A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

Background

Pancreas cancer remains a formidable challenge. We report the first prospective analysis of the 3-drug combination of gemcitabine (G), docetaxel (T) and capecitabine (X) (mGTX) with schedule modification to maximize biomodulation of X.

Methods

We conducted a dose escalation study of mGTX in first-line treatment of metastatic pancreas cancer using three dose levels (DL 1-3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750?mg/m² over 75?min, capecitabine was given twice daily and escalated from 500 to 650?mg/m² at DL2 and docetaxel increased from 30 to 36?mg/m² at DL3.

Results

Twenty-one patients (18 evaluable) were enrolled in the study. MTD was reached at DL3 and one DLT was observed at DL2 (prolonged neutropenia). The most common grade 3/4 toxicities were leukopenia (29%) and neutropenia (29%) and fatigue (25%). Tumor growth control rate was 80% (11% PR; 69% SD lasting at least 3?months). Median progression-free-survival was 5.8?months (95% CI 2.7, 10.6) and median overall survival was 7.4?months (95% CI 3.8 16.8). CA 19-9 decreased by at least 50% from baseline in half the patients.

Conclusion

mGTX demonstrates acceptable tolerability with interesting activity in patients with pancreatic cancer. The recommended doses for phase II studies are docetaxel 36?mg/m² days 1 and 8, gemcitabine 750?mg/m² over 75?min days 8 and 15, and capecitabine 625?mg/m² twice daily days 8 through 21.     

Combination chemotherapy of S-1 and taxanes in Korea

Various combination treatments incorporating S-1 are undergoing clinical trials in Korea, especially combinations with taxane, oxaliplatin, or irinotecan. In a phase I study to estimate the maximum tolerated dose of docetaxel in combination with S-1 administered at a fixed dose of 40 mg/m² twice daily on days 1–14 of each 3-week cycle in patients with advanced gastric cancer, 60 mg/m² docetaxel was declared to be the maximum tolerated dose. A phase I/II study of the same schedule of combination chemotherapy with S-1 plus docetaxel reported doses of S-1/docetaxel of 40/75 mg/m² as the maximum tolerated dose. In a phase I study of S-1 plus weekly docetaxel, the patients received variable doses of docetaxel administered intravenously over 1 h on days 1 and 8 and S-1 administered on days 1–14 of each 3-week cycle. The maximum-tolerated doses of S-1 and docetaxel were determined to be 45 mg/m² and 35 mg/m² in this study. A phase I/II study of docetaxel plus S-1 combination chemotherapy from Korea reported a response rate of 43.3%. Also, a phase II study of paclitaxel plus S-1 as first-line therapy in patients with advanced or relapsed gastric cancer showed an overall response rate of 49%. The most frequent significant toxicities in combination chemotherapies with taxane plus S-1 were neutropenia and febrile neutropenia. However, nonhematological toxicities were mild to moderate. A taxane plus S-1 combination regimen could be a new standard regimen for advanced gastric cancer, given its significant activity and favorable toxicity pattern.     

A phase I trial of docetaxel and gemcitabine in patients with advanced cancer

Background:Docetaxel and gemcitabine are active in a broad rangeof malignancies. The objective of this phase I trial was to determine themaximally tolerated doses of the combination of docetaxel and gemcitabine. Patients and methods:Patients with advanced cancer, WHOperformance status 0–2, who had received up to one prior chemotherapyregimen were treated with gemcitabine on days 1 and 8 and docetaxel on day 8repeated every 21 days. Prophylactic ciprofloxacin was commenced on day 11 ofeach cycle and continued until the neutrophil count reached 1.0 ×10⁹/l. G-CSF was not administered. Dose levels studied weredocetaxel/gemcitabine: 60/800, 60/1000, 75/1000, 75/1200, 85/1200 and 100/1200mg/m². Results:Thirty-nine patients were entered and all were assessablefor toxicity. The highest administered dose level was 100 mg/m²docetaxel and 1200 mg/m² gemcitabine with dose limiting toxicitiesof febrile neutropenia, grade 4 neutropenia 7 days, grade 4thrombocytopenia, grade 3 stomatitis and/or grade 3 fatigue in three out ofsix patients. Treatment was well tolerated (40 cycles) in the 10 patientstreated at the recommended dose level (85/1200) with only a single episode offebrile neutropenia and grade 3 or 4 non-hematologic toxicity was infrequent.There was no significant pulmonary toxicity. Responses were seen in a rangeof malignancies including non-small-cell lung cancer. Conclusions:The recommended dose level of 85 mg/m²docetaxel and 1200 mg/m² gemcitabine has a favourable toxicityprofile and is suitable for further investigation in phase II trials. Thisnon-platinum containing regimen warrants further investigation as a potentialalternative to platinum containing regimens in non-small-cell lung cancer andother malignancies.     

Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study

Purpose:The objective of this study was to determine thedocetaxel MTD when combined with gemcitabine or vinorelbine in advanced breastcancer patients who had received previous anthracycline-based chemotherapy foradvanced disease. Patients and methods:Advanced breast cancer patients aged between18 and 70 with ECOG PS 0–2 who had not responded to, or had relapsedafter, first-line anthracycline-based chemotherapy, were randomized to receiveeither gemcitabine 1000 mg/m² or vinorelbine 25 mg/m²in combination with escalating doses of docetaxel (starting from 30mg/m²), all on days 1 and 8 every three weeks. Escalation wasstopped if >33% of patients treated at a given dose level showed DLTat the first cycle. Results:A total of 34 patients with locally advanced (8) ormetastatic disease (26) were treated, for a total of 94 cycles delivered.Nineteen patients received docetaxel in combination with gemcitabine and 15with vinorelbine. All patients had been pretreated with anthracyclines, and24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of40/m² proved to be safe when combined on days 1 and 8 withgemcitabine, while a dose of 35 mg/m² was tolerated in combinationwith vinorelbine. Overall, nine episodes of DLT, all of them neutropenia,occurred at the first cycle. Considering all 94 cyles, grades 3 or 4neutropenia and thrombocytopenia occurred in 15 (44%), and 7(20%) patients. Non-hematologic toxicity was mild, except for threecases of grade 2 peripheral neuropathy. All patients were assessed forresponse on an 'intent-to-treat' basis. Overall, five partial responses wererecorded (docetaxel + gemcitabine = 3 and docetaxel + vinorelbine = 2), fora 15% (95% CI: 5%–31%) overall responserate. Only 1 of 24 (4%) patients who had received weekly dose-densepaclitaxel responded to treatment. Conclusions:The weekly docetaxel administration in combinationwith either gemcitabine or vinorelbine is a well-tolerated treatment forheavily pretreated advanced breast cancer patients. This approach, althoughsometimes capable of achieving a major response, does not seem advisable inadvanced breast cancer patients refractory to both anthracyclines andpaclitaxel.     

Paclitaxel and gemcitabine combination in a biweekly schedule in patients with advanced non small-cell lung cancer: a phase i study

Purpose: This phase I study was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the paclitaxel–gemcitabine combination in a biweekly schedule in chemotherapy-naive patients with advanced non small-cell lung cancer (NSCLC). Patients and methods: Treatment was administered on an outpatient basis every 2 weeks: paclitaxel over a 1-h IV infusion and gemcitabine as a 30-min IV infusion immediately following paclitaxel. Results: Twenty-nine patients were treated at six different dose levels, ranging from paclitaxel 135–175 mg/m² and gemcitabine 1,500–3,000 mg/m². A total of 198 cycles were administered (median 7, range 1–13). DLTs in the first two cycles were grade 4 neutropenia and myocardial ischemia at the dose level paclitaxel/gemcitabine 150/2,000 mg/m², febrile neutropenia and grade 4 neutropenia at the dose level paclitaxel/gemcitabine 175/2,500 mg/m², fatal pneumonitis, sudden death and grade 3 neutropenia at the dose level paclitaxel/gemcitabine 175/3,000 mg/m². The MTD was paclitaxel 175 mg/m² and gemcitabine 2,500 mg/m². The average dose intensity at this dose level was 98%. The overall intent-to-treat response rate was 35.7% (95% confidence interval [CI] 17.97% - 53.47%). Overall median survival was 36 weeks (95% CI, 24-48). Conclusion: Paclitaxel and gemcitabine can be safely administered at a high dose intensity on an every-other-week schedule. The recommended phase II dose is paclitaxel 175 mg/m² and gemcitabine 2,500 mg/m².     

Phase I trial of weekly docetaxel with a 4-weekly cisplatin administration in patients with advanced gastric carcinoma

The docetaxel-cisplatin combination is active against several tumors including gastric cancer but it is followed by severe myelosuppression. Recent experience with weekly taxanes has demonstrated a mild myelotoxicity with high dose intensity. We investigated in a phase I study a weekly schedule of docetaxel on days 1, 8 and 15 and cisplatin on day 1 every 4 weeks in 19 patients with advanced gastric cancer with no prior chemotherapy. Cohorts of patients were treated with escalating doses of docetaxel (starting dose 30 mg/m² per week and increments of 10 mg/m² per week) and cisplatin (starting dose 70 mg/m² and increments of 5 mg/m²). Febrile neutropenia was the only dose-limiting event occurring in four (20%) patients; the dose-limiting toxicity was reached at dose level three (docetaxel 40 mg/m² per week and cisplatin 75 mg/m²). The maximum-tolerated dose was 40 mg/m² per week for docetaxel and 70 mg/m² every 4 weeks for cisplatin. Grade 3/4 neutropenia occurred in six patients (30%); early death occurred in one patient with septic shock because of neutropenia and another with acute coronary ischemia. Two (11%) complete and two (11%) partial responses were documented (ORR 22%; 95% CI 3–39%), with a median response duration of 5 months and median time to progression of 7 months. In conclusion, the combination of weekly docetaxel plus cisplatin is feasible with moderate toxicity and merits further investigation in phase II studies in advanced gastric cancer.Presented as an abstract at the 15th International Congress on Anti-Cancer Treatment, Paris, 9–12 February 2004.     

Phase I dose-escalation study of docetaxel, nedaplatin, and 5-fluorouracil combination chemotherapy in patients with advanced esophageal cancer

More effective protocols are needed for unresectable and recurrent esophageal cancer. Therefore, we conducted a phase I trial to establish the recommended dose of docetaxel, nedaplatin, and 5-fluorouracil (DNF) as combination chemotherapy. Fourteen patients with esophageal cancer were enrolled and received DNF combination therapy at different dose levels according to the treatment and examination plan. Dose-limiting toxicities (DLTs) included febrile neutropenia. DLTs occurred in 3/5 patients at level 4. The recommended doses (level 3) of DNF were 60 mg/m² (day 1), 70 mg/m² (day 1), and 700 mg/m² (days 1–5), respectively, given at 3-week intervals. In conclusion, DNF combined chemotherapy for advanced esophageal cancer was associated with relatively minor adverse events and was safely administered at the recommended dose. A phase II study is now underway.     

A Phase 1 dose-escalation trial of glufosfamide in combination with gemcitabine in solid tumors including pancreatic adenocarcinoma

Absract Purpose To evaluate safety and pharmacokinetics and to establish the maximum tolerated dose of glufosfamide when administered in combination with gemcitabine in advanced solid tumors. Methods This Phase 1 dose-escalation study evaluated the combination of glufosfamide + gemcitabine in patients with advanced solid tumors. Cohorts of three to six patients were treated with glufosfamide doses from 1,500 to 4,500 mg/m² IV over 4 h on Day 1 and gemcitabine 1,000 mg/m² IV over 30 min on Days 1, 8 and 15 of every 28-day cycle. Detailed PK sampling was performed on days 1 and 8 of the first two cycles. Results Nineteen patients were enrolled. Two patients had dose-limiting toxicity: Grade 3 fatigue at 2,500 mg/m² and Grade 4 thrombocytopenia at 4,500 mg/m². Five patients completed six cycles and one patient remained on study for ten cycles. Two patients discontinued for adverse events. Grade 3/4 neutropenia and thrombocytopenia occurred in seven patients and five patients, respectively. The CrCL fell below 60 mL/min in two patients. There was one unconfirmed partial response and 10 of 19 (52.6%) patients had stable disease or better at 8 weeks and three patients had continuing stable disease at 24 weeks. Pharmacokinetic analyses suggest no interaction between glufosfamide and gemcitabine. Conclusion Phase I data indicate that full dose glufosfamide (4,500 mg/m²) can be given safely in combination with gemcitabine. A Phase II study in patients with pancreatic adenocarcinoma is ongoing. Presented in part at the 2006 ASCO Gastrointestinal Symposium. Research supported by Threshold Pharmaceuticals, Inc.     

A Phase II Trial of Neoadjuvant Gemcitabine,Epirubicin, and Docetaxel as Primary Treatment of Patients With Locally Advanced or Inflammatory Breast Cancer

BackgroundThree-drug regimens containing gemcitabine, an anthracycline, and a taxane produce response rates of 70%-90% in patients with metastatic breast cancer (MBC) although accompanied by considerable hematologic toxicity. We explored the combination of gemcitabine/epirubicin/docetaxel as neoadjuvant therapy. Docetaxel was administered weekly to decrease myelosuppression.Patients and MethodsA total of 110 patients with locally advanced or inflammatory breast cancer received neoadjuvant gemcitabine 800 mg/m² intravenously (I.V.) days 1 and 8, epirubicin 75 mg/m² I.V. day 1, and docetaxel 30 mg/m² I.V. days 1 and 8, repeated every 21 days for 4 cycles. Then patients had either mastectomy or breast conservation surgery, and pathologic treatment responses were assessed. After surgery, 4 cycles of adjuvant gemcitabine 1000 mg/m² I.V. days 1 and 8 and docetaxel 35 mg/m² I.V. days 1 and 8 were administered at 21-day intervals. After patients completed chemotherapy, locoregional radiation therapy and/or anti-estrogen therapy was administered per standard guidelines.ResultsTreatment with 4 cycles of neoadjuvant gemcitabine, epirubicin, and weekly docetaxel resulted in an objective response in 79 of 110 patients enrolled (72%; 95% CI, 63-80%). Twenty of 103 patients (19%) who had surgery had pathologic complete response (pCR). Moderate hematologic toxicity was evident during neoadjuvant therapy, with grade 3/4 neutropenia in 41% and febrile neutropenia in 11% of the patients. Protocol-specified dose modifications were required in 35% of the patients, and 58% of the patients used myeloid growth factors.ConclusionThe pCR rate of 19% achieved with gemcitabine, epirubicin, and weekly docetaxel confirms previous reports with similar 3-drug regimens. The use of a weekly schedule of docetaxel did not appear to reduce the incidence of grade 3/4 hematologic toxicity.     

A dose escalation and pharmacokinetic study of the biweekly administration of paclitaxel, gemcitabine and oxaliplatin in patients with advanced solid tumors

Purpose

To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors.

Patients and methods

Patients received escalated doses of paclitaxel (starting dose: 100 mg/m²), gemcitabine (starting dose: 800 mg/m²) and oxaliplatin (starting dose: 50 mg/m²) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle.

Results

Twenty-seven patients (median age 65 years) with performance status 0–1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m², gemcitabine 1,150 mg/m² and LOHP 70 mg/m². The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected.

Conclusions

The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m², gemcitabine 1,000 mg/m² and oxaliplatin 70 mg/m² every 2 weeks. The regimen is generally well tolerated and merits further evaluation.     

Phase I trial of weekly docetaxel and gemcitabine in patients with refractory malignancies

BACKGROUND: A Phase I study using weekly docetaxel and gemcitabine was conducted to investigate toxicity; to determine the maximum tolerated dose (MTD) of each agent; and, in a preliminary fashion, to determine the antitumor activity of the combination. METHODS: Docetaxel and gemcitabine were administered intravenously on Days 1, 8, and 15 every 28 days. The dose levels of docetaxel and gemcitabine were as follows: Level I, docetaxel 20 mg/m(2)and gemcitabine 400 mg/m(2); Level II, docetaxel 30 mg/m(2)and gemcitabine 400 mg/m(2); Level III, docetaxel 30 mg/m(2)and gemcitabine 600 mg/m(2); Level IV, docetaxel 36 mg/m(2)and gemcitabine 600 mg/m(2); and Level V, docetaxel 36 mg/m(2)and gemcitabine 800 mg/m(2). RESULTS: Thirty-three eligible patients were entered. The diagnoses were as follows: Eleven patients had nonsmall cell lung carcinoma, 3 patients had carcinoma of the bladder, 3 patients had renal carcinoma, 2 patients had adrenal carcinoma, 5 patients had unknown primary tumors, and 9 patients had miscellaneous malignancies. Fifty-nine percent of patients had received prior chemotherapy. The median age was 62 years (range, 27-77 years), and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0-1). Five patients were treated at Dose Levels I and II, 6 patients were treated at Dose Levels III and V, and 11 patients were treated at Dose Level IV. Grade 3-4 toxicities during Cycle I included neutropenia, thrombocytopenia, mucositis, and diarrhea. Dose-limiting toxicity, consisting of neutropenia and thrombocytopenia, occurred in three of six patients at Dose Level V. The combination of docetaxel 36 mg/m(2) and gemcitabine 600 mg/m(2) (Dose Level IV) was determined as the MTD and was the recommended Phase II dose. Two patients had a partial response: one patient with bladder carcinoma (Dose Level II) and one patient with nonsmall cell lung carcinoma (Dose Level III). CONCLUSIONS: Overall, weekly docetaxel and gemcitabine were well tolerated. Further studies using this combination are planned, including a Phase II trial in patients with advanced nonsmall cell lung carcinoma.     

Doxorubicin,Paclitaxel and Gemcitabine: a Phase I Study of a New Sequential Treatment in Stage III B - IV Breast Cancer

Abstract

Based on the synergistic interactions of the sequence doxorubicin-paclitaxelgemcitabine obtained in our preclinical study, a Phase I trial was conducted to evaluate the feasibility of this new sequence in breast cancer. Patients with stage IIIBIV breast cancer received doxorubicin on day 1, paclitaxel on day 2 and gemcitabine on day 6 and 13 (steps IIa, III and V) in cohorts of 3 patients. From March 1999 to December 2000, 9 patients were treated. The most important toxicity was hematological. The maximum tolerated dose was reached at the second level because dose-limiting toxicity occurred in 3 patients. Non hematological toxicities were alopecia, diarrhea, asthenia, nausea, mucositis, paresthesia and myalgia. A Phase II trial is ongoing to further investigate the activity of this new sequential treatment with doxorubicin (50 mg/m² day 1), paclitaxel (160 mg/m² day 2) and gemcitabine (800 mg/m² day 6) in advanced breast cancer.     

A pharmacological study of celecoxib and gemcitabine in patients with advanced pancreatic cancer

Purpose To evaluate whether celecoxib alters the conversion of gemcitabine into its active metabolite, difluorodeoxycytidine triphosphate (dFdCTP), in peripheral blood mononuclear cells (PBMCs).Methods Patients with advanced pancreatic cancer who had not received chemotherapy and had acceptable organ function were eligible for the study. The initial dose of gemcitabine was 750 mg/m² administered intravenously at a rate of 10 mg/m²/min on days 1, 8, and 15 every 4 weeks. Celecoxib was administered orally at 400 mg twice a day starting 2 days after the first dose of gemcitabine. Serial blood samples were taken during the first and second gemcitabine infusions and the cellular dFdCTP levels from PBMCs were analyzed.Results Five patients received gemcitabine at 750 mg/m² and six patients received it at 650 mg/m². Severe adverse events included neutropenia, thrombocytopenia, enteritis, and gastric perforation. Two patient died early during treatment. Cellular pharmacology studies showed that the conversion of gemcitabine into dFdCTP was not affected by celecoxib.Conclusion Despite the increased clinical toxicities encountered with the combination, celecoxib did not alter the conversion of gemcitabine into its active metabolites in PBMCs. Gemcitabine 650 mg/m² infusion over 65 min on days 1, 8, and 15 every 4 weeks in combination with celecoxib at 400 mg twice a day was the dose recommended for further study.     

Application of prolonged microdialysis sampling in carboplatin-treated cancer patients

Purpose  To determine the dose-limiting toxicity (DLT) and activity of combination with docetaxel and S-1 on unresectable gastric cancer. Patients and methods  Docetaxel was administered intravenously on day 1 and S-1 was administered orally on days 1–14, every 3 weeks. Doses of each drug in phase I study were docetaxel 60–75 mg/m² and S-1 60–80 mg/m². A phase II study was conducted with the recommended dose (RD) based on phase I. Results  Sixty-five patients (median age 54 years) were enrolled. The DLTs were neutropenia with fever or stomatitis. The RD was docetaxel 75 mg/m² and S-1 60 mg/m². Two patients (aged 66 and 64 years) developed septic shock during the initial part of phase II study. A phase I study at lower dose (docetaxel 60 mg/m² and S-1 80 mg/m²) was conducted for patients older than 60 years, and this dose was determined as the RD for these patients. In the phase II study, frequent grade 3/4 toxicities were neutropenia (47%) and febrile neutropenia (26%). The overall response rate was 50% (95% CI, 35–66%) and median survival was 15.3 months (95% CI, 10.0–20.6 months). Conclusions  Combination with docetaxel and S-1 was active against advanced gastric cancer and gave manageable toxicities. Supported in part by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (0412_CR01_0704_0001).     

Biweekly docetaxel in recurrent ovarian cancer: a phase I dose finding study

Purpose  To determine the maximum tolerated dose of biweekly docetaxel in patients with recurrent ovarian cancer, aiming at 70 mg/m². Methods  In this phase I trial, 8 patients were treated with biweekly docetaxel 50–65 mg/m². Dose-limiting toxicities were defined as any grade 3–4 non-hematological toxicity, prolonged (≥1 week) grade 4 neutropenia or platelet count <25 × 10⁹/L, any neutropenic sepsis or febrile neutropenia, or any grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding. Results  Two groups of 3 patients each were given docetaxel 50 and 60 mg/m², respectively, and 2 patients received 65 mg/m². A total of 43 cycles were given; 26% of these were delayed, while granulocyte colony stimulating factor (G-CSF) support was used in 33%. The main toxicity was neutropenia: at dose levels of 50, 60, and 65 mg/m², grade 3–4 neutropenia occurred in 2/3, 3/3 and 1/2 patients, respectively. One patient experienced febrile neutropenia. A dose reduction was needed in 6 out of 13 cycles at the 65 mg/m² dose level. The study had to be closed prematurely due to the frequent need for G-CSF support, precluding the exploration of the 70 mg/m² dose. Non-hematological toxicities were mild. One patient had a partial response and six patients showed a stable disease. Conclusions  The maximum tolerated dose of biweekly docetaxel could not be determined in this study. It seems that increasing the dose beyond 60 mg/m² without a routine use of G-CSF is difficult.     

Biweekly docetaxel and gemcitabine as neoadjuvant chemotherapy followed by adjuvant doxorubicin and cyclophosphamide therapy in stage II and III breast cancer patients: results of a phase II study

Introduction The purpose of this phase II study was to evaluate the efficacy and safety of neoadjuvant docetaxel/gemcitabine treatment in a biweekly regimen. Materials and methods Patients with stage II/III breast cancer were treated with docetaxel (65 mg/m²) followed by gemcitabine (2500 mg/m²) every 2 weeks for 6 cycles. Patients with a clinical response or stable disease underwent mastectomy or breast-conserving surgery plus axillary dissection. After surgery, patients received 4 cycles of standard doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 21 days. Results Thirty-five patients were included in the trial. The overall response rate was 71.4% (95% CI: 53.7–85.4), with 8 complete and 17 partial responses. Breast conservation was possible in 59% of the patients. Toxicity was manageable. Conclusions We consider biweekly docetaxel and gemcitabine could be an active and tolerable regimen option in the neoadjuvant setting sequentially with standard adjuvant doxorubicin-cyclophosphamide in patients with stage II or III breast cancer.     

Phase I study of docetaxel and cisplatin for patients with previously untreated metastatic non-small-cell lung cancer: a Japanese cooperative study

Background. Docetaxel is one of the most active agents used in the treatment of advanced non-small-cell lung cancer. This phase I study was performed to determine the toxicities, maximum tolerated dose, and pharmacokinetics of the combination of docetaxel and cisplatin in patients with non-small-cell lung cancer, and to recommend a dose for phase II study. Methods. Patients were required to have previously untreated metastatic non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 2 or less, be aged between 15 and 74 years, to have a measurable lesion, and to have adequate organ function. Treatment consisted of 1-h infusion of docetaxel on day 1, followed by 2-h infusion of cisplatin (3 h after docetaxel) at the following docetaxel/cisplatin (mg/m²) dose levels: 50/50, 60/50, 60/60, 60/70, and 60/80. At least three patients were accrued at each dose level. Treatment was repeated every 3 to 4 weeks for responders. Administration of granulocyte-colony stimulating factor was permitted when leukocytopenia or neutropenia of grade 3 or more occurred. Results. Of the 29 patients entered, all were assessable for toxicity and response, but 2 were excluded from analyses of dose-limiting toxicity and maximum tolerated dose. Neutropenia (grade 4, for 3 days or more; n = 1), hepatic dysfunction (grade 3 or more; n = 2) and renal dysfunction (grade 2 or more; n = 3) were observed as dose-limiting toxicities. However, the maximum tolerated dose was not detected, even at the highest dose examined. Tumor response occurred in 13 of the 29 patients (45%; 95% confidence interval; 26%–64%). The pharmacokinetic profiles of docetaxel and cisplatin (n = 17) were similar to those observed after the administration of each dose as a single agent. Conclusion. Docetaxel/cisplatin doses of 60/80 mg/m² were recommended for phase II study, because grade 4 neutropenia occurred in 50% or more patients at docetaxel/cisplatin dose levels of 60/60 mg/m² and above, and the doses of these drugs were restricted to within the approved dose ranges for single-agent use in Japan. The responses observed in this phase I study suggest a high degree of activity of this combination against previously untreated advanced non-small-cell lung cancer and warrant a phase II study at the recommended dose level. Received: February 29, 2000 / Accepted: June 22, 2000     

Weekly Vinorelbine and Docetaxel as Second-Line Chemotherapy for Pretreated Non-Small Cell Lung Cancer Patients: a Phase I-II Trial

Abstract

Docetaxel was proven to be effective as second-line therapy for patients with advanced NSCLC after failure of platinum-based front-line chemotherapy. We designed this phase I/II study to define the Maximum Tolerated Dose of weekly docetaxel combined with weekly vinorelbine, and subsequently evaluate tolerability and activity of this schedule in NSCLC patients who were progressive after treatment with either cisplatin and gemcitabine or carboplatin and paclitaxel regimens. To be eligible for the study, patients were required to have a WHO performance status ≤2, failure after at least two cycles of first platinum-based chemotherapy, and no prior treatment with docetaxel and vinorelbine. A total of 27 patients were enrolled in this phase I/II study. A weekly docetaxel dose of 25 mg/m² was recommended in combination with fixed vinorelbine dose of 20 mg/m², and 24 patients were treated at this dose level. Severe neutropenia (62%) and febrile neutropenia (29%) were the most frequent toxicities, with 83% of patients requiring dose modification or delay. In the phase II study, 5 (21%) patients obtained a partial response, 8 (33%) patients had stable disease, whereas 10 (42%) patients progressed. After a median follow-up of 18.7 months, median survival was 8 months, with 30% surviving at 1 year. Regardless of the use of weekly docetaxel schedule, this regimen was highly myelosuppressive, and did not seem to improve response rate and survival compared to single-agent docetaxel. No further developments of this schedule are warranted.     

A phase I,dose escalation trial of ZD0473, a novel platinum analogue,in combination with gemcitabine

Purpose To develop a combination regimen for clinical testing, we performed a dose escalation study of ZD0473 in combination with gemcitabine. ZD0473 is a novel platinum analogue with an aliphatic cyclic carrier ligand. In vitro and in vivo studies suggest that it possesses a different spectrum of antitumor activity from cisplatin and carboplatin. In single-agent studies of ZD0473, myelosuppression was the predominant toxicity and responses were observed.Methods In this combination phase I trial, 36 patients with advanced cancer were accrued to four dose levels, with doses of ZD0473 and gemcitabine ranging from 60 to 120 mg/m² and 600 to 750 mg/m², respectively. ZD0473 was administered on day 1 and gemcitabine was given on days 1 and 8 of a 21-day cycle.Results Hematologic toxicity was dose-limiting. Grade 3 and 4 thrombocytopenia and neutropenia occurred during 60% and 41% of all cycles. Nonhematologic toxicities were mild and reversible. Two partial responses and 19 patients with stable disease were observed.Conclusions The recommended phase II doses are 90 mg/m² of ZD0473 and 750 mg/m² of gemcitabine for lightly pretreated patients and 600 mg/m² for heavily pretreated patients. The combination of ZD0473 and gemcitabine is associated with dose-dependent thrombocytopenia and neutropenia as well as having promising clinical activity.     

Monthly docetaxel and weekly gemcitabine in metastatic breast cancer: A?phase II trial

Background:Docetaxel and gemcitabine are active againstbreast cancer. The purpose of this phase II study was to evaluate theefficacy and safety of monthly docetaxel combined with weeklygemcitabine in patients with chemotherapy-pretreated metastatic breastcancer. Patients and methods:Thirty-nine patients were enrolled, ofwhom thirty had received prior chemotherapy in the adjuvant setting,seven for metastatic disease, and two for both, including prioranthracycline in 33 patients. Treatment was gemcitabine 800mg/m² days 1, 8, 15 and docetaxel 100 mg/m² on day1, with cycles repeated every four weeks. Results:Response rate was 79% (95% confidenceinterval (CI): 63%–91%), with 2 complete and 29partial responses. Twenty-five of the responders remainedprogression-free for more than six months. Median survival was 24.5months. Delivered dose intensity of gemcitabine was lower than expected(63% of planned). The predominant hematologic toxicity was grade4 neutropenia in 36 patients, complicated by fever in three patients.With the exception of asthenia, severe non-hematological toxicities wereinfrequent. Conclusions:Monthly docetaxel, combined with weeklygemcitabine, has significant but manageable hematologic toxicity.Despite frequent dose adjustments, this doublet is very active inmetastatic breast cancer, producing a high proportion of durableresponses associated with favorable survival.