Phase I/II trial of docetaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

Background. This trial was conducted to determine the maximum tolerated dose (MTD) and principal toxicities of combinations of docetaxel and carboplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) previously untreated with chemotherapy, and to find suitable doses for phase II studies in Japanese subjects. Methods. Japanese patients with advanced NSCLC and performance status 0 to 2 according to the World Health Organization classification, but previously untreated with chemotherapy received docetaxel followed by carboplatin, each infused over a 1-h period. The carboplatin dose was based on the target area under the curve (AUC), using Calvert's formula. Dose levels studied were: docetaxel (mg/m²)/carboplatin AUC (mg/ml·min), 50/4, 60/4, and 60/5, repeated every 3 weeks. Granulocyte-colony stimulating factor (G-CSF) support was first used when dose-limiting toxicities (DLTs) were encountered. Results. Of 14 patients entered, 12 were assessable for toxicity and response. The MTD schedule was: docetaxel, 60 mg/m², with carboplatin, AUC 5 mg/ml·min (DLTs in 3 of 3 patients). The recommended dosage was: docetaxel, 60 mg/m², with carboplatin, AUC 4 mg/ml·min (DLTs in 2 of 6 patients). The main toxic effect was neutropenia, and any nonhematologic toxic effects were mild. No thrombocytopenia occurred. Six of the 12 patients (50%) showed responses; 4 of the 6 at the recommended doses. Conclusion. Docetaxel 60 mg/m², given over a 1-h period, followed by carboplatin, AUC 4 mg/ml·min, given over a 1-h period, is recommended for phase II studies in Japan. This combined chemotherapy has mild toxicity, except for neutropenia, and is useful and easy to administer. We therefore believe that phase II and phase III studies of this therapy would be well justified. Received: October 4, 1999 / Accepted: June 28, 2000     

Phase-I dose escalation and sequencing study of docetaxel and continuous infusion topotecan in patients with advanced malignancies

Purpose Anti-tumor activity can often be enhanced with combination therapy in managing patients with metastatic cancer. However, dose sequence and schedule of delivery can alter the pharmacokinetics, toxicity, and anti-tumor response. Therefore, attention to drug–drug interactions which may be sequence or schedule-dependent are necessary. Docetaxel and topotecan are non-cross-resistance cytotoxic agents with activity in a variety of malignancies. The goal of this study was to determine the maximum tolerated dose of docetaxel and continuous infusion topotecan using two sequences of administration.Experimental design Patients were randomized to schedule A or B and enrolled in four escalating-dose cohorts. On schedule A, docetaxel was administered over 1 h and followed by topotecan administered over 72 h. On schedule B, topotecan was given as a 72 h continuous infusion followed by a 1 h infusion of docetaxel. While the doses for the docetaxel and topotecan were the same for schedule A and schedule B, the toxicities, and thus the determination of maximum tolerated dose (MTD), were assessed independently. The plasma pharmacokinetic disposition of topotecan and docetaxel were evaluated during the first cycle of each sequence to assess drug interactions.Results Thirty patients, 20 males and 10 females were evaluable for toxicity and response. Four patients were chemonaive. Mean number cycles given were 3. Grade 3/4 thrombocytopenia and neutropenia were comparable on both schedules, as was the dose-limiting toxicity (DLT) for both schedules. There were no apparent differences in absolute neutrophil count or platelet nadirs between schedules A and B for three of the four cohorts. The principal non-hematologic toxicity was nausea and vomiting. The time of overlap of topotecan lactone or total concentrations and docetaxel concentrations were greater on schedule A as compared with schedule B and was associated with reduced clearance of docetaxel on schedule A as compared to schedule B. However, the mean clearance for docetaxel (1816 L h^–1 m^–2 and 2928 L h^–1 m^–2 on schedules A and B, respectively, and topotecan 1610 L h^–1 m^–2 and 76 L h^–1 m^–2 on schedules A and B, respectively) were not statistically different (P>0.05).Conclusions The observed toxicity was not sequence-dependent, despite the observed change in kinetics. Docetaxel and topotecan can be administered with acceptable toxicity at the recommended phase-II dose of docetaxel 60 mg m^–2 and topotecan 0.85 mg m^–2 day^–1×3 days.     

A phase I trial of oxaliplatin in combination with docetaxel in patients with advanced solid tumors

The primary objective of this trial was to establish the maximum tolerated dose (MTD) of oxaliplatin 130 mg/m² preceded by escalating doses of docetaxel 60 mg/m² (75, 90, 100 mg/m²) administered every 3 weeks. A total of 11 patients were entered; 10 evaluable for response: 4 stable disease (liver, ovary and esophagus) and 1 partial remission (esophagus). At dose level 1, there was 1 dose-limiting toxicity (DLT) (grade 3 allergic reaction). At dose level 2, there were 3 DLTs (3 grade 4 neutropenia, grade 3 gastritis, diarrhea, hypophosphatemia, neuro-mood). The MTD is docetaxel 60 mg/m² with oxaliplatin 130 mg/m².     

Phase I study of second-line chemotherapy with docetaxel and carboplatin in advanced non-small-cell lung cancer

PURPOSE: Docetaxel and carboplatin have a broad spectrum of antitumor activity. We conducted a phase I study of docetaxel and carboplatin as second-line chemotherapy in previously treated non-small-cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this second-line combination chemotherapy. METHODS: Patients with advanced NSCLC were treated with escalating docetaxel doses in combination with a fixed-target area under the concentration-time curve (AUC) of 5 mg min/ml of carboplatin on day 1 of a 3-4-week cycle. The carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The docetaxel dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2 increments. RESULTS: A total of 16 patients previously treated with anticancer drugs were enrolled through three dose levels (40, 50 and 60 mg/m2 of docetaxel). All patients were assessable for toxicity and response. The MTD was docetaxel 60 mg/m2 with a carboplatin target AUC of 5 mg min/ml, and the dose-limiting toxicities in two of four patients were neutropenia and thrombocytopenia. Overall, neutropenia and thrombocytopenia of grade 3/4 occurred in eight patients (50%) and three patients (19%), respectively. Four patients (25%) and two patients (13%) experienced both grade 1 diarrhea and dermatitis, respectively. Allergic reactions, fluid retention, pneumonitis, neurotoxicity and mucositis were not observed. Of 16 patients, 5 showed an objective response (response rate 31%; 95% CI 14-56%). CONCLUSIONS: The combination of docetaxel and carboplatin is a feasible and well-tolerated second-line chemotherapy regimen in the treatment of NSCLC. Docetaxel 50 mg/m2 under the carboplatin target AUC of 5 mg x min/ml using the Chatelut formula was the recommended dose for phase II study.     

A phase 1 study of vinblastine in combination with carboplatin for children with low-grade gliomas: a Children's Oncology Group phase 1 consortium study

Both carboplatin and vinblastine have demonstrated single-agent activity in children with low-grade gliomas. A phase 1 trial evaluating 2 different schedules of these 2 agents in combination was performed: (1) Schedule A = carboplatin (140 mg/m²) weekly × 3 + vinblastine (4.5 or 3.5 mg/m²) weekly × 6, every 6 weeks; (2) Schedule B = carboplatin (300, 400, or 500 mg/m²) on day 1 + vinblastine (4.0 mg/m²) weekly × 3, every 4 weeks. Twenty-six patients, median (range) age 4.4 (0.7–14.8) years, were enrolled. Four of 9 patients enrolled on Schedule A had recurrent grade 4 neutropenia, suggesting that this schedule was not feasible. Seventeen patients were enrolled on Schedule B. At the 500 mg/m² carboplatin dose level, 2 of 3 patients developed dose-limiting toxicity (elevated alkaline phosphatase, neutropenia). At the 400 mg/m² carboplatin dose level, none of the 6 patients had dose-limiting toxicity. Ten of 16 patients who received treatment on Schedule B completed the prescribed 12 courses. Of the 21 patients evaluable for response, central review confirmed 1 partial response and 6 minor responses. Eleven patients had stable disease (>3 months) and 3 developed progressive disease. Seven of 9 patients with visual pathway tumors and acute visual changes prior to enrollment had documented improvement. The recommended phase 2 dose and schedule is carboplatin, 400 mg/m²/dose on day 1, and vinblastine, 4 mg/m²/dose, weekly × 3, repeated every 4 weeks. Further study of this regimen in patients with low-grade glioma is warranted.     

Concurrent Chemoradiation Therapy With Docetaxel/Cisplatin Followed by Docetaxel Consolidation Therapy in Inoperable Stage IIIA/B Non–Small-Cell Lung Cancer: Results of a Phase I Study

IntroductionDocetaxel consolidation therapy (DCT) after concurrent cisplatin/docetaxel chemoradiation therapy (CRT) produces high tumor control in non–small-cell lung cancer (NSCLC); toxicity is, however, considerable. We aimed to determine the maximally tolerated dose (MTD) for DCT.Patients and MethodsPatients with inoperable stage IIIB NSCLC received docetaxel 20 mg/m² and cisplatin 25 mg/m² on days 1, 8, 15, 22, 29, and 36, with concurrent radiation therapy 5 days per week for a total dose of 66 Gy. Patients achieving stable disease, partial response, or complete response were given DCT on days 71, 92, and 113. DCT was started with 75 mg/m² and titrated depending on tolerability. The MTD of docetaxel was defined as the dose preceding that at which 3 or more patients experienced dose-limiting toxicity (DLT).ResultsOf 23 patients enrolled (median age, 58.8 years ± 7.3 years), 19 received complete CRT (4 withdrew because of toxicity). Of the patients receiving complete CRT, 1 patient died and 1 became operable, leaving 17 patients eligible for DCT starting at 75 mg/m². After the third patient with DLT, dose was reduced to 60 mg/m². Median survival was 27.6 months ± 23.1 months. Median TTP was 12.4 months ± 10.7 months.ConclusionThe MTD of DCT after concurrent cisplatin/docetaxel CRT was determined to be 60 mg/m², but toxicity was considerable. The benefit-risk ratio of DCT has, however, been questioned by a placebo-controlled phase III trial. Further phase III trials need to consider further stratification factors (pretreatment forced expiratory volume [FEV]₁, hemoglobin, performance, and stage) to define a role for DCT in patients with NSCLC.     

Phase I trial of dose escalation of capecitabine combined with fixed docetaxel in previously treated patients with non-small cell lung cancer

Objective

Capecitabine combined with docetaxel have demonstrated antitumor synergy for non-small cell lung cancer (NSCLC). Due to absence of phase I trial in China, we conducted this study to define the maximum-tolerated dose (MTD) of capecitabine with fixed docetaxel for Chinese patients with previously treated NSCLC.

Methods

Previously treated patients with NSCLC were entered into this study. Escalating doses of capecitabine with fixed docetaxel were administered in a modified Fibonacci sequence. The initial doses were capecitabine 625 mg/m², bid, on days d5?Cd18, and docetaxel 30 mg/m² on days 1 and 8, respectively. The regimen was repeated every 21 days. If no dose-limiting toxicity (DLT) was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be one dose level below the level at which DLT appeared.

Results

Eighteen patients received 67 cycles at capecitabine of level I (1250 mg/m², divided into 625 mg/m², bid) and level II (1500 mg/m², 750 mg/m², bid). The most common toxicities were neutropenia, hand and feet syndrome, fatigue and nausea. Eight DLTs occurred in 5 patients in the whole group, including 1 DLT in dose level I and 7 DLTs in dose level 2. Since 4 of 6 patients in level II experienced DLTs, we declared thus level I was MTD.

Conclusion

MTD of our phase I trial was capecitabine of 1250 mg/m²/d combined with docetaxel of 30 mg/m²/wk. This combination regimen was well tolerated for previously treated patients with NSCLC. The efficacy of this schedule is currently being further evaluated in a prospective phase II trial.     

Phase I/II docetaxel plus concurrent hyperfractionated radiotherapy in locally advanced unresectable head and neck cancer (TAX.ES1.102 study)

Introduction

Concurrent chemotherapy and radiotherapy is recommended for the treatment of locally advanced unresectable head and neck (H&N) cancer.

Objective

The primary purpose of the Phase I part of the study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose (RD) of docetaxel with hyperfractionation radiotherapy. The primary objective of the Phase II part was to determine the response rate to the RD of treatment and, secondarily, to assess the toxicity of the schedule, time to progression, duration of response and overall survival (OS).

Materials and methods

Patients (n=9 in Phase I; n=19 in Phase II) had unresectable H&N cancer. The starting docetaxel dose was 20 mg/m² plus hyperfractionated radiotherapy. Ramping of docetaxel was 5 mg/m² if MTD was not reached.

Results

MTD of docetaxel was 20 mg/m². Limiting toxicities were grade 4 pneumonia and grade 4 mucositis. The RD was 15 mg/m2. Phase II initial response was 76% (CR=18%; PR=9%); updated response was 89% (CR=59%; PR=29%). The median progression-free survival was 7.8 months (95%CI: 0?C22.3) and the median OS was 15.1 months (95%CI: 0?C35.9). Grade 3?C4 toxicities included mucositis (91%), pneumonia (27%) and fatigue (27%). There were 5 toxic deaths (2 from intestinal perforation, 3 from pneumonia).

Conclusions

Weekly docetaxel+hyperfractionation radiotherapy is active but with high toxicity rates and, hence, this treatment regimen would be difficult to justify.     

Phase I clinical trial of liposomal-encapsulated doxorubicin citrate and docetaxel, associated with trastuzumab, as neo-adjuvant treatment in stages II and IIIA, HER2-overexpressing breast cancer patients. GEICAM 2003-03 study

Background: We carried out a phase I clinical trial to establishthe dose-limiting toxicity (DLT) and the maximum tolerated dose(MTD) of the combination of liposome-encapsulated doxorubicincitrate (LD) and docetaxel in breast cancer patients. Patients and methods: Patients with HER-2-overexpressing stagesII and IIIA breast cancers were treated in different dose cohortsof three patients. The MTD cohort was expanded up to six patients.The patients received LD and docetaxel every 21 days, plus weeklytrastuzumab, with pegfilgrastim support. Results: A total of 20 patients were enrolled, 18 of them beingassessable for toxicity and response. DLTs observed for thiscombination were diarrhea, fatigue, febrile neutropenia, stomatitis,myalgia, and nonneutropenic infection (pneumonia). LD 50 mg/m²and docetaxel 60 mg/m² every 21 days have been the MTD, withno episode of DLT observed. Seven patients developed left ventricularejection fraction decline (six grade 1 and one grade 2). Nointerruptions of the treatment were needed as a consequenceof cardiac toxicity. Pathologic complete response was achievedin eight patients (44%). Conclusions: The MTD and recommended dose for phase II trialsof LD and docetaxel are 50 and 60 mg/m², respectively. The achievedresults on cardiotoxicity are promising. Key words: Her2 positive, breast cancer, neoadjuvant chemotherapy, liposomal doxorubicine, docetaxel, trastuzumab, cardiotoxicity Received for publication August 26, 2008. Accepted for publication September 5, 2008.     

Dose-finding study of docetaxel, oxaliplatin, and S-1 for patients with advanced gastric cancer

Purpose  To determine the maximum tolerated dose (MTD), recommended dose (RD), and activity of combined docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy on metastatic gastric cancer. Patients and methods  Docetaxel and oxaliplatin were administered intravenously on day 1 and S-1 was administered orally on days 1–14 of every 21-day cycle. The doses of docetaxel/oxaliplatin/S-1 in the phase I study were level −1A, 52.5/80/60 mg/m²; level −1B, 52.5/80/80 mg/m²; level 1A, 52.5/105/80 mg/m²; level 1B, 52.5/130/80 mg/m²; level 2A, 60/105/80 mg/m²; level 2B, 60/130/80 mg/m²; level 3A, 67.5/105/80 mg/m²; level 3B, 67.5/130/80 mg/m²; level 4A, 75/105/80 mg/m²; level 4B, 75/130/80 mg/m². Results  Nine patients were enrolled. One of six patients at level 1A and two of three patients at level 1B developed dose-limiting toxicity (febrile neutropenia) during the initial two cycles. Therefore, the doses used at levels 1B and 1A were defined as the MTD and RD, respectively. All patients were evaluated for toxicity and response. Six partial responses were noted, and the overall response rate was 67%. Conclusion  The RD of the DOS regimen in patients with advanced gastric cancer was docetaxel 52.5 mg/m² and oxaliplatin 105 mg/m² on day 1 and S-1 80 mg/m² on days 1–14 of every 21-day cycle. A phase II study using the RD is currently underway.     

Dose-escalation study of CHOP with or without prophylactic G-CSF in aggressive non-Hodgkin's lymphoma

Background:CHOP is accepted as the gold standard for first linechemotherapy of aggressive non-Hodgkin's lymphoma (NHL). A dose-escalationstudy of CHOP was conducted to determine the maximal tolerated dose (MTD) andtoxicity profile of CHOP at three-week intervals with or without prophylacticrecombinant human granulocyte colony-stimulating factor (rHuG-CSF) in patientswith aggressive NHL. Patients and methods:The doses of drugs were escalated from 50mg/m² to 70 mg/m² for doxorubicin and from 750mg/m² to 2250 mg/m² for cyclophosphamide, withconventional doses of vincristine and oral prednisolone. After the MTD wasdetermined without rHuG-CSF, dose escalation was conducted with prophylacticrHuG-CSF. Results:Thirty-three patients with NHL were enrolled into thestudy. The MTD without prophylactic rHuG-CSF was 70 mg/m² ofdoxorubicin and 1250 mg/m² of cyclophosphamide, with neutropeniaas a dose-limiting toxicity. The MTD with prophylactic rHuG-CSF was 70mg/m² of doxorubicin and 2250 mg/m² of cyclophosphamide.The overall response rate was 100% (76% complete response and24% partial response). Progression-free survival and overall survivalat five years were 45% and 66%, respectively. Conclusions:Significant dose escalation of doxorubicin andcyclophosphamide was feasible with prophylactic rHuG-CSF. The efficacy ofdose-escalated CHOP should be compared with that of standard CHOP.     

卡培他滨二线治疗非小细胞肺癌的剂量递增研究

目的 探讨卡培他滨(capecitabine,CAPE)联合多西紫杉醇(docetaxel,TXT)二线治疗非小细胞肺癌(NSCLC)时卡培他滨的最大耐受剂量(maximum-tolerated dose,MTD).方法 应用改良的Fibonacci法给予复治的NSCLC患者递增剂量的CAPE联合固定剂量TXT化疗,剂量Ⅰ(625 mg/m2,每天2次)和剂量Ⅱ(7 50 mg/m2,每天2次),两组1 8例患者共接受了67周期化疗.起始剂量为CAPE625 mg/m2,每天2次,d5～d18,TXT 30 mg/m2,d1,d8,每21天重复.如果没有剂量限制性毒性(dose limiting toxicity,DLT)出现,则升至下一剂量组,直至出现DLT.MTD定义为DLT出现的剂量水平的低一剂量.结果 主要的不良反应为粒细胞减少症、手足综合征、乏力和恶心.全组共5例发生8个DLT,剂量Ⅰ组1个(1例患者),剂量Ⅱ组7个(4例患者).由于在剂量Ⅱ组6例患者中4例出现了DLT,根据定义笔者确定剂量T为MTD.结论 此剂量递增试验的MTD是:卡培他滨1 250 mg/(m2·d)(625 mg/m2,每天2次)联合多西紫杉醇30mg/m2,d1,d8,每21天重复.复治NSCLC患者对此联合方案耐受性良好.     

局部晚期鼻咽癌调强放疗同期化疗前TPF诱导化疗Ⅰ和Ⅱ期临床研究

目的 探讨局部晚期鼻咽癌调强放疗同期化疗前多西泰索加顺铂加氟尿嘧啶方案诱导化疗中顺铂最大耐受剂量(MTD)及方案安全性、有效性。方法 选取 33例局部晚期鼻咽癌患者,通过剂量递增试验确立顺铂MTD并评价临床疗效及不良反应。结果 多西泰索60 mg/m²第1天、氟尿嘧啶550 mg/m²第 1~5天剂量下顺铂MTD为65 mg/m²第1天,每3周重复下3、4级不良反应发生率分别为中性粒细胞降低 67%,粒细胞缺乏性发热9%,腹泻21%,口腔黏膜炎6%。除剂量限制性毒性患者外,其余均完成了治疗。诱导化疗后有效率为97%,其中完全缓解率为21%。结论 鼻咽癌流行地区每3周重复用多西泰索60 mg/m²第1天、顺铂65 mg/m²第1天、氟尿嘧啶550 mg/m²第 1~5天治疗局部晚期鼻咽癌患者是安全有效的。     

Phase I/II dose escalation study of docetaxel and carboplatin combination supported with amifostine and GM-CSF in patients with incomplete response following docetaxel chemo-radiotherapy: additional chemotherapy enhances regression of residual cancer

Taxanes have been shown to interact with anti-apoptotic proteins. In the present study we investigated whether the addition of taxane in combination with DNA damaging drugs can further enhance tumor shrinkage in cases with incomplete response to radiotherapy. Since the dose of docetaxel in combination with carboplatin is not known, the above hypothesis was tested in the context of a dose escalation phase I study. Twenty-eight patients with locally advanced chest or pelvic tumors, showing residual disease on CT scans performed 40 d following docetaxel radio-chemotherapy, were recruited in a dose escalation protocol of docetaxel/carboplatin supported with amifostine and GM-CSF. The starting dose of docetaxel was 40 mg/m² every 2 weeks. Carboplatin dose was calculated using the Calvert formula and was escalated in cohorts of 4 patients (starting dose AUC2 every two weeks; AUC0.5 increments up to AUC3). Thereafter the docetaxel dose was increased to 50 and 60 mg/m², while carboplatin was escalated (by AUC0.5 increments) starting from AUC3 and AUC4 respectively. Amifostine (600 mg/m²) was administered i.v. before carboplatin and GM-CSF (480μg) was injected s.c. on days 5, 6 and 10, 11 of each cycle. Six cycles were given and response was assessed 2 weeks after the end of chemotherapy. None out of four patients treated in the 6th dose level cohort (50mg/m² of docetaxel and AUC4 of carboplatin every 2 weeks) showed any grade 2–4 hematologic toxicity. Mild non-hematologic toxicity such as neuropathy, leg edema, pleural effusion, pyrexia, alopecia grade 2 and hypersensitivity was observed in 4–12% of patients. Out of four patients treated in a 7th cohort (docetaxel 60mg/m² and carboplatin AUC4), one developed grade IV neutropenia and two developed grade 3 severe asthenia requiring treatment delay for 2 weeks. Out of 11 patients with PR following docetaxel radio-chemotherapy, 7 (63%) showed CR after docetaxel/carboplatin additional chemotherapy. Eight out of 17 patients with MR following docetaxel radio-chemotherapy showed PR (47%) and one showed CR (6%) after additional chemotherapy. High dose combined docetaxel (50 mg/m²) and carboplatin (AUC4) chemotherapy can be safely administered on a two-weekly basis if supported with amifostine and GM-CSF. Such an additional therapy may be important in patients with incomplete response after chemo-RT. Broad spectrum cytoprotection with amifostine and GM-CSF may also contribute to the reduction of incidence of neurosensory reactions and asthenia in patients treated with taxanes.     

Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study

Purpose The aim of this study was to investigate the combination of vinorelbine (VRL) alternating intravenous (i.v.) and oral in combination with docetaxel (DCT) as first-line chemotherapy of patients with metastatic breast cancer. Patients and methods Tested doses were 60 or 70 mg m⁻² given on day 1 for DCT, 20 to 25 mg m⁻² for i.v. VRL on day 1, 60 mg m⁻² on day 8 or day 15 for oral VRL. Day 1 was administered every 3 weeks. Three to six patients were treated per dose level. Results The median age of the 30 treated patients was 60 years. Four patients were non evaluable for the maximum tolerated dose (MTD) and were replaced. Reported dose-limiting toxicities were 11 omissions of oral VRL for neutropenia, two cases of febrile neutropenia and two grade 4 neutropenia ≥7 days. Dose levels using DCT doses >60 mg m⁻² and/or i.v. VRL doses >20 mg m⁻² met the criteria for MTD. Most frequent toxicities were febrile neutropenia in seven patients and neutropenic infection in four patients (one fatal). Therefore, the recommended schedule was established at i.v. VRL 20 mg m⁻² with DCT 60 mg m⁻² on day 1 and oral VRL 60 mg m⁻² given on day 15 every 3 weeks. At this recommended schedule, only one of six patients experienced febrile neutropenia. Among 22 patients evaluable for tumour response, 2 complete and 10 partial responses were reported. Pharmacokinetics of combined VRL and DCT demonstrated the absence of mutual interaction. Conclusions This phase I study established the recommended doses and schedules of the combination alternating i.v. and oral VRL with DCT, this recommended regimen being further explored in a phase II study.     

Phase I-II parallel study of docetaxel on a bimonthly schedule in refractory metastatic breast carcinoma

Background. The 3-week schedule with docetaxel (DTC) 75–100 mg/m² is associated with severe neutropenia, gastro-intestinal side-effects and fluid retention in a significant proportion of patients, which may be of concern in more elderly or poor performance status patients. A phase I–II trial was carried out to test the feasibility and the activity of a new bimonthly schedule of DCT. Patients and methods. The trial included a phase I study which aimed at the identification of dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of DCT on a bimonthly schedule. The first group of three patients received DCT 40 mg/m², and in absence of DLT, DCT dosage was escalated by 10 mg/m²/cycle until DLT was reached. In the phase II study, patients were randomized to receive: (a) standard 3-weekly DCT at the dose of 75 mg/m² (calibration arm); or (b) bimonthly schedule with DCT at the dose recommended in the phase I study. All patients were pretreated with chemotherapy, mostly anthracycline-based regimens, for advanced/metastatic disease. Analysis of response rates, toxicity, and dose-intensity were the main aims of the study. Results. The DLT was represented by severe myelosuppression which was recorded in all patients treated at 70 mg/m² dose level. Therefore, the MTD was 60 mg/m² on a bimonthly schedule. However, the dose recommended for the phase II trial was 50 mg/m², because no difference in delivered dose-intesity was seen between the 50 and 60 mg/m² dose levels, and the latter dosage was still associated with grade 3 neutropenia in most patients. The parallel phase II study showed that the bimonthly schedule of DCT (50 mg/m²) allows to deliver the same dose-intensity of DCT 75 mg/m² every 3 weeks. Grade 3–4 side-effects were rather infrequent in patients treated with the bimonthly schedule. Overall response rate (ORR) was 41 and 44% for the DCT 50 mg/m² bimonthly and the DCT 75 mg/m² every 3 weeks, respectively. Conclusions. Data achieved in the phase I part of the study showed that DCT 50 mg/m² every 15 days is the recommended dose for phase II studies, while results achieved in the phase II trial suggest that DCT 50 mg/m² in a bimonthly schedule is active as second-line chemotherapy for MBC being able to induce an ORR in the range reported for DCT 75–100 mg/m² every 3 weeks. The bimonthly schedule is, however, associated with relatively low toxicity. This characteristic may render the bimonthly schedule particularly attractive for future phase II trials of DCT in combination with other antineoplastic agents.     

A phase I trial of AUC-directed carboplatin with infusional doxorubicin and ifosfamide plus G-CSF in patients with advanced gynecologic malignancies

The effect of the addition of G-CSF to carboplatin, ifosfamide and doxorubicin (CIA) at the maximally tolerated dose (MTD) was studied in a phase I clinical trial. Nine patients with incurable solid tumors were treated: six endometrial and epithelial ovarian cancers, one colon cancer with pelvic masses and two unknown primary cancers. The carboplatin dose was calculated using the Calvert formula and administered in a standard 30-min intravenous infusion. The initial carboplatin dose was AUC 4.0 mg/ml per min. Fixed doses of ifosfamide (1.25 g/m² per day), mesna (1.0 g/m² per day, and doxorubicin (15 mg/m² per day) were combined and given as a 4-day continuous intravenous infusion in an attempt to decrease nonhematologic toxicity. The dose-limiting toxicity of CIA was myelosuppression, mainly neutropenia and thrombocytopenia. Nonhematologic toxicities were hemorrhagic cystitis, weakness, fatigue, and nausea and vomiting. The MTD for CIA was established at the first dose level of carboplatin (4.0 mg/ml per min). Following this, G-CSF was added to the regimen in an unsuccessful effort to escalate the carboplatin dose. Free and total carboplatin pharmacokinetics were determined using flameless atomic absorption spectroscopy. There was one complete response and one partial response among eight evaluable patients. Both responding patients had advanced ovarian cancer. We conclude that carboplatin dose intensification beyond an AUC of 4.0 mg/ml per min is not made feasible by the addition of G-CSF to infusional doxorubicin and ifosfamide in patients with advanced gynecologic cancer. Received: 22 December 1999 / Accepted: 28 April 2000     

Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule

Background Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing.Methods Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m², respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay.Results A total of 35 patients were treated. The MTD was docetaxel 30 mg/m² plus irinotecan 65 mg/m². Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease.Conclusions The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.     

A combination study of S-1 and docetaxel in patients with head and neck cancer

We determined the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and efficacy of drug sequence on toxicities of the combination of S-1 and docetaxel for head and neck cancers. S-1 was administered at the full dose of 80 mg/m2 for two weeks and docetaxel on day 1 according to the following dose escalation schedule: level 1: 40 mg/m2, level 2: 50 mg/m2, and level 3: 60 mg/m2. DLT was observed in two cases of level 3. Although grade 3 leukopenia was observed in level 3, all of the toxicities were not severe. Recommended doses for the next phase evaluation were determined to be 80 mg/m2 of S-1 and 50 mg/m2 of docetaxel. Oral S-1 combination with docetaxel is a feasible and promising combination regimen that is appropriate for an outpatient setting.     

A Phase I Trial of Outpatient Weekly Docetaxel and Concurrent Radiation Therapy for Stage III Unresectable Non–Small-Cell Lung Cancer: A Vanderbuilt Cancer Center Affiliate Network (VCCAN) Trial

Docetaxel has demonstrated activity as a radiosensitizer in numerous preclinical studies, probably due to its role as a cell cycle synchronizer for the G2/M radiosensitive phase of the cell cycle. We conducted a phase I trial to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of docetaxel with concurrent thoracic radiation therapy (TRT) to patients with unresectable stage III non–small-cell lung cancer (NSCLC). Fifteen patients were entered into this study. Docetaxel was administered as a 1-hour intravenous (I.V.) infusion, repeated every week for 6 weeks with starting dose of 20 mg/m². Doses were escalated in 10 mg/m² increments in successive cohorts of three new patients, if tolerated. Unacceptable toxicity was defined as grade ≤ 3 nonhematologic or hematologic toxicity according to Eastern Cooperative Oncology Group (ECOG) toxicity criteria. TRT was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy). At the first dose level (20 mg/m²/week), one patient developed grade 4 hyperglycemia and accrual was expanded to five patients. At the second level (30 mg/m²/week), two out of six patients developed grade 3 esophagitis. At the third level (40 mg/m²/week), two out of four patients developed grade 3 esophagitis and one patient developed grade 3 pulmonary toxicity. The weekly docetaxel MTD with concurrent radiation therapy (RT) was found to be 30 mg/m². The DLT was esophagitis and pulmonary toxicity. Other toxicities encountered included skin reaction, nausea and vomiting, as well as diarrhea. Additionally, there were no treatment-related mortalities or late-occurring toxicities. Esophagitis was the principal DLT of concurrent weekly docetaxel and thoracic radiation in the outpatient setting. The MTD of concurrent weekly docetaxel with TRT is 30 mg/m² weekly for 6 weeks. This study is still open to accrual with weekly docetaxel and TRT in locally advanced NSCLC patients.