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1.
Smitha Subramanyan Martin D. Abeloff Stephen E. Bond Nancy E. Davidson John H. Fetting Gary B. Gordon M. John Kennedy 《Cancer chemotherapy and pharmacology》1999,43(6):497-502
Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination
with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic
disease. Patients treated at the first dose level received vinorelbine 20 mg/m2 on day 1, doxorubicin 40 mg/m2 on day 1, methotrexate 100 mg/m2 on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The
vinorelbine dose was escalated by 5 mg/m2 for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients
enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was
then escalated by 10 mg/m2 with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8)
were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m2, doxorubicin 40 mg/m2, and methotrexate 100 mg/m2 with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were
dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT
consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were
3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and
an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from
the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m2 can be safely administered with doxorubicin at 40 mg/m2 and methotrexate at 100 mg/m2 with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents
may not be more effective than the combination of vinorelbine and doxorubicin.
Received: 27 April 1998 / Accepted: 17 September 1998 相似文献
2.
Joel M. Reid John S. Kovach Michael J. O'Connell Pamela G. Bagniewski Charles G. Moertel 《Cancer chemotherapy and pharmacology》1998,41(6):477-484
Purpose: To determine the maximum tolerable dose (MTD) and activity of levamisole administered concurrently with 5-fluorouracil (5-FU)
in a standard 5-day course. To determine the pharmacokinetics of levamisole during the course of treatment. Patients and methods: Levamisole was administered to 38 patients orally three times a day for 5 days concurrently with a course of 5-FU administered
daily by rapid intravenous injection for 5 days. Toxicity was evaluated in 20 patients who received escalating doses of levamisole.
The activity of the combination was evaluated in 18 patients who received levamisole at the MTD with 5-FU. The pharmacokinetics
of levamisole were characterized in ten patients at the MTD level. Results: Intractable vomiting, confusion and vertigo were the major dose-limiting toxicities. The MTD of oral levamisole was 100 mg/m2 administered three times a day concurrently with 450 mg/m2 per day intravenous 5-FU for 5 consecutive days. Partial responses lasting 5 and 11 months were observed in 2/18 patients
with measurable disease at the MTD. Peak plasma concentrations of 1 μg/ml (range 0.6–1.3 μg/ml) were achieved 90 min (range
60–360 min) after an oral dose of 100 mg/m2 levamisole with a 3.5-fold accumulation noted following 4 days of administration. Peak plasma concentrations of p-hydroxylevamisole were about 5% of parent drug. Little parent drug (2–5%) was detected in urine. Conclusions: Levamisole may be administered safely with 5-FU at doses which are up to four to five times greater than those presently
given in conventional regimens. The recommended dose of levamisole combined with 5-FU for future research protocols is 75 mg/m2 t.i.d for 5 days.
Received: 31 December 1996 / Accepted: 11 September 1997 相似文献
3.
Lopez AM Ketchum M Nichols H Xu MJ Peng YM Dorr R Alberts DS 《Cancer chemotherapy and pharmacology》2000,46(5):411-415
The effect of the addition of G-CSF to carboplatin, ifosfamide and doxorubicin (CIA) at the maximally tolerated dose (MTD)
was studied in a phase I clinical trial. Nine patients with incurable solid tumors were treated: six endometrial and epithelial
ovarian cancers, one colon cancer with pelvic masses and two unknown primary cancers. The carboplatin dose was calculated
using the Calvert formula and administered in a standard 30-min intravenous infusion. The initial carboplatin dose was AUC
4.0 mg/ml per min. Fixed doses of ifosfamide (1.25 g/m2 per day), mesna (1.0 g/m2 per day, and doxorubicin (15 mg/m2 per day) were combined and given as a 4-day continuous intravenous infusion in an attempt to decrease nonhematologic toxicity.
The dose-limiting toxicity of CIA was myelosuppression, mainly neutropenia and thrombocytopenia. Nonhematologic toxicities
were hemorrhagic cystitis, weakness, fatigue, and nausea and vomiting. The MTD for CIA was established at the first dose level
of carboplatin (4.0 mg/ml per min). Following this, G-CSF was added to the regimen in an unsuccessful effort to escalate the
carboplatin dose. Free and total carboplatin pharmacokinetics were determined using flameless atomic absorption spectroscopy.
There was one complete response and one partial response among eight evaluable patients. Both responding patients had advanced
ovarian cancer. We conclude that carboplatin dose intensification beyond an AUC of 4.0 mg/ml per min is not made feasible
by the addition of G-CSF to infusional doxorubicin and ifosfamide in patients with advanced gynecologic cancer.
Received: 22 December 1999 / Accepted: 28 April 2000 相似文献
4.
Purpose: We conducted a phase I/II study in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC)
to: (1) determine the maximum tolerated dose (MTD) of cisplatin combined with a fixed schedule of ifosfamide and irinotecan
with rhG-CSF support; and (2) to determine the overall response rate and median survival of patients entered on this study.
Methods: Ifosfamide (1.5 g/m2) and irinotecan (60 mg/m2) were administered at fixed doses on days 1–4 and on days 1, 8 and 15, respectively. Cisplatin was given on day 1 at 60 mg/m2 and was increased in 10-mg/m2 increments. This regimen was repeated every 4 weeks. rhG-CSF (nartograstim) was administered subcutaneously at a dose of
1 μg/kg on days 5–18 except on the day of irinotecan treatment. Results: Between June 1995 and April 1998, 46 patients were registered onto this phase I/II study. The MTD of cisplatin was defined
according to toxicity and the dose during three courses was increased. Since at the 80 mg/m2 dose level more than one-third of the patients were treated with dose modification, the dose of 70 mg/m2 was recommended for phase II study. The dose-limiting toxicity was leukopenia. The overall response rate was 62.2% (95% CI
48.0–76.4%), the median response duration was 144 days, and the median survival time was 393 days. Conclusion: For phase II study, we recommend doses of cisplatin 70 mg/m2 on day 1 combined with ifosfamide and irinotecan with rhG-CSF support. Both the response rate and preliminary survival data
in this study suggest a high degree of activity of this combination in previously untreated NSCLC.
Received: 29 April 1999 / Accepted: 15 September 1999 相似文献
5.
Murren JR Peccerillo K DiStasio SA Li X Leffert JJ Pizzorno G Burtness BA McKeon A Cheng Y 《Cancer chemotherapy and pharmacology》2000,46(1):43-50
Purpose: Based on preclinical data demonstrating synergy between camptothecin analogues and taxanes, we determined the maximum tolerated
dose (MTD) of irinotecan that could be given in combination with a fixed dose of paclitaxel of 75 mg/m2, when both drugs were delivered on a weekly schedule. The pharmacokinetics of this combination were explored to determine
whether the sequence of administration affected the elimination of irinotecan. Methods: For the first cycle patients with advanced cancer were treated with irinotecan given as a 90-min infusion followed immediately
by paclitaxel given at a dose of 75 mg/m2 over 1 h. The sequence of drug administration was reversed in subsequent cycles for most patients. Chemotherapy was given
weekly for 4 weeks, followed by a 2-week rest. In selected patients, plasma concentrations of irinotecan were determined by
high-performance liquid chromatography during the first 24 h of cycle 1 and after the first dose of cycle 2 to determine whether
the order of drug administration affected the elimination of irinotecan, or the toxicologic effects of the chemotherapy. Results: A total of 53 cycles were delivered to 21 patients. Reversible neutropenia was dose-limiting. Suppression of the other blood
cell elements was modest. There was one partial response in a man with a previously treated cholangiocarcinoma that lasted
26 weeks. Prolonged stabilization of disease (6 months or more) was observed in five of the patients (24%). At the recommended
dose of irinotecan (50 mg/m2), transfusions of red cells and platelets were not required. The sequence of drug administration produced no significant
differences in the pharmacokinetic parameters of irinotecan or SN-38, which were similar to the values reported when irinotecan
is administered alone. The most prominent nonhematologic toxicities were mild diarrhea and fatigue. Conclusions: The recommended dose of irinotecan on this schedule is 50 mg/m2. The sequence of drug administration affects neither the elimination of irinotecan nor the chemotherapy-related toxicity.
This combination is well tolerated and causes minimal clinical side effects.
Received: 5 July 1999 / Accepted: 3 February 2000 相似文献
6.
Aamdal S Lund B Koier I Houten M Wanders J Verweij J 《Cancer chemotherapy and pharmacology》2000,45(1):85-88
Purpose: EO9 is a new synthetic bioreductive alkylating indoloquinone, with preferential activity against solid tumors and higher
antitumor activity under anaereobic conditions compared with aerobic conditions. In preclinical models EO9 demonstrated no
major organ toxicity. The aim of the present phase I study was to determine the toxicities and the maximal tolerated dose
(MTD) of EO9 administered as a 5-min i.v. infusion weekly to patients with solid cancers. Methods: Twenty-eight patients entered the study. The dose was escalated from 2.7 mg/m2 according to a Fibonacci-like schedule. Results and conclusion: The dose-limiting toxicity was proteinuria. No other major toxicities were detected and in particular there was no significant
increase in serum creatinine. This was in contrast to findings in a previous phase I trial using EO9 in a 3-weekly schedule,
where a number of patients experienced severely decreased kidney function. The MTD in the present study was 15.0 mg/m2 weekly and the recommended dose for phase II studies was 12.0 mg/m2 weekly. Compared with 3-weekly EO9, the dose intensity could be increased from 22 mg/m2 to 36 mg/m2 with the weekly administration. Phase II studies have been performed by the EORTC Early Clinical Study Group in advanced
breast, gastric, colorectal, pancreatic, and non-small-cell lung cancer.
Received: 5 July 1999 / Accepted: 20 July 1999 相似文献
7.
David A. Rinaldi John G. Kuhn Howard A. Burris F. Andrew Dorr Gladys Rodriguez S. Gail Eckhardt Suzanne Jones James R. Woodworth Sharyn Baker Connie Langley David Mascorro Trent Abrahams Daniel D. Von Hoff 《Cancer chemotherapy and pharmacology》1999,44(5):372-380
Purpose: To determine toxicities, maximally tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of MTA,
a novel antifolate compound which inhibits the enzymes thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase
(GARFT), and dihydrofolate reductase (DHFR). Methods: Patients with advanced solid tumors were given MTA intravenously over 10 min every 21 days. Dose escalation was based on
the modified continual reassessment method (MCRM), with one patient treated at each minimally toxic dose level. Pharmacokinetic
studies were performed in all patients. Results: A total of 37 patients (27 males, 10 females, median age 59 years, median performance status 90%) were treated with 132
courses at nine dose levels, ranging from 50 to 700 mg/m2. The MTD of MTA was 600 mg/m2, with neutropenia and thrombocytopenia, and cumulative fatigue as the dose-limiting toxicities. Hematologic toxicity correlated
with renal function and mild reversible renal dysfunction was observed in multiple patients. Other nonhematologic toxicities
observed included mild to moderate fatigue, anorexia, nausea, diarrhea, mucositis, rash, and reversible hepatic transaminase
elevations. Three patients expired due to drug-related complications. Pharmacokinetic analysis during the first course of
treatment at the 600 mg/m2 dose level demonstrated a mean harmonic half-life, maximum plasma concentration (Cpmax), clearance (CL), area under the curve
(AUC), and apparent volume of distribution at steady state (Vdss) of 3.08 h, 137 μg/ml, 40.0 ml/min per m2, 266 μg · h/ml, and 7.0 l/m2, respectively. An average of 78% of the compound was excreted unchanged in the urine. Partial responses were achieved in
two patients with advanced pancreatic cancer and in two patients with advanced colorectal cancer. Minor responses were obtained
in six patients with advanced colorectal cancer. Conclusions: The MTD and dose for phase II clinical trials of MTA when administered intravenously over 10 min every 21 days was 600 mg/m2. MTA is a promising new anticancer agent.
Received: 20 October 1998 / Accepted: 30 March 1999 相似文献
8.
Patrick J. Creaven Lakshmi Pendyala Neal J. Meropol Neil J. Clendeninn Ellen Y. Wu Gregory M. Loewen April Proefrock Amanda Johnston Mary Dixon 《Cancer chemotherapy and pharmacology》1997,41(2):167-170
Purpose: To establish the maximum tolerated dose (MTD), dose-limiting and other major toxicities and the major pharmacokinetic parameters
of a 10-day infusion of the nonclassical antifolate ThymitaqTM. Methods: The drug was given by 10-day infusion via a portable pump. The starting dose was 286 mg/m2 per day with escalation to 572 and 716 mg/m2 per day. Thymitaq in plasma was assayed by a validated isocratic reverse-phase HPLC assay with detection at 273 nm. Results: The dose of 716 mg/m2 per day × 10 was considered too high as none of three patients completed a 10-day infusion and two of three developed grade
IV myelotoxicity. At 572 mg/m2 per day three of four patients completed a 10-day infusion. Dose-limiting myelosuppression was seen in one of four but owing
to a high incidence of thrombotic phenomena, no further patients were added. Conclusion: Continuous 10-day infusions of Thymitaq should be limited to low doses until further studies can be done.
Received: 4 March 1997 / Accepted: 14 July 1997 相似文献
9.
Kathleen A. Havlin Michael J. Ramirez Christine M. Legler Lydsay N. Harris Ursula A. Matulonis John A. Hohneker Daniel F. Hayes Eric P. Winer 《Cancer chemotherapy and pharmacology》1999,43(1):68-72
Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting
toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define
the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support.
Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC)
and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in
the metastatic setting and had to have an ANC >1500/mm2, PLT >100 000 m3, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine
was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without
growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m2 per day and dose escalations of 5 mg/m2 were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm3 for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second
phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm3. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m2. Results: At DUMC, DLT was seen at 20 mg/m2 in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade
III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m2 and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients
at DFCI were treated with vinorelbine at a dose of 25 mg/m2 with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis.
Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic
and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen
in patients with previously treated metastatic breast cancer.
Received: 27 October 1997 / Accepted: 16 April 1998 相似文献
10.
Kobayashi K Hino M Fukuoka M Takeuchi K Furuse K Yoneda S Hasegawa K Noda K Kinoshita H Kimura I Taguchi T Kanamaru R Horikoshi N Niitani H 《International journal of clinical oncology / Japan Society of Clinical Oncology》2002,7(3):177-186
Background. SmithKline Beecham synthesized camptothecin analogs and identified nogitecan hydrochloride (topotecan) with a broad spectrum
of antitumor activity and less toxicity than camptothecin. Because preclinical and overseas clinical data indicated the antitumor
effect of nogitecan hydrochloride with a 5-day repeat-dose schedule, we carried out phase I studies in Japan to determine
the maximum tolerated dose (MTD), pharmacokinetics, and antitumor effect of nogitecan hydrochloride.
Methods. Phase I studies of nogitecan hydrochloride given by single and 5-day repeat dosing were carried out in patients with various
solid tumors at 15 medical institutions in Japan. Pharmacokinetic evaluations were performed for both single and 5-day repeated
dosing.
Results. The dose-limiting factor (DLF) was reversible leucopenia, and the maximum tolerated dose (MTD) was higher than 22.5 mg/m2 in the single-dose study. In the 5-day repeat-dose study, the DLF was also reversible leucopenia, and the MTD was estimated
to be 1.5 mg/m2 per day. The plasma concentration of nogitecan hydrochloride increased with increasing dose, and the half-life after single
dosing ranged from 3 to 5 h. There was no evidence of accumulation or delayed excretion during 5-day repeat dosing.
Conclusion. Based on these results and the finding that there were responders among patients treated at 1.5 mg/m2 per day by 5-day repeat dosing in overseas studies, 5-day repeat dosing of 1.2 mg/m2 per day, one dose level lower than the MTD, was selected for phase II studies in Japan.
Received: July 30, 2001 / Accepted: February 28, 2002 相似文献
11.
Watanabe Y Nakai H Shimaoka M Tobiume T Tsuji I Hoshiai H 《International journal of clinical oncology / Japan Society of Clinical Oncology》2006,11(4):309-313
Background Although the prognostic advantages of concurrent cisplatin (CDDP) chemoradiation therapy (CCRT), for uterine cervical cancer
(UCC) has been demonstrated, the feasibility of concurrent CDDP administration has not yet been evaluated. We determined the
optimal CDDP dose for both weekly and monthly schedules during primary and adjuvant CCRT in patients with UCC.
Methods The study was conducted as a phase I, dose-escalation trial. Concurrent CDDP was started at the dose of 30 mg/m2 for the weekly schedule and at 50 mg/m2 for the monthly schedule, and the doses were steadily escalated to the maximum tolerated dose (MTD).
Results A total of 45 patients with UCC (25 receiving primary CCRT and 20 receiving adjuvant CCRT) were entered in the study. In both
the primary and adjuvant CCRT patients, the MTD was observed to be 40 mg/m2 for the weekly schedule and 80 mg/m2 for the monthly schedule. Dose-limiting toxicity was observed in 10 patients (granulocytopenia in 9 patients and diarrhea
in 1 patient). Disease recurrence was confirmed in 6 patients in the primary CCRT group during a mean follow-up period of
22.4 ± 13.2 months, and in patients 3 in the adjuvant CCRT group during a mean follow-up period of 17.7 ± 6.8 months.
Conclusion For Japanese patients with UCC receiving primary or adjuvant CCRT therapy, the recommended CDDP dose was determined to be
30 mg/m2 for the weekly schedule and 75 mg/m2 for the monthly schedule. 相似文献
12.
Brigitte Tranchand Gilles Catimel Catherine Lucas Marlis Sarkany Gérard Bastian Eric Evene Jean-Paul Guastalla Sylvie Négrier Paul Rebattu Arlette Dumortier Maurice Foy François Grossin Béatrice Mazier Marios Froudarakis Nicolas Barbet Michel Clavel Claude Ardiet 《Cancer chemotherapy and pharmacology》1998,41(4):281-291
Purpose: The objectives of this phase I study were to evaluate the toxic effects and the maximum tolerated dose (MTD) of S9788, a
new modifier of multidrug resistance (MDR), when given alone and in combination with doxorubicin to patients with advanced
solid tumors; to achieve a potentially active plasma concentration of S9788; and to study the pharmacokinetics of both drugs.
Methods: A total of 26 patients (median age 58 years) entered the study. S9788 was given alone as a 30-min infusion at day 1 and
in combination with a 50-mg/m2 bolus of doxorubicin at days 8 and 29. Dose levels of S9788 were escalated from 8 to 96 mg/m2 according to the modified Fibonacci scheme. Plasma samples were taken predose as well as during and up to 48 h after the
beginning of infusion for S9788 and doxorubicin quantitation. Fractionated urine samples were also collected for up to 24
h for S9788 determination. Results: The dose-limiting side effects of S9788 consisted of bradycardia, sometimes associated with faintness or dizziness. The
MTD of S9788 was 96 mg/m2. No enhancement of doxorubicin toxicity was observed. One partial response (duration 140 days) was observed at 96 mg/m2 in a patient with multiple lung metastases from a refractory urothelial carcinoma. Pharmacokinetic studies were performed
in 24 patients. Since the mean apparent elimination half-life of S9788 was 46 ± 23 h and the last plasma sampling time was
48 h, only model-independent parameters were considered. Plasma levels of S9788 were below the limit of quantitation (4 × 10–3μM ) before each drug administration. S9788 plasma levels of up to 3.7 μM could be obtained with this administration schedule. The urinary elimination of the unchanged drug was negligible, whatever
the collection period. In spite of the large inter- and intraindividual variability, plasma pharmacokinetics of S9788 given
as a 30-min i.v. infusion were linear up to 96 mg/m2 and were not modified by doxorubicin administration. Doxorubicin pharmacokinetic parameters did not seem to be influenced
by S9788 coadministration. Conclusion: The dose-limiting toxicity of S9788 consisted of bradycardia or clinical symptoms suggesting a vasovagal impact such as
faintness or dizziness. The MTD of S9788 was 96 mg/m2. The pharmacokinetic parameters of doxorubicin in this study were close to those usually described and were not influenced
by escalation of the S9788 dose. No pharmacokinetic interaction was observed between S9788 and doxorubicin. The clinical tolerability
of the combined treatment is in good agreement with the pharmacokinetic findings, since no enhancement of doxorubicin toxicity
was observed.
Received: 13 July 1996 / Accepted: 4 July 1997 相似文献
13.
Supko JG Lynch TJ Clark JW Fram R Allen LF Velagapudi R Kufe DW Eder JP 《Cancer chemotherapy and pharmacology》2000,46(4):319-328
Purpose: The dolastatins are a class of naturally occurring cytotoxic peptides which function by inhibiting microtubule assembly
and tubulin polymerization. Cemadotin is a synthetic analogue of dolastatin 15 with potent antiproliferative and preclinical
antitumor activity. This report describes a phase I study to evaluate the administration of cemadotin to adult cancer patients
by a 5-day continuous intravenous (CIV) infusion. Methods: All patients had histologically confirmed refractory solid tumors. The dose was escalated from an initial level of 2.5 mg/m2 (0.5 mg/m2 daily) according to a modified Fibonacci algorithm. A minimum of three patients was evaluated at each dose level until the
maximum tolerated dose (MTD) was established. Treatment was repeated every 21 days until patients were removed from the study
due to toxicity or disease progression. Drug-related toxicities were evaluated and graded by the U.S. National Cancer Institute's
Common Toxicity Criteria. A radioimmunoassay (RIA) that detected both the parent drug and its metabolites with an intact N-terminal
region of the molecule was used for pharmacokinetic studies. Results: Twenty heavily pretreated patients received a total of 40 courses of cemadotin over five dose levels ranging from 2.5 to
17.5 mg/m2. Reversible dose-related neutropenia was the principal dose-limiting toxicity and 12.5 mg/m2 was established as the MTD. Nonhematologic toxicities attributed to the drug were moderate, and there was no evidence of
the cardiovascular toxicity noted in the prior phase I studies of cemadotin given IV as a 5-min injection or 24-h infusion.
There were no objective antitumor responses. Time courses of the cemadotin RIA equivalent concentration in whole blood were
defined in 14 patients during the first cycle of therapy. The RIA-detectable species exhibited apparent first-order pharmacokinetics
across the entire range of doses. The mean ± SD of the observed steady-state blood concentration at the 12.5 mg/m2 MTD was 282 ± 7 nM (n=3). Blood levels decayed monoexponentially following the end of the infusion, with a mean half-life of 13.2 ± 4.3 h (n=14) in all patients. Mean values (n=14) of the total blood clearance and apparent volume of distribution at steady state were 0.52 ± 0.09 l/h/m2 and 9.9 ± 3.3 l/m2, respectively. Conclusions: The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus, cardiovascular
toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas
myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data
acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing
this compound into disease-oriented efficacy studies is merited.
Received: 8 November 1999 / Accepted: 28 April 2000 相似文献
14.
Kaichiro Yamamoto Kiichiro Noda Akinobu Yoshimura Masahiro Fukuoka Kiyoyuki Furuse Hisanobu Niitani 《Cancer chemotherapy and pharmacology》1998,42(2):127-134
E7010 is a novel sulfonamide which was discovered using slow-growing colon 38 carcinoma cells as a screening model. E7010
exhibits a broad spectrum of antitumor activity against human tumor xenografts. The mechanism of action is by arresting the
progression of cells in M phase of the cell cycle by inhibiting tubulin polymerization. The objective of this phase I study
was to determine the maximum allowable dose (MAD), toxicity, and pharmacokinetics of single or 5-day repeated doses of E7010.
In the single-dose study, E7010 was administered orally to 16 patients at doses ranging from 80 to 480 mg/m2. The dose-limiting toxicity was peripheral neuropathy at a dose of 480 mg/m2. Hematological and gastrointestinal toxicities were mild. In the 5-day repeated-dose study, 41 patients were given E7010
at doses ranging from 30 to 240 mg/m2 per day. The dose-limiting toxicities were peripheral neuropathy and intestinal paralysis. Gastrointestinal toxicity was
dose-dependent but not severe. Hematological toxicity was not dose-dependent. Pharmacokinetic analysis in the single-dose
study showed a rapid increase in the plasma levels of the drug after administration, followed by disappearance with a t1/2 of 4.4–16.6 h. The variation in area under the plasma concentration-time curve (AUC) between the patients was small and increased
in a dose-dependent manner. Total drug recovery in urine 72 h after administration was 77.8 ± 11.4%, indicating that E7010
has favorable absorption and elimination profiles. The changes in the plasma levels of E7010 on day 5 in the 5-day repeated-dose
study were almost the same as those on day 1, indicating that the drug did not accumulate. In the single-dose study, spinal
cord metastasis exhibited a 74% reduction in a patient with uterine sarcoma and a minor response (MR) was observed in a pulmonary
adenocarcinoma patient. In the 5-day repeated-dose study decreases in the tumor markers carcinoembryonic antigen (CEA) and
squamous cell carcinoma antigen (SCC) were observed in a patient with stomach cancer and in a patient with recurrent uterine
cervical carcinoma, respectively. The recommended phase II doses are 320 mg/m2 for a single-dose study and 200 mg/m2 per day for a 5-day repeated-dose study. Since the activity of E7010 is time-dependent, i.e. a certain concentration of E7010
is required for more than 12 h to suppress the growth of P388 leukemia cells, it is recommended that subsequent phase I/II
studies be conducted using a divided dose schedule in order to maintain the blood level of E7010.
Received: 12 February 1997 / Accepted: 6 November 1997 相似文献
15.
Roberts JD Shibata S Spicer DV McLeod HL Tombes MB Kyle B Carroll M Sheedy B Collier MA Pithavala YK Paradiso LJ Clendeninn NJ 《Cancer chemotherapy and pharmacology》2000,45(5):423-427
Purpose: To identify a recommended phase II dose for the second generation glycinamide ribonucleotide transformylase (GARFT) inhibitor,
AG2034, administered by intravenous bolus every 3 weeks without folate supplementation and to describe AG2034 pharmacokinetics.
Methods: Adults with advanced malignancies were enrolled in cohorts of three per dose level with expansion to six upon observation
of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was defined as the dose at which two of up to six patients
experienced DLT. Upon identification of an MTD and evidence of cumulative toxicity, a lower intermediate dose was explored
as a candidate phase II dose. AG2034 plasma concentrations were measured using an ELISA assay. Results and conclusions: The recommended phase II dose is 5.0 mg/m2. DLTs were anemia, thrombocytopenia, mucositis, diarrhea, hyperbilirubinemia, fatigue, and insomnia. Toxicities were modestly
cumulative over three courses. Pharmacokinetic analysis showed a dose-AUC0–24 relationship and a progressive increase in AG2034 AUC0–24 over three courses. Both pharmacokinetic and pharmacodynamic factors may contribute to the modest cumulative toxicity observed
with AG2034.
Received: 18 May 1999 / Accepted: 25 October 1999 相似文献
16.
Michael R. McCrystal Barrie D. Evans Vernon J. Harvey Paul I. Thompson David J. Porter Bruce C. Baguley 《Cancer chemotherapy and pharmacology》1999,44(1):39-44
N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA) is a new DNA-intercalating drug with a dual mode of cytotoxic action
that is thought to involve topoisomerases I and II. On the basis of novelty of action and promising preclinical activity against
solid tumours in mice, DACA was selected for clinical trial under the auspices of the Cancer Research Campaign, United Kingdom.
We report the phase I findings of a 3-h infusion regimen, repeated 3-weekly, of escalating doses through 18–1000 mg/m2 given to 31 patients with solid malignancies. A maximum tolerated dose (MTD) of 750 mg/m2 was identified, with 3 of 6 cycles being abandoned at 1000 mg/m2. Dose-limiting toxicity took the form of infusional arm pain, in some cases associated with facial discomfort, that was of
rapid onset and subsided quickly on the cessation of infusion. The mechanism is unclear but is modulated to some extent by
the rate of drug delivery, and it was unaffected in this study by concurrent anti-inflammatory or opiate medication. No host
or tumour anti-proliferative activity was observed at these doses, and only minimal toxicity of any other kind was evident.
Animal data suggest that the MTD achieved with this schedule may be sub-therapeutic in humans. It is therefore important that
efforts be continued to explore methods of giving higher doses of DACA.
Received: 21 August 1998 / Accepted: 10 December 1998 相似文献
17.
Jon C. Mirsalis Janice Schindler-Horvat James R. Hill Joseph E. Tomaszewski Susan J. Donohue Charles A. Tyson 《Cancer chemotherapy and pharmacology》1999,44(5):395-402
Purpose: Dolastatin 10 (DOL 10), an oligopeptide isolated from the sea hare Dolabella auricularia, has been shown to be a highly potent cytotoxic agent in a variety of human tumor cell lines. The purpose of this study was
to conduct preclinical toxicity evaluations to determine the target organ(s) of toxicity and its reversibility, the dose-limiting
toxicity and the maximum tolerated dose (MTD), and to use this information for arriving at a safe starting dose and dose schedule
for phase I clinical trails. Methods: DOL10 was administered as a single intravenous bolus dose to CD2F1 mice, Fischer-344 rats and beagle dogs. Endpoints evaluated
included clinical observations, body weights, hematology, serum clinical chemistry, and microscopic pathology of tissues.
Results: The MTD (i.e. the highest dose that did not cause lethality but produced substantial toxicity) was approximately 1350 μg/m2 body surface area (450 μg/kg) in mice, 450 μg/m2 (75 μg/kg) in rats and ≤400 μg/m2 (≤20 μg/kg) in dogs. Adverse signs were observed at doses ≥1350 μg/m2 in mice, ≥150 μg/m2 in rats and ≥400 μg/m2 in dogs. Decreased weight gain or actual weight loss was observed at doses ≥1350 μg/m2 in mice, ≥600 μg/m2 in rats and ≥450 μg/m2 in dogs. In all three species, the primary target organ of toxicity was the bone marrow, as indicated by decreases in the
numbers of erythroid cells, myeloid cells, and megakaryocytes in the femoral bone marrow and by decreased white blood cell
(WBC) and reticulocyte counts in peripheral blood. Marked neutropenia (i.e. >50% decrease compared to control animal or baseline
values) was the principal effect on WBCs and occurred within a week of dosing. A mild anemia was evident 1 week after administering
the drug to rats and dogs. The hematologic effects were transient and reversed by study termination. Other lesions at the
MTD levels were cellular depletion and necrosis in lymphoid organs (rats and dogs), marked depletion of extramedullary hematopoietic
cellular elements in the spleen (rats), thymic atrophy (mice and dogs), and minimal cellular necrosis in the ileum (rats).
More extensive and severe pathology was observed in animals sacrificed in a moribund condition or found dead. Conclusions: Myelotoxicity was dose-limiting in all three species with mice being the least sensitive. In a phase I clinical trial, granulocytopenia
was dose-limiting. Moreover, the MTD of DOL10 for rats and dogs is comparable to the human MTD. Therefore, the results from
the preclinical toxicology studies correctly predicted a safe starting dose, the dose-limiting toxicity, and the MTD in humans.
Received: 20 May 1998 / Accepted: 11 February 1999 相似文献
18.
Kunihiko Kobayashi Ayako Shinbara Mitsuhiro Kamimura Yuichiro Takeda Koichiro Kudo Junzaburo Kabe Suguru Hibino Mitsunori Hino Masahiko Shibuya Shouji Kudoh 《Cancer chemotherapy and pharmacology》1998,42(1):53-58
Purpose: CPT-11 (60 mg/m2 on days 1, 8 and 15) in combination with CDDP (80 mg/m2 on day 1) has shown promising antitumor activity for non-small-cell lung cancer (NSCLC), but dose-limiting toxicities (DLT)
are leukopenia and diarrhea, with a wide variation among patients. To estimate weekly CDDP administration in combination with
CPT-11, a phase I study for patients with advanced NSCLC was conducted. Methods: Patients were treated with CPT-11 at a fixed dose of 60 mg/m2 together with CDDP at 27 mg/m2 (level 1, 6 patients), 33 mg/m2 (level 2, 12 patients), and 40 mg/m2 (level 3, 6 patients) with 1600 ml hydration on days 1, 8 and 15 over 4 weeks. During the treatment course, drug was not
administered on the day it was due in the presence of leukopenia (<3000/ml) and/or diarrhea. Results: The planned administration was completed in 5 of 6 patients at level 1, 6 of 12 patients at level 2, and 2 of 6 patients
at level 3. The most common toxicity observed was leukopenia (five patients with grade 3 and one patient with grade 4). Leukopenia
was considered to be a DLT, and the maximum tolerated dose (MTD) was level 2. Although there were patients who suffered from
diarrhea (four patients with higher than grade 2), diarrhea was judged not to be a DLT with this weekly regimen. Nausea and
vomiting were mild. Pharmacokinetic analysis of free platinum from CDDP demonstrated that the area under the curve (AUC) from
33 mg/m2 CDDP was 0.92 ± 0.29 g/ml h. In 13 patients evaluated for response, the response rate was 54%. Conclusion: The value of weekly administration of CDDP in combination with CPT-11 was shown by (1) diarrhea not being dose-limiting,
(2) mild nausea, (3) well-maintained AUC of free platinum, and (4) promising activity.
Received: 4 April 1997 / Accepted: 8 October 1997 相似文献
19.
Kobayashi M Matsui K Hirashima T Nitta T Sasada S Tada T Minakuchi K Furukawa M Ogata Y Kawase I 《International journal of clinical oncology / Japan Society of Clinical Oncology》2006,11(4):314-319
Background The combination of chemotherapy and thoracic radiation therapy (TRT) is considered as a standard treatment for locally advanced
non-small-cell lung cancer (NSCLC). Although the frequent interaction of anticancer agents and irradiation may produce stronger
radio-sensitizing effects, the daily administration of these agents is complicated. We therefore used weekly administration
of these agents, and conducted a phase I study of weekly cisplatin, vinorelbine, and concurrent TRT. The purpose of this study
was to identify the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the recommended dose of this treatment.
Methods Patients with locally advanced NSCLC were enrolled in this study. Both cisplatin and vinorelbine were given intravenously
on a weekly schedule for 6 weeks, starting on the first day of TRT, i.e., on days 1, 8, 15, 22, 29, and 36. The total dose
of TRT was 60 Gy. The dose of cisplatin was fixed at 20 mg/m2 per week. The starting dose of vinorelbine was 15 mg/m2 per week (dose level 1).
Results Nine patients were enrolled in this study. All three patients at dose level 1 experienced DLTs. We decreased the dose of vinorelbine
to 10 mg/m2 per week (dose level 0). Two of the six patients at dose level 0 experienced DLTs. Therefore, dose level 1 was considered
as the MTD, and dose level 0 as the recommended dose. The DLTs of this treatment were esophagitis, fatigue, infection, and
hyponatremia.
Conclusion The recommended dose of cisplatin is 20 mg/m2 per week and that of vinorelbine is 10 mg/m2 per week with standard TRT. A phase II study of this treatment is warranted.
The results of this study were presented in part at the 43rd Annual Meeting of the Japan Lung Cancer Society in Fukuoka, Japan,
November 21–22, 2002. 相似文献
20.
Tkaczuk KH Zamboni WC Tait NS Meisenberg BR Doyle LA Edelman MJ Hausner PF Egorin MJ Van Echo DA 《Cancer chemotherapy and pharmacology》2000,46(6):442-448
Purpose: Both docetaxel (DOC), a promoter and stabilizer of microtubule assembly, and topotecan (TOPO), a topoisomerase I inhibitor,
have shown antitumor activity in a variety of solid tumor malignancies. This phase I trial was conducted to determine the
overall and dose-limiting toxicities (DLT), the maximum tolerated dose (MTD) and the pharmacokinetics of the combination of
DOC and TOPO in patients with advanced solid tumor malignancies. Methods: DOC was administered first at 60 mg/m2 without G-CSF and at 60, 70, and 80 mg/m2 with G-CSF by 1-h infusion on day 1 of the odd-numbered cycles (1, 3, 5, etc.) and on day 4 of the even-numbered cycles (2,
4, 6, etc.). TOPO 0.75 mg/m2 was administered as a 30-min infusion on days 1, 2, 3 and 4 of each cycle. G-CSF 300 μg was administered subcutaneously (s.c.)
on days 5–14. Cycles were repeated every 21 days. All patients were premedicated with dexamethasone 8 mg orally every 12 h
for a total of six doses starting on the day before DOC infusion. Results: A total of 22 patients were treated. Six patients were treated in cohort I with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, without G-CSF, and two patients developed DLT (febrile neutropenia). Four patients were treated in cohort
II with DOC and TOPO doses of 60 and 0.75 mg/m2, respectively, with G-CSF, and no DLT was observed. Four patients were treated in cohort III with DOC and TOPO doses of 80
and 0.75 mg/m2, respectively, with G-CSF, and three developed DLT (febrile neutropenia). DOC was then de-escalated to 70 mg/m2 and delivered with TOPO 0.75 mg/m2 and G-CSF (cohort IV). Eight patients were treated at this dose level, and one DLT (febrile neutropenia) was observed. Two
patients developed a severe hypersensitivity reaction shortly after the DOC infusion was started, one in cycle 1 and one in
cycle 2. Both patients were removed from the study. Two patients developed severe dyspnea in the presence of progressive pulmonary
metastases. Other nonhematological toxicities were mild. One patient with extensively pretreated ovarian carcinoma had a partial
response, and eight patients with various solid tumor malignancies had stable disease with a median time to progression of
12 weeks (range 9–18 weeks). Administration of TOPO on days 1–4 and DOC on day 4 resulted in increased neutropenia. Conclusions: DOC 80 mg/m2 given first as a 1-h infusion on day 1 with TOPO 0.75 mg/m2 given as a 0.5-h infusion on days 1, 2, 3 and 4 with G-CSF was considered the MTD. The recommended phase II dose for DOC
given on day 1 is 70 mg/m2 with TOPO 0.75 mg/m2 given on days 1, 2, 3 and 4 every 21 days with G-CSF 300 μg s.c. on days 5–14. The alternative schedule with DOC given on
day 4 and TOPO on days 1–4 is not recommended.
Received: 18 February 2000 / Accepted: 19 July 2000 相似文献