination of docetaxel with continuous infusion of 5-FU in patients with metastatic breast cancer and with cisplatin (Platinol) and continuous infusion of 5-FU, with and without leucovorin, in patients with head and neck cancer. Preliminary results are encouraging and warrant further study.

Adult↗
PubMed1996

A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.

PURPOSE: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS: Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION: Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

Adenocarcinoma↗
PubMed1996

A phase I clinical and pharmacokinetic study of the angiogenesis inhibitor, tecogalan sodium.

BACKGROUND: Tecogalan sodium is an angiogenesis inhibitor isolated from a sulfated polysaccharide produced by the bacterium Arthrobacter. The antiangiogenic effect of tecogalan sodium is thought to be mediated by the inhibition of binding of basic fibroblast growth factor to cellular receptors. PATIENTS AND METHODS: A phase I study was conducted in thirty-three patients with refractory malignancies, including AIDS-associated Kaposi's sarcoma. Patients received a single i.v. infusion every three weeks with the infusion duration ranging from one to twenty-four hours. Seven different dosage levels were studied (125, 185, 240, 300, 390, 445, and 500 mg/m2). RESULTS: The primary dose-limiting toxicity was prolongation of the activated partial thromboplastin time with peak times being between 1.0-4.0 times the upper limit of normal. This toxicity was ameliorated at a given dose level by prolonging the infusion time. Other common toxicities included fever (40%) and rigors (31%) which were well controlled with acetominophen and meperidine. The serum half-life of tecogalan sodium was between 1-1.5 hours and < 25% of unchanged drug was excreted in the urine. CONCLUSIONS: The recommended phase II dose of tecogalan sodium on this schedule is 390 mg/m2 over 24 hours. Other schedules including continuous administration should be investigated to maximize the efficacy of this novel angiogenesis inhibitor.

Antineoplastic Agents↗
PubMed1996

Vinorelbine: a new antineoplastic drug for the treatment of non-small-cell lung cancer.

OBJECTIVE: To review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, and dosage and administration guidelines for vinorelbine in the treatment of non-small-cell lung cancer (NSCLC). DATA SOURCES: A MEDLINE search (1989-1995) using the terms vinorelbine and Navelbine was conducted. Additional unpublished data were provided by Glaxo Wellcome Drug Information. STUDY SELECTION AND DATA EXTRACTION: The articles chosen for inclusion all appeared in peer-reviewed journals. Pertinent abstracts, as judged by the authors, were also included. DATA SYNTHESIS: Vinorelbine is a new semisynthetic vinca alkaloid approved by the Food and Drug Administration for the first-line treatment of patients with advanced NSCLC. The drug demonstrated a broad spectrum of antitumor activity in preclinical studies and produced dose-limiting neutropenia in Phase I trials. In Phase II studies, an overall response rate of approximately 30% was reported with single-agent vinorelbine. Furthermore, in large, multicenter, randomized Phase III trials, treatment with vinorelbine alone and in combination with cisplatin resulted in improved survival compared with controls. The drug was well tolerated, with granulocytopenia being the most commonly reported adverse effect. However, the incidence of fever and hospitalization associated with this granulocytopenia was exceptionally low. The recommended dose is 30 mg/m2 weekly administered by intravenous injection or infusion. CONCLUSIONS: As no specific chemotherapy regimen has previously been regarded as standard therapy for advanced NSCLC, vinorelbine is a promising new treatment for this patient population. It has been shown in several randomized, controlled trials to increase survival without compromising quality of life.

Antineoplastic Agents, Phytogenic↗
PubMed1996

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Adenocarcinoma↗
PubMed1996

Optimal use of docetaxel (Taxotere): maximizing its potential.

The safety of docetaxel (Taxotere) has been evaluated in the safety overview population consisting of 1070 patients recruited to phase II trials. These patients received a total of 4989 cycles of therapy (median four cycles per patient). Since docetaxel is known to be metabolized in the liver, hepatic impairment was predicted to be a risk factor for increased toxicity and was studied prospectively, comparing the 42 patients in the overview population with moderate hepatic impairment with the 1028 patients with liver function within normal limits. Hepatic dysfunction was associated with an increase in the percentage of cycles of therapy during which febrile neutropenia occurred and the number of patients suffering documented infection and severe (grade 3/4) stomatitis. The incidence of toxic death was also increased in patients with moderate hepatic impairment. The severity of fluid retention, a cumulative toxicity of docetaxel, was found to be reduced, and its onset delayed, by prophylactic treatment with corticosteroids for 5 days, starting 1 day before docetaxel administration. Treatment with corticosteroids was also recommended to reduce the incidence and severity of hypersensitivity reactions and cutaneous toxicities. The most frequent severe non-haematological toxicity of docetaxel was asthenia. Other non-haematological toxicities were generally mild or moderate.

Antineoplastic Agents, Phytogenic↗