A phase I study of paclitaxel and 5-fluorouracil in advanced gastric cancer

This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of paclitaxel and 5-Fluorouracil (5-FU) in advanced gastric cancer patients. The patients, refractory to the PELF regimen (5-FU, leucovorin, cisplatin, epidoxorubicin), received weekly 5-FU at the fixed dose of 500 mg/m2, and escalating doses of paclitaxel every 3 weeks with a starting dose of 150 mg/m2 given as in 3-h infusion. The dose was escalated by 25 mg/m2 every 3 patients. Fifteen patients entered the study. The upper paclitaxel dose (225 mg/m2) was given to 6 patients. Up to this dose, no severe toxicity (grade 3-4) was recorded. Apart from alopecia, grade 1-2 leukopenia occurred in 5 patients and grade 1-2 neurotoxicity in 2 patients. All patients were evaluable for response (at least 2 cycles): 2 patients achieved an objective response (200 and 225 mg/m2). In 6 patients, treatment resulted in notable relief from symptoms. Out-patient paclitaxel given over 3 h and 5-FU may be combined safely for the treatment of patients with advanced gastric cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and 5-FU 500 mg/m2.     

A guinea pig''s view on prostate cancer screening trials

Although the combination of paclitaxel with doxorubicin has yielded high response rates in metastatic breast cancer, severe cardiotoxic events have been reported in several patients. The rationale for our study was to evaluate the activity of paclitaxel/doxorubicin combination in patients with this disease but to avoid excessive cardiotoxicity. Therefore, we administered 4 cycles of doxorubicin/paclitaxel followed by 6 cycles of standard cyclophosphamide, methotrexate and 5-fluorouracil (CMF) regimen. Study medication consisted of doxorubicin 60 mg/m2 as a 15-min intravenous infusion followed by paclitaxel 175 mg/m2 as a 3-hour infusion. CMF regimen consisted of cyclophosphamide 600 mg/m2 as 1-hour intravenous infusion followed by methotrexate 40 mg/m2 and 5-fluorouracil 600 mg/m2 bolus injection. The main toxicity of doxorubicin/paclitaxel treatment phase was neutropenia (WHO grade 3/4, 58%), but we observed only one cardiac adverse event. Toxicities of the CMF treatment phase were not significant. Of 24 patients evaluable for response, 2 (8%) had complete responses and 11 (46%) achieved partial response. Ten additional patients (42%) had stable disease. The median time to progression was 12 months and the median overall survival was 18.5 months. The sequential administration of doxorubicin and paclitaxel followed by CMF appeared active and well tolerated in patients with metastatic breast cancer.     

Paclitaxel with mitoxantrone, fluorouracil, and high-dose leucovorin in the treatment of metastatic breast cancer: a phase II trial

PURPOSE: Paclitaxel is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. In this phase II study, we added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin (NFL). PATIENTS AND METHODS: Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous (i.v.) infusion on day 1, mitoxantrone 10 mg/m2 by i.v. bolus on day 1, 5-FU 350 mg2/m by i.v. bolus on days 1, 2, and 3, and leucovorin 300 mg i.v. over 30 to 60 minutes immediately preceding 5-FU on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. RESULTS: Twenty-three of 45 assessable patients (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. Hospitalization for treatment of fever during neutropenia was required in 13% of courses, and two patients died as a result of sepsis. Two patients developed severe congestive heart failure after a large cumulative anthracycline dose. CONCLUSION: This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although its activity compared with other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than anticipated based on previous results with the NFL regimen or with paclitaxel administered at this dose and schedule as a single agent. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with the paclitaxel/doxorubicin combination.     

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.     

The relationship between AIDS dementia complex and the presence of macrophage tropic and non-syncytium inducing isolates of human immunodeficiency virus type 1 in the cerebrospinal fluid

CPT-11 is a camptothecin derivative with a broad spectrum of antitumor activity, both in vitro and in vivo. Like camptothecin, CPT-11 is a selective DNA topoisomerase I inhibitor. Phase I trials were conducted in Europe to determine the dose and schedule for phase II trials. These phase I trials assessed the toxicity of CPT-11 in 235 patients and tested three administration schedules: a single infusion once every 3 weeks; a weekly infusion for 3 out of 4 weeks; and a daily infusion for 3 consecutive days every 3 weeks. The maximum tolerated dose (MTD) was 115 mg/m2 in the daily schedule and 145 mg/m2 in the weekly schedule. When the drug was administered once every 3 weeks, diarrhea became the dose-limiting toxicity at doses above 350 mg/m2. This schedule offered the highest dose intensity and the best tolerability profile, and was the most convenient for outpatient treatment. Finally, using this schedule, concomitant administration of high-dose loperamide allowed the dose of CPT-11 to be increased to 750 mg/m2. An ongoing phase I trial is investigating the combination of CPT-11 and 5-fluorouracil (5-FU) in various solid tumors. Although the MTD has not yet been reached, preliminary results show no pharmacokinetic interaction between the two drugs, contrary to a previous Japanese study. Based on the results of the three phase I trials, CPT-11 350 mg/m2 as an intravenous infusion over 30 minutes once every 3 weeks was recommended for phase II trials, which started in Europe in 1992. To date, CPT-11 has shown remarkable efficacy in colorectal cancer, even in patients resistant to 5-FU. Interesting results have also been obtained in pancreatic, cervical and lung cancers. Future trials will explore the place of CPT-11 in combination with other cytotoxic agents or radiotherapy.     

Phase I study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas

PURPOSE: Astrocytomas are extremely resistant to currently available treatments. Cranial irradiation is a mainstay of frontline therapy, but tumor recurrence is nearly universal. Paclitaxel has shown antitumor efficacy against astrocytoma cell lines, and is a potent radiosensitizer. For these reasons, we conducted a phase I study of weekly paclitaxel and concurrent cranial irradiation in patients with newly diagnosed astrocytomas. PATIENTS AND METHODS: Patients with astrocytomas were eligible for this study following initial surgery if they had a Karnofsky performance score (KPS) > or = 60%; normal hematologic, liver, and renal function; and could give informed consent. Beginning on day 1 of treatment, patients received paclitaxel by 3-hour infusion once weekly for 6 weeks, concurrent with standard cranial irradiation. Pharmacokinetic studies were performed on 10 patients. RESULTS: Sixty patients were enrolled; 56 were fully assessable. Forty-eight had glioblastomas (GBMs), 10 anaplastic astrocytomas (AAs), and two astrocytomas. Age ranged from 21 to 81 years (median, 55); KPS ranged from 60 to 100 (median, 70). The paclitaxel dose was escalated from 20 mg/m2 to 275 mg/m2. No clinically significant anemia or thrombocytopenia occurred. Only one patient (175 mg/m2) became neutropenic. Sensory neuropathy was dose-limiting. The maximum tolerated dose (MTD) was 250 mg/m2. Paclitaxel pharmacokinetic profiles in study patients were identical to those of previously reported patients with other solid tumors. CONCLUSION: The MTD of paclitaxel administered weekly for 6 weeks by 3-hour infusion is 250 mg/m2. Since patients with brain tumors often have preexisting neurologic deficits, we suggest 225 mg/m2 as the optimum dose for phase II trials in this group of patients.     

Phase I study of a weekly 1 h infusion of paclitaxel in patients with unresectable hepatocellular carcinoma

The majority of patients with hepatocellular carcinoma will develop either unresectable or metastatic disease and, therefore, are candidates for systemic chemotherapy. Only a few chemotherapeutic agents have shown documented activity in the treatment of advanced hepatocellular carcinoma and there is clearly a need for the evaluation of new active drugs. Therefore, we performed a phase I trial with a weekly schedule of paclitaxel in patients with advanced hepatocellular carcinoma. 16 patients with documented progression of unresectable hepatocellular carcinoma were included. After premedication, paclitaxel was given as a 1 h infusion on days 1, 8, 15, 22, 29 and 36 representing one treatment cycle. The cycle was repeated every 50 days. The starting dose was 70 mg/m2 and the doses were escalated in steps of 10 mg/m2/week. A minimum of 3 patients were treated at each dose level. All treatment was given on an out-patient basis. Dose-limiting toxicity was reached at a dose of 100 mg/m2/week with 2 of 6 patients treated at that dose level having WHO grade 4 neutropenia. Other toxic side-effects were only mild. 1 partial response and 9 cases with disease stabilisation were observed in 16 patients with initially progressive disease. We, therefore, conclude that the recommended dose for a further phase II trial in patients with hepatocellular carcinoma is 90 mg/m2/week. These data indicate that paclitaxel given at this dose and schedule might have activity in hepatocellular carcinoma and further investigation in phase II trials is warranted.     

Hepatitis G virus RNA and hepatitis G virus-E2 antibodies in Dutch hemophilia patients in relation to transfusion history

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.     

Exercise testing and prognosis in adult cystic fibrosis

PURPOSE: The objective of our study was to determine the maximum tolerable doses (MTDs) of both paclitaxel and cisplatin when given in a weekly schedule alone or simultaneously with G-CSF in advanced solid neoplasms. PATIENTS AND METHODS: Patients with advanced cancer either chemotherapy-naive or resistant to standard treatments received paclitaxel in a three-hour infusion followed by cisplatin, with or without the addition of r-HuG-CSF (5 micrograms/kg s.c. days three to five). The starting doses of CDDP and paclitaxel were 25 mg/m2/week and 45 mg/m2/week, respectively. During the first six courses the dosages of the two drugs were alternately escalated by 20% (CDDP = 5 mg/m2/week, and paclitaxel 10 mg/m2/week) at each step until the appearance of dose-limiting toxicity (DLT) in one-third or more of the patients enrolled in that cohort. RESULTS: Fifty-five patients with cancer (16 lung, 16 breast, 11 ovarian, 7 head and neck, 1 renal, 1 esophageal, 1 cervical, 1 soft-tissue sarcoma, and 1 of unknown primary), 25 of whom were pretreated, were entered into the study. A total of 439 weekly courses were delivered. In chemotherapy-na?ve patients, the MTDs of cisplatin and paclitaxel were 30 mg/m2/week and 65 mg/m2/week, respectively, in the absence of G-CSF support, which increased to 40 mg/m2/week and 85 mg/m2/week, respectively, when G-CSF was given. There were no toxic deaths in this study. Neutropenia was the main dose-limiting toxicity (100/439 courses), but was seldom severe. Neurotoxicity was quite frequent (18 of 55 patients for the total of 88 courses) but never dose-limiting. It was more frequent and clinically relevant in cisplatin-pretreated patients. Overall 18 patients (eight ovarian, five breast, three lung, and two head and neck) achieved objective responses. CONCLUSIONS: The cisplatin-paclitaxel weekly administration seems a safe, practical and effective therapeutical approach in patients with advanced solid neoplasms. Large phase II trials are warranted to accurately define the efficacy of this schedule in cisplatin-paclitaxel sensitive tumors.     

Phase I/II study of a short course of weekly cisplatin in patients with advanced solid tumours

Twenty-five patients with advanced solid tumours were entered in a phase I/II study of six, weekly cycles of cisplatin. Nineteen patients were chemonaive and six were previously treated. The starting dose was 50 mg m-2 week-1. This dose could be escalated without major toxicity to 70 mg m-2 week-1. At a dose of 80 mg m-2 myelosuppression grade 3 occurred as well as grade 1 nephro- and neurotoxicity. The maximum tolerated dose was 85 mg m-2 with dose limiting thrombocytopenia. Hypertonic saline was effective in preventing nephrotoxicity. Ondansetron was a very effective antiemetic in the first weeks of treatment but its efficacy waned later on. Responses were observed in head and neck cancer, melanoma and mesothelioma. At the dose level of 80 mg m-2 the optimal dose intensity was reached. This schedule will be tested further in phase II studies.     

Three unrelated perturbations similarly uncouple fluid, bulk-membrane, and receptor endosomal flow in rat fetal fibroblasts

AIMS AND BACKGROUND: We investigated the efficacy and tolerability of two doses of paclitaxel, 175 mg/m2 and 135 mg/m2, over a 3-hr infusion, without prophylactic G-CSF, in heavily pretreated patients with anthracycline-resistant breast cancer. Although paclitaxel may share with anthracyclines a common mechanism of drug resistance, there is evidence that the two drugs are not completely cross resistant. METHODS: From July 1994 to January 1996, 42 patients were treated every 3 weeks, for a maximum of 6 cycles; paclitaxel dose was established according to pretreatment extension. RESULTS: In 41 assessable patients we observed 9 partial responses, for an overall response rate of 22% (95% CI, 10-34%). There was no difference in response rate between the two dose levels. Median duration of response was 9 months, median time to progression 5 months, and median survival 9 months. The dose-limiting toxicity was neutropenia, which was grade 3-4 in 40% (135 mg/m2) and 62% (175 mg/m2) of the patients (P = 0.28); neutropenic fever occurred in 24% of the patients, without significant differences between the two dose levels. Other toxicity was mild to moderate. CONCLUSIONS: Paclitaxel at doses of 175 mg/m2 or 135 mg/m2 is active and well tolerated in advanced breast cancer patients resistant to anthracyclines. The prophylactic use of colony-stimulating factors seems appropriate in heavily pretreated patients given the higher dose level.     

Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen

PURPOSE: The objective of this trial was to define the maximum-tolerated dose (MTD) of topotecan for a 21-day infusion schedule, repeated every 28 days, in patients with cancer. PATIENTS AND METHODS: Cohorts of four patients received continuous ambulatory infusions of topotecan in escalated duration with doses beginning at 0.20 mg/m2/d for 7 days. Forty-four patients with a histologic diagnosis of cancer refractory to standard therapy were treated with infusions of topotecan for a total of 115 cycles and 1,780 patient-days of infusion. The median number of treatment cycles per patient was two (range, one to eight). All patients were heavily pretreated with chemotherapy and/or radiation. RESULTS: The dose-limiting toxicity (DLT) was myelo-suppression, with thrombocytopenia greater than neutropenia seen at the dose level of 0.70 mg/m2/d for 21 days. At the MTD of 0.53 mg/m2, ten patients were treated for a total of 20 courses, resulting in one episode of grade 4 thrombocytopenia and leukopenia, one grade 3 thrombocytopenia, and two grade 3 leukopenias. This dose regimen was well tolerated, with minimal nonhematologic toxicity. Local infusion port complications developed in two patients and two had bacteremia, including one patient with repeated local skin infections. Objective responses were observed in this heavily pretreated population for patients with ovarian cancer (two partial responses and one mixed response in six patients), breast cancer (one partial response and one mixed response in two patients), and for one patient each with renal and non-small-cell lung cancer (two partial remissions). CONCLUSION: Twenty-one-day topotecan infusion is well tolerated at 0.53 mg/m2, with dose-intensity exceeding other schedules for administration of topotecan. The DLT is hematologic, with thrombocytopenia somewhat exceeding leukopenia. Objective responses were observed in seven patients with breast, ovarian, renal, and non-small-cell lung cancer.     

Loss of biological activity due to Glu-->Arg mutation at residue 11 of the B subunit of cholera toxin

PURPOSE: To determine the maximum tolerated dose, toxicities, and potential antitumor activity of edatrexate (E), an antifolate agent with enhanced in vitro antitumor activity as compared with methotrexate (M), when given in combination with vinblastine, doxorubicin, cisplatin, and filgrastim (G-CSF) to patients with advanced malignancies. PATIENTS AND METHODS: Thirty-seven patients with advanced malignancies were treated with escalating doses of edatrexate in combination with vinblastine (V), doxorubicin (A), cisplatin (C), and filgrastim (EVAC/G-CSF) following three different subsequently developed schedules. Schedule 1 was patterned after the MVAC regimen, a combination chemotherapy program with activity against different epithelial malignancies, and consisted of E, 40 mg/m2/day, days 1/15/22; V, 3 mg/m2/day, days 2/15/22; A, 30 mg/m2/ day, day 2; C, 70 mg/m2/day, day 2; repeated every 28 days. Schedules 2 and 3 were designed to avoid observed dose-limiting toxicity on schedule 1 consisting of transient elevation of serum creatinine levels and delayed myelosuppression. Schedule 2 consisted of E, 40 or 60 mg/ m2/day, days 1 and 15; V, 3 mg/m2/day, days 2 and 15; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 28 days. Schedule 3 consisted of E, 60 to 120 mg/m2/day, day 1; V, 3 mg/m2/day, day 2; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 21 days. Filgrastim 5 micrograms/kg/day was given to all patients subcutaneously until the absolute neutrophil count was greater than 10,000/microL postnadir. Three patients were treated on schedule 1, 10 on schedule 2 (four at an E dose of 40 mg/m2/day and six at an E dose of 60 mg/m2/day), and 24 on schedule 3 (six at each of the following E dosages: 60, 80, 100, and 120 mg/m2/day). RESULTS: Dose-limiting toxicities of grade 3 to 4 leukopenia and transient elevation of serum creatinine values were observed in two of three patients treated on schedule 1. A dose-limiting toxicity of grade 3 to 4 leukopenia was noted in two of six patients treated on schedule 2 at an edatrexate dose of 60 mg/m2/day. Two of six patients treated on schedule 3 at an edatrexate dose of 120 mg/m2/day had a dose-limiting toxicity of grade 3 stomatitis (one patient) and grade 3 cytopenia (one patient). Nineteen of 37 patients with evaluable or measurable disease had a response to treatment (response rate 51%, 95% confidence intervals = 35%-67%). Nine of 15 patients with metastatic non-small cell lung cancer responded, including one complete remission (response rate 60%, confidence intervals = 35%-85%). A median survival of 517 days (confidence interval = 163-808 days) and a 1-year survival rate of 60% (confidence interval = 35%-85%) was seen in patients with advanced non-small cell lung cancer. CONCLUSIONS: The maximum tolerated dose and the recommended phase II dose of edatrexate is 100 mg/m2/day when administered as part of the EVAC/G-CSF program following schedule 3. Promising antineoplastic activity against non-small cell lung carcinomas was observed, and a phase II study is planned.     

A phase I-II study of paclitaxel, ifosfamide, and vinorelbine with filgrastim (rhG-CSF) support in advanced non-small-cell lung cancer

PURPOSE: We designed a phase I-II trial of three active agents, paclitaxel, ifosfamide, and vinorelbine, in advanced non-small-cell lung cancer (NSCLC) to: 1) define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of paclitaxel with filgrastim (G-CSF) support; and 2) determine the overall response rate and median survival of patients treated on this regimen. PATIENTS AND METHODS: We treated cohorts of patients with stage IIIB or IV NSCLC with ifosfamide 1.2-1.6 g/m2/day x 3 and vinorelbine 20-25 mg/m2/day x 3 and escalating doses of paclitaxel at 100-175 mg/m2 on day 2 with G-CSF support on a 21-day cycle. One prior experimental single-agent chemotherapy regimen was allowed. RESULTS: Fifty-six patients, were enrolled on this trial: 27 on the phase I portion of the study and an additional 29 at the recommended phase II dose (RPTD). Thirteen patients had received prior chemotherapy. Paclitaxel doses of 175 mg/m2 and 150 mg/m2 produced dose-limiting myelosuppression, and the RPTD was determined to be paclitaxel 135 mg/m2 with ifosfamide 1.2 g/m2/day on days 1-3 and vinorelbine 20 mg/m2/ day on days 1-3 with G-CSF support. The overall response rate was 18%, with a median survival of 6.1 months. Six of 35 patients (17%) treated at the RPTD achieved a partial response to therapy. Grade IV neutropenia was observed in 19 of 35 patients at this dose, with eight patients suffering febrile neutropenia. CONCLUSIONS: This non-cisplatin-containing three-drug regimen has substantial toxicity and low activity in advanced NSCLC, and does not seem to improve on prior regimens. It is unclear whether the lack of efficacy relates to an antagonistic reaction between the specific drugs, administration schedule, or to subtherapeutic doses of the individual agents.     

Radiotherapy and concomitant weekly 1-hour infusion of paclitaxel in the treatment of head and neck cancer--results from a Phase I trial

PURPOSE: To define the maximum tolerated dose (MTD) by describing the dose-limiting toxicity (DLT) of weekly paclitaxel (PAC) given as a 1-h I.V. infusion in patients with head and neck cancer concomitant to irradiation. METHODS AND MATERIALS: Patients with unresectable or incompletely resected head and neck cancer were enrolled into a prospective, dose-escalating Phase I study. Toxicity was graded according to the WHO toxicity score. MTD dose was defined when two out of six patients developed DLT. The starting dose of PAC was 20 mg/m2 once weekly I.V. over 60 min, with a subsequent dose escalation of 10 mg/m2 in cohorts of three new patients. Radiation therapy was administered in three field technique over 6-7 weeks in 2.0 Gy/daily fractions for 5 consecutive days/week up to total doses of 60-70 Gy. RESULTS: From 1994-1996, 18 patients completing three dose levels were included into the study. Altogether, 101 courses of chemotherapy were evaluable for toxicity. On the second dose level (30 mg/m2) one of three patients experienced DLT with Grade IV mucositis. On the next dose level with 40 mg/m2 PAC weekly one patient experienced DLT being prolonged Grade III mucositis. From the following three patients required, two patients showed no DLT. The third patient showed mucositis of WHO Grade 4 and died from hemorrhage caused by a rupture of the a pharyngeal wall. Dose level 2 (30 mg/m2) was repeated and one of the three newly treated patients again suffered from mucositis WHO Grade 4. CONCLUSION: When PAC is given weekly as a 1-h infusion concomitant to radiotherapy, MTD is 30 mg/m2 with mucositis being DLT; hematological and further nonhematological toxicity is mild.     

Distributed clinical neurophysiology

We have performed a clinical phase I trial of a combination treatment with paclitaxel given as 3-hour infusion and cisplatin to determine the maximum tolerated dose and the dose-limiting toxicity in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Treatment was repeated every 21 days. Doses administered ranged from 135 mg/m2 paclitaxel/75 mg/m2 cisplatin to 250 mg/m2 paclitaxel/100 mg/m2 cisplatin. Twenty-four patients have been entered into this study. The maximum tolerated dose was determined to be 225-250 mg/m2 paclitaxel/100 mg/m2 cisplatin. The dose-limiting toxicity of this regimen was myelosuppression (granulocytopenia). Neurosensory and neuromotor toxicity was moderate. However, analyses of threshold electrotonus studies indicated subclinical neurotoxicity in most patients. One patient receiving 200 mg/m2 paclitaxel/100 mg/m2 cisplatin developed grade 3 motor-neurotoxicity. Orthostatic hypotension was observed in 8 patients receiving doses of 200 mg/m2 paclitaxel/100 mg/m2 cisplatin or higher. Objective responses were observed at paclitaxel 175 mg/m2/ cisplatin 100 mg/m2 (n = 5; complete response in 1 patient), paclitaxel 200 mg/ m2/cisplatin 100 mg/m2 (n = 3; partial response in 3 patients) and at paclitaxel 225 mg/m2/cisplatin 100 mg/m2 (n = 8; partial response in 1 patient). Eleven additional patients had stable disease. We conclude that paclitaxel administered as a 3-hour infusion followed by cisplatin is an active regimen in advanced head and neck cancer and that orthostatic hypotension may be a potentially significant clinical toxicity.     

Purification and characterization of human sarcomeric mitochondrial creatine kinase

PURPOSE: A dose-escalation study of irinotecan hydrochloride (CPT-11) combined with fixed-dose cisplatin was conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and objective response rate in patients with advanced gastric cancer. PATIENTS AND METHODS: Twenty-four patients with or without prior chemotherapy were enrolled. All patients were assessable for toxicities and response. On day 1, CPT-11 was administered as a 90-minute intravenous (I.V.) infusion, which was followed 2 hours later by a 120-minute I.V. infusion of cisplatin 80 mg/m2. CPT-11 alone at the same dose was administered again on day 15. The treatment was repeated every 4 weeks until disease progression was observed. The initial dose of CPT-11 was 60 mg/m2, and was escalated in increments of 10 mg/m2 until severe or life-threatening toxicity was observed. RESULTS: The MTD of this combination was CPT-11 80 mg/m2. At this dose level, 16.7% of patients (two of 12) had leukopenia of less than 1,000/microL, 66.7% (eight of 12) had neutropenia of less than 500/microL, and 16.7% (two of 12) had severe diarrhea of grade 4 during the first course. The dose-limiting toxicity was neutropenia. Ten patients achieved a partial response (PR), and the overall response rate was 41.7% among 24 patients (95% confidence interval, 21.9% to 61.4%). CONCLUSION: The recommended dose and schedule is CPT-11 70 mg/m2 on days 1 and 15 and cisplatin 80 mg/m2 on day 1 every 4 weeks. This combination of CPT-11 and cisplatin, considered to be active against advanced gastric cancer with acceptable toxicity, should be further assessed in a phase II study.     

Paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of small-cell lung cancer: comparison of sequential phase II trials using different dose-intensities

PURPOSE: In two sequential phase II studies, we evaluate the feasibility and efficacy of adding paclitaxel to a standard platinum/etoposide regimen in the first-line treatment of small-cell lung cancer. PATIENTS AND METHODS: One hundred seventeen patients with small-cell lung cancer were treated between June 1993 and July 1996. The first 38 patients received a lower-dose regimen: paclitaxel 135 mg/m2 by 1-hour infusion, carboplatin at an area under the concentration-time curve (AUC) of 5.0, and etoposide 50 mg alternating with 100 mg orally on days 1 to 10. When only mild myelosuppression was observed, doses of paclitaxel and carboplatin were increased in the subsequent 79 patients (paclitaxel 200 mg/m2 by 1-hour infusion and carboplatin at an AUC of 6.0). All patients received four courses of treatment, administered at 21-day intervals. Patients with limited-stage small-cell lung cancer also received thoracic radiation therapy (1.8 Gy/d; total dose, 45 Gy) administered concurrently with courses 3 and 4 of chemotherapy. RESULTS: Seventy-two of 79 patients (91%) who receive the higher-dose regimen had major responses. Thirty-two of 38 (84%) with extensive-stage disease responded (21% complete response rate); median survival was 10 months for this group. With limited-stage disease, the overall response rate was 98%, with 71% complete responses; the median survival time has not been reached at 16 months. Median survival in extensive-stage patients was longer in patients who received the higher-dose regimen (10 months) than in the previous group treated with lower doses (7 months; P = .008). The higher-dose regimen was well tolerated, with myelosuppression being the major toxicity. Compared with the lower-dose regimen, grade 3/4 neutropenia increased from 8% to 38% of courses, but the incidence of hospitalization for neutropenia and fever did not increase. Other nonhematologic toxicities were uncommon, and did not increase substantially with the higher-dose regimen. CONCLUSION: Paclitaxel can be added at full dose (200 mg/m2) to a carboplatin/etoposide combination while maintaining a tolerable toxicity profile. Median survival times in both extensive- and limited-stage patients compare favorably with other reported regimens. This regimen merits further investigation, and a randomized trial to compare this regimen with a standard carboplatin/etoposide combination is underway.     

Phase I study of docetaxel dose escalation in combination with fixed weekly gemcitabine in patients with advanced malignancies

PURPOSE: To determine the maximum-tolerated dose of monthly docetaxel combined with fixed-dose weekly gemcitabine and describe the dose-limiting toxicities (DLTs) of the combination. PATIENTS AND METHODS: Patients with refractory solid tumors were treated with gemcitabine days 1, 8, and 15 every 4 weeks at a fixed dose of 800 mg/m2. Two docetaxel administration schedules were studied, with the drug administered either day 1 or day 15 at doses of 45, 60, 75, and 100 mg/m2 per cycle. RESULTS: Forty patients received 132 cycles of chemotherapy. On the day-1 schedule, the maximum-tolerated docetaxel dose was the highest planned dose of 100 mg/m2 with two DLT episodes among 12 patients treated with 34 cycles at this dose level. On the day-15 schedule, delivery of the planned docetaxel doses was not feasible because of thrombocytopenia and hepatic dysfunction. Hematologic toxicities included grade 4 neutropenia in 16 patients, with three episodes of febrile neutropenia; grades 3 to 4 thrombocytopenia in nine patients; and anemia that required RBC transfusions in 10 patients. For patients treated at the highest docetaxel dose level, myelosuppression was not dose limiting and only one of 34 cycles was complicated by febrile neutropenia. The most common nonhematologic toxicities were asthenia, flu-like symptoms, and fluid retention. Antineoplastic activity was noteworthy, with partial responses in nine of 21 patients with pretreated non-small-cell lung cancer (NSCLC; 43%; 95% confidence interval, 22 to 66), in four of seven patients with breast cancer, and in one patient with esophageal adenocarcinoma. CONCLUSION: Gemcitabine 800 mg/m2 days 1,8, and 15 can be safely combined with docetaxel 100 mg/m2 day 1 of a 28-day cycle. The observed antitumor activity warrants phase II evaluation.     

Clinical pharmacokinetics and pharmacodynamics of paclitaxel: a 3-hour infusion versus a 24-hour infusion

The present study was conducted to compare the pharmacokinetics and pharmacodynamics (PD) of paclitaxel between Phase I trials of 3- and 24-h infusions and to determine the most informative pharmacokinetic parameter to describe the PD. Twenty-seven patients were treated in a Phase I study of paclitaxel by a 3-h infusion at one of six doses: 105, 135, 180, 210, 240, and 270 mg/m2. Pharmacokinetic data were obtained from all patients. Paclitaxel concentrations were measured in the plasma and urine using HPLC. The pharmacokinetics and PD were compared with those of a Phase I trial of paclitaxel by a 24-h schedule previously performed. The maximum tolerated dose of paclitaxel by a 3-h infusion was determined to be 240 mg/m2. The major toxicities were granulocytopenia, neuromuscular toxicities, and hypotension. Apparent differences in pharmacodynamic relationships for the change in granulocytes with dose, peak concentration, and areas under the concentration versus time curve were observed between the 3- and 24-h schedules. However, the relationship between the duration of plasma concentration above 0.05 microM and the change in granulocytes could be fitted to the same sigmoid maximum effect model in either schedule (P < 0.01). There were no clear relationships between peripheral neuropathy or hypotension and any pharmacokinetic parameters. The pharmacokinetics and PD of paclitaxel were schedule dependent. The duration of plasma concentration above 0.05 microM could be a common pharmacokinetic parameter predicting granulocytopenia for both schedules.