Purpose : To define the maximum-tolerated dose and dose-limiting toxicities (DLTs) of an oral formulation of ZD9331, a novel thymidylate synthase inhibitor that is not a substrate for folylpolyglutamate synthase.Patients and Methods: Patients had Cancer and Leukemia Group B performance status less than or equal to 2 and refractory solid tumors. Initially, patients received ZD9331 daily for 2 weeks, with the duration of treatment escalated to a maximum of 4 weeks, followed by a 2-week rest period. Once the maximum-tolerated duration of treatment was determined, the dose of ZD9331 was increased until DLT occurred.Results: Fifty-five patients were enrolled at eight dose levels. The DLTs were thrombocytopenia and neutropenia. At 3 mg/d, two of 19 patients developed DLT, one patient had grade 3 thrombocytopenia and grade 4 neutropenia, and the other patient had grade 3 thrombocytopenia only. Anemia was common, with a median hemoglobin nadir of 75% of baseline, before recovery or transfusion. The apparent oral clearance of ZD9931 was 11.6 +/- 6.3 mL/min. Dose-limiting myelosuppression was associated with both an increased 24-hour ZD9931 concentration and blood urea nitrogen.Conclusion: The recommended phase 11 dose on this schedule is 3 mg/d for 4 weeks, followed by a 2-week rest period. ZD9331 seems to have a manageable toxicity profile, although it should be used with caution in patients with renal impairment. (C) 2003 by American Society of Clinical Oncology.

Conversion of a 150 million transistor microprocessor from a 0.18 /spl mu/m bulk process to a 0.13 /spl mu/m SOI process is described. Shorter channels and SOI characteristics cause leakage that must be managed. System requirements drive duplication of signal characteristics and integrity for all I/O. Adaptation of the Si to a 200 /spl mu/m bump structure that is 50 /spl mu/m smaller than the previous generation is shown.

PURPOSE:The goals of this phase I study were to determine the maximum-tolerated doses of capecitabine and gemcitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT) and safety profile of this combination.PATIENTS AND METHODS:Eligible patients had advanced solid tumors that had failed to respond to standard therapy or for which no standard therapy was available, measurable or assessable disease, Karnofsky performance status > or = 70%, and acceptable organ function. Capecitabine was administered twice daily by mouth each day for 21 consecutive days followed by a 1-week break. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break.RESULTS:Forty patients were enrolled onto the study, and 33 are fully assessable for toxicity. The most common toxicities during the first cycle of chemotherapy were neutropenia and mucositis. Only one patient treated at gemcitabine and capecitabine doses of 800 and 2000 mg/m(2), respectively, met protocol-specified DLT criteria; however, at these doses 65% of successive cycles required dose reduction or delay for toxicity. No episodes of DLT were observed at gemcitabine and capecitabine doses of 1,000 and 1,660 mg/m(2), respectively, and 70% of cycles of therapy were delivered without dose reduction or delay. Therefore, these doses are recommended for further study. Tumor responses were observed in patients with metastatic colorectal and pancreatic cancer.CONCLUSION:Gemcitabine and capecitabine can be combined with acceptable toxicity at nearly full doses. Antitumor activity of the combination merits further investigation in phase II studies.

PURPOSE:O6-benzylguanine (BG) provides a means to effectively inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) and increase the chemotherapeutic effectiveness of chloroethylating and methylating agents in preclinical and clinical studies. Two different doses of BG have been reported as the optimal biochemical modulatory dose for patients (i.e., 100 and 120 mg/m2). The objective of our study was to compare these doses by measuring AGT in surgically removed specimens after treatment with BG. EXPERIMENTAL DESIGN:BG was administered to patients as an i.v. infusion 16 +/- 4 h before surgical resection of their systemic tumor. AGT activity was measured in the tumor using a methylated DNA substrate. The target end point was defined as > or =11 of 13 patients with undetectable tumor AGT levels (<10 fmol/mg protein). RESULTS:Of the 28 patients enrolled, 25 of whom were analyzed for AGT activity, the most common primary sites of cancer included the colon (n = 11), bladder (n = 3), rectum (n = 4), and stomach (n = 3). Positive (DaOY cells) and negative (Chinese hamster ovary cells) control cell lines were included in each assay. Seven of the 12 patients treated with 100 mg/m2 BG had AGT activity of >10 fmol/mg protein (15-147 fmol/mg protein). Only 2 of the 13 patients treated with 120 mg/m2 BG had AGT activity of >10 fmol/mg protein (11 and 12 fmol/mg protein). CONCLUSIONS:From our surgically removed tissue data, a dose of 120 mg/m2 BG is recommended to deplete systemic tumors of AGT activity.

BACKGROUND:The combination of doxorubicin, paclitaxel, and cisplatin has activity in gynecologic malignancies but requires colony stimulating factor (G-CSF) support. Moreover, there is concern about cardiotoxicity with doxorubicin/paclitaxel combinations. Pegylated liposomal doxorubicin may result in less myelosuppression and cardiac toxicity than free doxorubicin. The purpose of this study was to determine the maximal tolerated dose of pegylated liposomal doxorubicin with fixed doses of paclitaxel and cisplatin without using G-CSF support in advanced solid malignancies.PATIENTS AND METHODS:Twenty-three patients were enrolled; none of the patients had received prior doxorubicin. Patients received paclitaxel (90 mg/m2 for dose level one, escalating to 135 mg/m2 for all subsequent dose levels), with a fixed dose of cisplatin (60 mg/m2), followed by escalating doses of pegylated liposomal doxorubicin every 21 days.RESULTS:A total of 73 cycles was administered. Grade 4 neutropenia was seen after cycle one in two of eight patients receiving 30 mg/m2 of pegylated liposomal doxorubicin and three of seven patients receiving 40 mg/m2 of pegylated liposomal doxorubicin when combined with 135 mg/m2 of paclitaxel and 60 mg/m2 of cisplatin. Two additional patients at the 40 mg/m2 dose level developed grade 4 neutropenia following cycles 2 and 5. The mean decline in left ventricular ejection fraction (LVEF) after 2 cycles was 5 percentage points (P = 0.012).CONCLUSION:The combination of pegylated liposomal doxorubicin, paclitaxel and cisplatin is feasible without G-CSF support.

PURPOSE: To conduct a phase I study of ZD9331, a potent, nonpolyglutamatable thymidylate synthase inhibitor using a short daily infusion for 5 consecutive days every 21 days. PATIENTS AND METHODS: Patients with refractory cancer or cancer for which no standard therapy was available were treated in escalating doses using an accelerated titration design. Plasma and urine samples were collected at timed intervals in the first cycle for pharmacokinetic analysis. RESULTS: Seventy-four patients were enrolled at 12 dose levels from a starting dose of 0.4 mg/m2/d to 16 mg/m2/d and 25 mg/d fixed dosing, of which 67 were assessable for toxicity. Maximum-tolerated dose was reached at 16 mg/m2/d. Myelosuppression was dose-limiting, consisting of thrombocytopenia associated with neutropenic fever. Body-surface area did not correlate with drug clearance; therefore, fixed daily dosing of 25 mg/d was studied and found to be tolerable, with two of 12 dose-limiting events. Dose-limiting nonhematologic toxicity consisted of grade 3 erythematous maculopapular rash observed in one patient at 12 mg/m2/d and one patient at 25 mg/d. Pharmacokinetic analysis showed nonlinearity, with clearance increasing with dose. The mean clearance and terminal half-life of the drug were 6.6 ± 2.0 mL/min and 71.3 ± 27.0 hours, respectively. Area-under-the concentration-time curve was a better predictor of toxicity than dose, using multiple linear regression analyses. Minor response (40% shrinkage of tumor) was observed in one patient with colorectal cancer treated at 12 mg/m2/d. CONCLUSION: The recommended dose for ZD9331 on this schedule is 25 mg/d. Neutropenia, thrombocytopenia, and rash were dose-limiting, and efficacy studies in colorectal cancer are indicated.

BACKGROUND. The purpose of this study was to determine the maximum tolerated dose and toxicity profile of gemcitabine given on a weekly schedule with continuous infusion 5-fluorouracil. PATIENTS ANDMETHODS. Eligible patients with advanced solid tumors received escalating doses of gemcitabine 200 and 300 mg/m(2) weekly as a 30-minute infusion on Days 1, 8, and 15 every 4 weeks (schedule 1) or 450, 600, 800, 1000, 1250, 1500, 1800, and 2200 mg/m(2) on Days 1 and 8 (schedule 2) every 3 weeks, respectively. At the completion of gemcitabine infusion (Day 1), patients received fixed dose continuous infusion of 5-fluorouracil at either 300 mg/m2 (Days 1-21) or 200 mg/m(2) (Days 1-21; schedule 1) every 4 weeks or 200 mg/m2 (Days 1-14; schedule 2] every 3 weeks, respectively. Toxicity assessments were performed weekly on study, and efficacy measurements were performed every 6-8 weeks.RESULTS. Seventy patients with advanced solid malignancies received a total of 220 cycles of combination chemotherapy. Eleven (14.3%) patients received no more than 1 treatment cycle of combination therapy. Schedule I maximum tolerated dose of gemcitabine was 600 mg/m(2)/week when combined with 5-fluorouracil (5-FU) at 200 mg/m(2)/day (Days 1-21) repeated every 4 weeks. The schedule 2 maximum tolerated dose of gemcitabine was 2200 mg/m(2)/week when combined with 5-FU dosed at 200 mg/m(2)/day (Days 1-14) repeated every 3 weeks. In schedule 1, the limiting factor for gemcitabine delivery was the Day 15 dose that often was omitted because of myelosuppression and/or mucositis. In schedule I cycle 1, nonhematologic toxicity was common and included Grade 3-4 toxicities: mucositis (8 patients), fatigue (2 patients), and anorexia (I patient). One patient had Grade 3-4 neutropenia at dose level 5 (maximum tolerated dose). In schedule 2 cycle 1, hematologic toxicities were more common than nonhematologic toxicity and included Grade 3 anemia (3 patients), Grade 3 neutropenia (4 patients), and Grade 3 thrombocytopenia (2 patients). The nonhematologic toxicities included Grade 3 mucositis (3 patients), Grade 3 fatigue (2 patients), and Grade 3 dehydration (I patient). Overall, antitumor activity was observed in seven patients. Three of 30 patients with cytokine refractory renal cell carcinoma (RCC; relative risk [RR] 10 %; 95% confidence interval [CI], 0.82-22%) had a partial response. Of the remaining 27 patients with RCC, 4 patients had a minor response, and 10 patients had stable disease lasting a median of 6.4 (range, 4-12) months. The remaining 5 responses occurred in 40 patients (RR, 12.5%; 95% CI, 4.2-26.8%): 2 patients with 5-FU refractory colon carcinoma, I patient with hepatoma, I patient with paclitaxel-cisplatin-resistant ovarian carcinoma, and I patient with cisplatin- resistant head and neck squamous cell carcinoma had a partial response.CONCLUSIONS. For Phase II development, gemcitabine 450-600 mg/m(2) on Days 1, 8, and 15 can be safely combined with 5-FU 200 mg/m2 given as a continuous infusion (Days 1-21) of a 28-day cycle or gemcitabine 1800 mg/m(2) Days I and 8 given with 5-FU 200 mg/m(2) as a continuous infusion (Days 1-14) of a 21-day cycle. The observed antitumor activity in several solid tumors, especially in renal cell carcinoma, warrants broad Phase II evaluation. (C) 2001 American Cancer Society.

O6-benzylguanine (BG) is a potent inactivator of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) that enhances sensitivity to nitrosoureas in tumor cell lines and tumor-bearing animals. The major objectives of this study were to define the optimal modulatory dose and associated toxicities of benzylguanine administered alone and in combination with carmustine; to define the maximally tolerated dose and associated toxicities of carmustine administered with benzylguanine and to describe the pharmacokinetics of BG in humans and its effects on AGT depletion and recovery in peripheral blood mononuclear cells. Patients with histologically confirmed advanced solid tumors or lymphoma that had failed to respond to standard therapy or for which no standard therapy was available were eligible to participate in this study. Patients initially received BG as a 1-h i.v. infusion without carmustine. After a 14-day washout (ie., without therapy) period, patients received BG as a 1-h i.v. infusion followed, 1 h later, by a 15-min i.v. infusion of carmustine. Cycles of chemotherapy were repeated every 6 weeks. Cohorts of patients received BG doses ranging from 10 to 120 mg/m2 and carmustine doses ranging from 13 to 50 mg/m2. Plasma and urine samples were collected and analyzed for BG, and O6-benzyl-8-oxoguanine concentrations and AGT activity was determined in peripheral blood mononuclear cells. There was no toxicity attributable to BG alone at any dose tested. Bone marrow suppression was the primary and dose-limiting toxicity of BG combined with carmustine and was cumulative in some patients. The neutrophil nadir occurred at a median of day 27, with complete recovery in most patients by day 43. Nonhematological toxicity included fatigue, anorexia, increased bilirubin, and transaminase elevation. Recommended doses for Phase II testing are 120 mg/m2 BG given with carmustine at 40 mg/m2. BG rapidly disappeared from plasma and was converted to a major metabolite, O6-benzyl-8-oxoguanine, which has a 2.4-fold higher maximal concentration and 20-fold higher area under the concentration versus time curve than BG. AGT activity in peripheral blood mononuclear cells was rapidly and completely suppressed at all of the BG doses. The rate of AGT regeneration was more rapid for patients treated with the lowest dose of BG but was similar for BG doses ranging from 20-120 mg/m2. In conclusion, coadministration of BG and carmustine is feasible in cancer patients, but the maximal dose of carmustine that can be safely administered with BG is approximately one-third of the standard clinical dose. Bone marrow suppression, which may be cumulative, is the dose-limiting toxicity of the combination. Prolonged AGT suppression is likely attributable primarily to the effect of O6-benzyl-8-oxoguanine.

BACKGROUND. Raltitrexed is a novel thymidylate synthase inhibitor with single agent activity in colorectal, nonsmall cell lung, and breast carcinomas. The recommended Phase II dose of raltitrexed administered as a single agent is 3 mg/m(2) every 3 weeks. Paclitaxel also has a broad spectrum of activity. A Phase I study of both agents in combination therapy was conducted.METHODS. Eligible patients had refractory solid tumors and a Cancer and Leukemia Group B performance status of 0 to 2. Cohorts of patients were treated with escalating doses of raltitrexed as a 15-minute intravenous infusion immediately followed by 175 mg/m(2) of paclitaxel administered over 3 hours. Dose-limiting toxicity was defined as World Health Organization Grade 4 neutropenia with fever, Grade 4 thrombocytopenia requiring platelet transfusion, a nonhematologic toxicity of Grade 3 or higher (excluding nausea, emesis, and alopecia), or failure of toxicities to recover to Grade 1 or lower within 21 days after causing a dose delay.RESULTS. A total of 33 patients enrolled in the study. Raltitrexed was escalated in increments of 0.5 mg/m(2), from 0.5 mg/m(2) to the recommended Phase II dose of 3 mg/m(2). Dose-limiting toxicity first was observed at a raltitrexed dose of 2 mg/m(2). At a dose of 3 mg/m(2), dose-limiting neutropenia was observed in 2 of 12 patients. Diarrhea was the other dose-limiting toxicity. Two patients achieved a partial response (one patient with. carcinoma of die head and neck and another with gallbladder carcinoma).CONCLUSIONS. The authors conclude that raltitrexed and paclitaxel may be administered in combination at their respective single agent Phase II doses. Phase II testing of this combination is indicated. (C) 1999 American Cancer Society.

This custom CPU derived from the StrongARM/sup TM/ 110 is capable of more than 2 billion 16 b operations per second (2 BOPs). Starting with the original design, an attached media processor (AMP) is integrated along with a synchronous DRAM memory controller and separate I/O bus. In addition, several enhancements are made to the CPU and cache subsystem and the chip is reduced from 0.35 /spl mu/m to 0.28 /spl mu/m technology. The chip includes 3.3M transistors and measures 60 mm/sup 2/. It dissipates less than 3 W at 300 MHz at 2.0 V internal, 3.3 V I/O. The chip supports dynamic clock frequency switching for reduced operating power during low performance demands. There are 333 separately conditioned clocks on the chip. For battery powered applications, Vdd is reduced to achieve <0.5 W operation at 150 MHz. The chip is pseudo-static and supports clock stop and IDDQ testing.

A RISC (reduced-instruction-set computer)-style microprocessor operating up to 200 MHz, implements a 64-b architecture that provides huge linear address space without bottlenecks that would impede highly concurrent implementations. Fully pipelined and capable of issuing two instructions per clock cycle, this implementation can execute up to 400 M operations per second. The chip includes an 8-kB I-cache, an 8-kB D-cache, and two associated translation buffers, a four-entry 32-B/entry write buffer, a pipelined 64-b integer execution unit with 32-entry register file, and a pipelined floating-point unit with an additional 32 registers. The pin interface includes integral support for an external secondary cache. The package is a 431-pin PGA with 140 pins dedicated to VDD/VSS. The chip is fabricated in 0.75- mu m n-well CMOS with three layers of metallization. The die measures 16.8*13.9 mm/sup 2/ and contains 1.68 M transistors. Power dissipation is 30 W from a 3.3-V supply at 200 MHz.< >