Phase I dose escalation study of gemcitabine and paclitaxel plus colony-stimulating factors in previously treated patients with advanced breast and ovarian cancer

Gemcitabine and paclitaxel (PTX) are among the most active new drugs in advanced breast and ovarian cancer. In this Phase I study, we used fixed doses of gemcitabine administered on days 1 and 8 and escalating doses of paclitaxel on day 1 of a 21-day cycle in patients with pretreated metastatic breast or ovarian cancer. The dose of gemcitabine was fixed at 1,000 mg/m2; PTX was commenced in the first small patient group at a dose of 90 mg/m2, which was then escalated in subsequent groups by 30 mg/m2 per step. From the third dose level onwards, all patients received granulocyte colony-stimulating factor 300 microg by subcutaneous injection on days 5 and 6, and granulocyte macrophage colony-stimulating factor on days 15-18. Cohorts of at least 3 patients were treated at each dose level. Dose escalation was stopped if at least a third of the patients in a given cohort had dose-limiting toxicity (DLT), which was defined as grade 4 neutropenia or thrombocytopenia, or grade 3-4 non-haematological toxicity. The maximum tolerated dose (MTD) was defined as the dose level immediately below that causing DLT in one-third of the patients or more. Evaluation of the tumour response was performed every three cycles. Forty-five patients (31 with breast cancer, 14 with ovarian cancer) were treated at seven different dose levels. Only at the seventh PTX dose level was DLT observed after the first course of therapy: three grade 4 neutropenia, one grade 4 thrombocytopenia, and one grade 4 anaemia. DLT occurred in 5/6 patients at at PTX dose of 270 mg/m2; therefore dose escalation was stopped at that level and the dose immediately before it (PTX 240 mg/m2) was considered as the MTD and recommended for further studies. No toxic deaths occurred. Grade 3-4 uncomplicated neutropenia was observed in four patients. Three had uncomplicated grade 3-4 thrombocytopenia. One patient had grade 3 and one grade 4 anaemia. Nonhaematological side effects were generally mild. Among 30 evaluable patients with metastatic breast cancer, four complete responses (CR) (13%) and 12 partial responses (PR) (40%) were observed, for an overall response rate of 53% (95% confidence interval (CI) 34-72). The median duration of response was 31 weeks. Among 13 evaluable patients with advanced ovarian cancer, one CR (8%) and five PRs (38%) were observed, for an overall response rate of 46% (95% CI 19-78). The median duration of response was 32 weeks. Our study shows that gemcitabine and PTX can be administered in combination in patients with breast and ovarian cancer without unexpected toxicities and with encouraging therapeutic results.     

A phase I study of ixabepilone in combination with epirubicin in patients with metastatic breast cancer

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer.Patients and MethodsPatients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m²) and escalating doses of ixabepilone (25, 30, and 35 mg/m²).ResultsForty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m² (n = 6) in combination with 75 mg/m² epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m² was 30 mg/m², and the DLT dose was 35 mg/m² with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels.ConclusionsThe combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m², followed by ixabepilone 30 mg/m² every 3 weeks.     

Weekly paclitaxel plus capecitabine in advanced breast cancer patients: dose-finding trial of GOIRC and GOL.

BACKGROUND: Paclitaxel and capecitabine have demonstrated a synergic effect and significant antitumor activity in patients with advanced breast cancer. A weekly schedule of paclitaxel obtained a response rate of 50-68% in advanced breast cancer and less serious side-effects. PATIENTS AND METHODS: Thirty-two patients with advanced breast cancer pretreated with chemotherapy were enrolled in a dose-finding trial to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of paclitaxel given on days 1, 8 and 15 of each cycle combined with capecitabine given twice daily from day 1 through day 14, every 21 days. Three patients were recruited at one of six dose levels (paclitaxel 70-100 mg/m2, capecitabine 1650-2500 mg/m2). RESULTS: Thirty-two patients were accrued and 31 were evaluated for toxicity. One DLT has been experienced at level VI as diarrhea grade 3. We determined dose level V as the MTD, but we recommend dose level IV for phase II studies (capecitabine 1250 mg/m2 orally twice daily plus paclitaxel 80 mg/m2 intravenously weekly), owing to cumulative toxicity at level V. The objective response rate was 43%. CONCLUSIONS: Weekly paclitaxel plus capecitabine is a safety and active chemotherapy in previously treated metastatic breast cancer.     

Phase I/II trial of gemcitabine plus cyclophosphamide in patients with metastatic breast carcinoma previously treated with taxanes

The purpose of this study was to determine the maximum tolerated dose (MTD) of infusional gemcitabine given in conjunction with intravenous (i.v.) cyclophosphamide, and to determine whether the regimen produced a response rate of at least 40% in patients with metastatic breast cancer who have been previously treated with taxanes. Patients received cyclophosphamide (600 mg/m2) i.v. followed immediately by gemcitabine (100, 150, or 200 mg/m2) given as a 24-hour infusion (every 3 weeks) using an accelerated dose-escalation schema. Dose-limiting toxicity was defined as a neutrophil nadir < 500/microL, platelet nadir < 50,000/microL, or > or = grade 2 nonhematologic toxicity (> or = grade 3 toxicity during the standard dose-escalation portion of the study). Twelve patients received a total of 32 cycles of therapy. The MTD of gemcitabine was 150 mg/m2. Dose-limiting toxicities at 200 mg/m2 included neutropenia and mucositis. One patient with lymphangitic lung metastases had a partial response (8%; 95% confidence intervals: 0%, 23%). This patient developed grade 4 transaminase and total bilirubin elevation that occurred after the sixth cycle of therapy. The study was terminated due to an insufficient number of responses. The MTD of gemcitabine given as a 24-hour infusion is 150 mg/m2 when used in conjunction with cyclophosphamide (600 mg/m2) every 3 weeks. This regimen is not likely to produce more than a 40% response rate in patients with metastatic breast cancer previously treated with taxanes.     

A dose-finding study of the weekly administration of paclitaxel in patients with advanced solid tumors

The purpose of this study was to determine the dose-limiting toxicities and the maximum-tolerated dose (MTD) of weekly administration of paclitaxel in patients with advanced solid tumors. Twenty-six patients with advanced solid tumors were treated with escalated doses of paclitaxel (starting dose 70 mg/m(2)/wk with increments of 10 mg/m(2)/wk) for 4 consecutive weeks every 6 weeks. No intrapatient escalation or growth factor support was allowed. The DLT was exceeded at the dose of 120 mg/m(2)/wk, and the dose-limiting events were grade IV neutropenia and treatment delay because of incomplete hematologic recovery. There was no cumulative myelosuppression. Grade IV neutropenia occurred in four (6%) cycles, and there was one episode of febrile neutropenia. Grade II/III fatigue occurred in 19 (73%) patients, resulting in discontinuation of treatment in 2 of them; grade II neurosensory toxicity and grade II alopecia occurred in 8 (31%) patients each. The MTD, which is also the recommended dose for further phase II studies, was 110 mg/m(2)/wk. Among the 21 patients with bidimensionally measurable disease, 2 (10%) partial responses were observed, both in patients with heavily pretreated advanced breast cancer. The weekly administration of paclitaxel for 4 consecutive weeks in cycles of 6 weeks is a feasible, safe, and active outpatient regimen that merits further evaluation in combination with other anticancer agents.     

Phase I trial of gemcitabine,administered as a standard and constant dose-rate infusion,in combination with paclitaxel in patients with advanced solid tumors (LOA-2)

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine and paclitaxel combination therapy when administered to patients with advanced solid tumors, using two infusion schedules of each agent. Paclitaxel was administered on day 1, followed by gemcitabine, and gemcitabine alone was administered on day 8, of each 21-day treatment course. In the initial phase of the trial, paclitaxel was administered during 3 hours and gemcitabine during 30 minutes (schedule A). After the MTD was determined on this schedule, patients were then treated with paclitaxel during 1 hour and gemcitabine at a fixed dose-rate of 10 mg/m(2)/min (schedule B). Forty-six patients were treated with 176 courses at 7 dose levels. The MTD for schedule A was 1,300 mg/m(2) and 200 mg/m(2) and for schedule B was 1,000 mg/m(2) and 200 mg/m(2) for gemcitabine and paclitaxel, respectively. The DLT for schedule A was neutropenia and for schedule B was neutropenia and thrombocytopenia. Nonhematologic toxicity was relatively mild. Gemcitabine and paclitaxel, using both schedules of administration in the current trial, is a promising chemotherapeutic regimen.     

Phase I study of weekly paclitaxel and liposomal doxorubicin in patients with advanced solid tumours

The aim of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of a weekly administration of paclitaxel and pegylated liposomal doxorubicin (Caelyx; Schering Plough Pharmaceutical) in patients with advanced solid tumours. 19 pretreated patients with solid tumours received escalated doses of pegylated liposomal doxorubicin (6-12 mg/m(2)) as a 1-h intravenous (i.v.) infusion followed by a fixed dose of paclitaxel (80 mg/m(2)) weekly for 4 consecutive weeks in cycles of 6 weeks. DLT was defined as grade 4 neutropenia or thrombocytopenia, febrile neutropenia, grades 3 or 4 non-haematological toxicity or treatment delay due to unresolved toxicity during cycle 1. The MTD was reached at the dose of pegylated liposomal doxorubicin of 10 mg/m(2)/week and paclitaxel of 80 mg/m(2)/week. The DLTs were treatment delay due to grade 3 neutropenia and grade 3 diarrhoea. A total of 55 chemotherapy cycles were administered, and grades 3-4 neutropenia occurred in seven cycles (13%); the non-haematological toxicity was mild with grades 2/3 diarrhoea occurring in 4 (7%), grades 2-4 asthenia in 11 (20%) and grade 2 mucositis in 7 (13%) cycles. There was no case with more than a 10% LVEF decrease after a median of 3 (range 2-6) administered cycles/patients. One patient with breast cancer and 1 with ovarian cancer experienced a major partial response. The weekly administration of pegylated liposomal doxorubicin at the dose of 10 mg/m(2) in combination with paclitaxel at the dose of 80 mg/m(2) for 4 consecutive weeks, in cycles of 6 weeks which represent the recommended doses for further phase II studies, is a well tolerated regimen, which merits further evaluation in tumours known to be sensitive to taxanes and/or anthracyclines.     

A multicentre phase II pilot study of epirubicin and Taxol (paclitaxel) in patients with advanced breast cancer

Anthracyclines are the gold standard monotherapy for metastatic breast cancer. Higher response rates are seen with drug combinations, especially with newer agents such as taxanes. The purpose of this study was to evaluate the toxicity and activity of the combination of paclitaxel and epirubicin in patients with advanced breast cancer. Thirty-five women with locally advanced or metastatic breast cancer (first and second relapse) were treated with epirubicin 75 mg/m2 and paclitaxel 200 mg/m2 3-weekly. Six centres recruited 35 patients; 34 (97%) were assessable for response. Eighteen had undergone prior chemotherapy, including six (17%) with anthracycline-containing regimens. Grade 4 neutropenia was found in 33 patients (94%), which was of 4 days' average duration; however, infective complications were rare, with only nine cycles (6%) complicated by neutropenic sepsis. There were two sepsis-related deaths. Symptomatic cardiotoxicity was infrequent, although a >15% decline in cardiac function was recorded in five patients (14%). Grade 3 peripheral neuropathy occurred in three patients (9%). The overall response rate was 50% (95% confidence interval 33-67) (complete response 12%; partial response 38%), with a median duration of response of 31 weeks. The median time to progression was 27 weeks, with a median survival of 48 weeks. This regimen appears to be a relatively safe, tolerable and effective treatment for advanced breast cancer. A United Kingdom Co-ordinating Committee for Cancer Research Phase III trial (AB-01) comparing this combination of epirubicin and paclitaxel with cyclophosphamide and paclitaxel completed accrual in November 1999.     

A phase I study of paclitaxel and epirubicin, without and with filgrastim, for the treatment of platinum-resistant advanced ovarian cancer.

The aim of the study was to determine the maximum tolerated dose (MTD) of epirubicin combined with a fixed dose of paclitaxel, without and with support of filgrastim, in patients with platinum resistant or refractory ovarian cancer. Paclitaxel (150 mg/m2) and epirubicin (starting dose 90 mg/m2, 15 mg/m2 escalation per level) were given on day 1, every 28 days for 4-6 cycles. Filgrastim (F) (5 microg/kg/die) was given in case of grade 4 leukopenia (levels without support) or from day 4 up to leukocyte count >10,000/mm3 after nadir (levels with support). Cohorts of 3 patients were enrolled at each level and further 3 patients were planned if 1 or 2 unacceptable toxic events (UTE) were registered. MTD was determined first without and then with filgrastim. Four levels were studied (90, 90+F, 105+F, 120+F) with 4, 6, 5 and 4 patients enrolled, respectively. UTE (grade 4 neutropenia) were observed in 3 patients at level 1. Thus, 90 mg/m2 was the MTD for epirubicin without filgrastim. MTD of epirubicin with filgrastim was not reached at 120 mg/m2. Hematological toxicity was mild. Grade 3 mucositis was reported in 1 patient. Among the 14 patients with measurable or evaluable disease, 3 objective responses were observed (1 complete and 2 partial) for an overall response rate of 21.4%. The combination of paclitaxel 150 mg/m2 and epirubicin at 120 mg/m2 with filgrastim is a feasible therapy. Grade 4 leukopenia is the dose limiting toxicity using epirubicin at 90 mg/m2 without filgrastim.     

An EORTC phase I study of capecitabine (Xeloda) in combination with fixed doses of cyclophosphamide and epirubicin (cex) as primary treatment for large operable or locally advanced/inflammatory breast cancer

In breast cancer, chemotherapy regimens that include infusional 5-fluorouracil (5-FU) lead to high response rates, but require central venous access and pumps. To avoid these inconveniences, we substituted infusional 5-FU with capecitabine. The main objective of this study was to determine the maximum tolerated dose (MTD) of capecitabine when given in combination with fixed doses of epirubicin and cyclophosphamide (100 and 600 mg/m(2) day 1 every (q) 3 weeks) as primary treatment for large operable or locally advanced/inflammatory breast cancer without distant metastasis. Capecitabine was escalated from 750 mg/m(2) twice a day (bid) to 1250 mg/m(2) bid from day 1 to day 14 in four dose levels. Dose escalation was permitted if 0/3 or 1/6 patients experienced dose-limiting toxicity (DLT). A total of 23 patients were included and 117 courses were administered. At dose level 4, 2 of 2 patients presented DLTs defining the MTD. A high rate of capecitabine treatment modification was required with capecitabine 1050 mg/m(2) bid (dose level 3). 19 patients achieved an objective response (83%). In conclusion, we believe that capecitabine 900 mg/m(2) bid (dose level 2) is the recommended dose in combination with epirubicin 100 mg/m(2) and cyclophosphamide 600 mg/m(2). The acceptable toxicity profile and encouraging activity of this regimen warrant further evaluation.     

Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients.

Oral idarubicin (IDA) is an active drug in metastatic breast cancer, but its role in the management of this tumor is yet not established completely. To investigate a new modality of IDA administration, a dose-finding study was designed with hyperfractionated doses. The purpose was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patients with progressive metastatic breast cancer and pretreated with chemotherapy (including epirubicin and doxorubicin) were enrolled. DLT was defined as G4 hematological toxicity or any other toxicity G3 or higher (Bloom and Richardson grading). Inter- and intrapatient dose increases were studied. Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, with the larger dose given in the evening. MTD was reached at 10 mg/day. Overall, the therapy cycles were 69 (median/patient, 2; range, 1-6). DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one patient and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. The two patients developing DLT at the daily dose of 10 mg received a dose normalized for body surface of 6.85 and 5.65 mg/m2/day, respectively. We considered 5.5 mg/m2/day to be the MTD. Other toxicities were nausea, vomiting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, significant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33), IDA Cmax (P = 0.0067; r = -0.38), IDOL area under the curve (P = 0.0009; r = -0.43), and IDOL Cmax (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA Cmax was the strongest determinant for neutropenia (R2 = 0.14; P = 0.01). Among the 21 patients evaluable for response, 3 (14.3%) had partial response (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a complete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhea. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycline-pretreated patients. IDOL could have a role for the pharmacological effect. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.     

Weekly first-line chemotherapy of metastatic breast cancer with cyclophosphamide and epirubicin.

Forty-six patients with metastatic breast cancer who had not received previous chemotherapy for advanced disease entered a phase II trial of weekly chemotherapy with cyclophosphamide (250 mg/m2) + epirubicin (25 mg/m2) for 16 weeks. The overall response rate was 61% (95% confidence limits, 47-75%), with 10 complete and 17 partial responses. Toxicity was mild and confined to nausea and vomiting and asymptomatic neutropenia (except in 2 cases). Sixty-three per cent of patients had no side effects. Weekly cyclophosphamide + epirubicin is an active and nontoxic regimen for patients with metastatic breast cancer who have had no prior anthracycline-containing adjuvant chemotherapy.     

Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics.

BACKGROUND: The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide. PATIENTS AND METHODS: Patients with advanced cancer, World Health Organization (WHO) performance status 0 to 2, who had received up to one prior chemotherapy regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated every 21 days. The cyclophosphamide dose was fixed at 600 mg/m(2) and the dose levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and 85/105 mg/m(2). There was provision for the addition of prophylactic ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps if dose-limiting toxicity (DLT) was neutropenia related. RESULTS: Forty-three patients were entered and all were assessable for toxicity. Dose-limiting toxicity, predominantly febrile neutropenia, was surprisingly seen at the first dose level. The addition of prophylactic ciprofloxacin did not permit dose escalation, but dose escalation was possible with the addition of G-CSF. The highest administered dose level with G-CSF was docetaxel 85 mg/m(2) and epirubicin 105 mg/m(2) with DLTs in five of six patients. Treatment was well tolerated in 10 patients treated at the recommended dose level (85/90) with only one patient experiencing DLT. Responses were seen in a range of malignancies including breast and anaplastic thyroid cancers. No significant pharmacokinetic interaction was observed, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion. CONCLUSIONS: The recommended dose level of docetaxel 85 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2) with G-CSF support has a favorable toxicity profile and is suitable for further investigation in phase II and III trials.     

Gefitinib (ZD1839) combined with weekly epirubicin in patients with metastatic breast cancer: a phase I study with biological correlate.

PURPOSE: Epidermal growth factor receptor (EGFR) is overexpressed in approximately 50% of invasive breast carcinomas and it is correlated with hormone resistance and poor prognosis. EGFR suppression by gefitinib, a quinazoline derivative that inhibits phosphorylation of the specific receptor, represents a novel therapeutic strategy. A dose-finding study was performed to evaluate the combination of gefitinib with weekly epirubicin in patients with pretreated metastatic breast cancer. METHODS: Fifteen patients were enrolled at four sequential dose levels. Gefitinib was administered orally, at the fixed daily dose of 250 mg. The starting dose of epirubicin was 20 mg/m2. Escalating dose levels of epirubicin were planned by increments of 5 mg/m2 per level, up to the maximum tolerated dose (MTD). Pharmacodynamic studies were performed by determining serum and tissue ERBB2 and EGFR. RESULTS: At the first three dose levels tested no patient experienced a dose-limiting toxicity (DLT). In cohort 4, two patients experienced DLTs (grade 4 dyspnea and asthenia, grade 3 diarrhea and thrombocytopenia) identifying the MTD of epirubicin as 35 mg/m2. Of the 14 cases assessable for response, partial response was documented in two patients, and stable disease in seven, giving an overall disease control rate of 64.2%. The comparison of pre- and post-therapy ERBB2 and EGFR values was not statistically significant between the subgroups of patients regarding responsiveness to treatment. CONCLUSIONS: The recommended dose of epirubicin for phase II studies is 30 mg/m2 in combination with gefitinib at the daily dose of 250 mg. Pharmacodynamic studies did not identify any biomarker predictive of response.     

A phase I study of pemetrexed (ALIMTA) and cyclophosphamide in patients with locally advanced or metastatic breast cancer.

PURPOSE: Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with locally advanced or metastatic breast cancer and WHO performance status 0 to 2 were eligible. Pemetrexed (range, 400-2,400 mg/m(2)) was administered on day 1 of a 21-day schedule followed by cyclophosphamide (range, 400-800 mg/m(2)). Folic acid and vitamin B(12) supplementation began 1 to 2 weeks before the first pemetrexed dose. RESULTS: Fifty-seven pretreated patients were enrolled and received 342 cycles (median, 4 cycles; range, 1-26) through 14 dose levels. The MTD of pemetrexed was 2,400 mg/m(2) (combined with cyclophosphamide, 600 mg/m(2)) with dose-limiting toxicities of grade 4 neutropenia with grade 4 infection and grade 3 diarrhea. Other grade 3 or 4 toxicities included (febrile) neutropenia, thrombocytopenia, anemia, elevated alanine aminotransferase/aspartate aminotransferase, and diarrhea. Pharmacokinetic analysis indicated that pemetrexed clearance and central volume of distribution were 40% lower than single-agent reference data, yielding a 68% increase in total systemic exposure and a 56% increase in maximal plasma concentration. Among the 50 patients evaluable for efficacy, 13 (26%) patients had a partial response and 17 (34%) patients had stable disease. CONCLUSIONS: Pemetrexed was generally well tolerated. The observed toxicities were consistent with the known toxicity profiles of pemetrexed and cyclophosphamide. Considering the MTD and the toxicity and efficacy results in this and prior studies, a low (600 mg/m(2)) and a high (1,800 mg/m(2)) dose of pemetrexed with cyclophosphamide (600 mg/m(2)) will be evaluated in the consecutive prospective randomized phase II study.     

Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial.

PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer. PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m(2) as an intravenous bolus plus paclitaxel 175 mg/m(2) as a 3-hour infusion) or AC (doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2)) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m(2)) and cyclophosphamide (750 mg/m(2)) dose escalation was planned at cycle 2 if no grade >or= 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life. RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm. CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen     

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL).Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages.Results: The MTD in stage I was epirubicin 150 mg/m² and cyclophosphamide 1500 mg/m² with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m², cyclophosphamide 1500 mg/m², vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir <0.5 × 10⁹/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (<25 × 10⁹/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity.Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.     

A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer

A phase I study was conducted in order to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination of vinorelbine and capecitabine in patients affected with metastatic breast cancer. Eighteen patients with histologically confirmed advanced breast cancer, who had failed =1 prior chemotherapy regimen, were enrolled. The median age was 56 years (range, 39-70 years). All but 1 had previously received a combination of anthracyclines and taxanes; performance status (Eastern Cooperative Oncology Group) was 0/1 or 2 in 13 and 5 patients, respectively. Vinorelbine was administered at a fixed dosage of 25 mg/m2 on days 1 and 8 every 3 weeks. Capecitabine was administered orally, at an escalated dose ranging from 1400 mg/m2 to 2250 mg/m2 for 14 consecutive days starting on day 1 of the cycle, divided into 2 daily doses delivered half an hour after eating at 12-hour intervals. Three patients were treated at each dose level: if 1 patient developed a DLT, an additional 3 patients were treated at the same dose level. If 2 additional patients experienced DLT, no further escalation was allowed and the previous dose level was declared MTD. Dose-limiting toxicity was reached at 2250 mg/m2 of capecitabine with 3 out of 3 patients experiencing grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis in 1 patient). Thus, MTD was defined at 2000 mg/m2 capecitabine. Other observed grade 2 side effects were: 1 patient with neutropenia, 1 with hand-foot syndrome, 2 with mucositis, 1 with cutaneous rash, and 1 with thrombocytopenia. With regard to response rate, we observed 1 complete response (5.5%), 6 partial responses (33%), and 4 disease stabilizations (22%). The median time to progression was 12 weeks and the median survival 41 weeks. The MTD of capecitabine in combination with vinorelbine at 25 mg/m2 dosage on days 1 and 8 of a 3-week schedule is 2000 mg/m2/day for 14 consecutive days. Moreover, this regimen showed interesting activity with 61% overall disease control (complete plus partial response plus disease stabilization) in patients pretreated with anthracyclines and taxanes warranting further investigations in a large, multicenter phase II study.     

Phase I and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies.

PURPOSE: The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly. EXPERIMENTAL DESIGN: Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797. RESULTS: Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m(2). The number of patients evaluated at each dose level was as follows: 35 mg/m(2) (n = 3); 50 mg/m(2) (n = 9); and 65 mg/m(2) (n = 6). At 65 mg/m(2), three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m(2) dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration (C(max)) and area under the curve (AUC(0-48)) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC. CONCLUSIONS: The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m(2). The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.     

Pharmacokinetic/pharmacodynamic modeling and simulation of neutropenia during phase I development of liposome-entrapped paclitaxel

PURPOSE: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of liposome-entrapped paclitaxel easy-to-use (LEP-ETU) and to characterize the relationship between LEP-ETU concentrations and the time course of neutropenia in cancer patients. EXPERIMENTAL DESIGN: LEP-ETU was administered to 88 patients and 63 were evaluable for pharmacokinetic/pharmacodynamic (PK/PD) analysis following 1.5- and 3-h infusions every 3 weeks (q3w; dose range, 135-375 mg/m(2)). MTD was identified using a 3 + 3, up-and-down dose-finding algorithm. PK/PD modeling was done to describe the temporal relationship between paclitaxel concentrations and neutrophil count. Simulations assessed the influence of dose and schedule on neutropenia severity to help guide dose selection. RESULTS: The MTD of LEP-ETU was identified as 325 mg/m(2). DLTs occurring at 375 mg/m(2) consisted of febrile neutropenia and neuropathy. The C(max) and area under the plasma concentration-time curve of LEP-ETU were less than proportional with increasing dose. The PK/PD model showed that LEP-ETU inhibition of neutrophil proliferation was 9.1% per 10 mug/mL of total paclitaxel concentration. The incidence of grade 4 neutropenia increased from 33% to 42% across the dose range of 275 to 325 mg/m(2) q3w. For a dose of 110 mg/m(2) given weekly, grade 4 neutropenia was estimated to be 16% compared with 42% for the same total dose administered q3w. CONCLUSIONS: LEP-ETU can be administered safely at higher doses than Taxol. Modeling and simulation studies predict that 325 mg/m(2) LEP-ETU q3w provides acceptable neutropenic events relative to those observed at 175 mg/m(2) Taxol q3w. A 275 mg/m(2) dose may offer an improved therapeutic index.