Phase I study of amrubicin and vinorelbine in non-small cell lung cancer previously treated with platinum-based chemotherapy

Background  Combination chemotherapy comprising amrubicin and vinorelbine as a second-line therapy for advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. To determine the maximum tolerated dose (MTD) and recommended dose (RD), the present phase I study examined patients with advanced NSCLC. Methods  The subjects were nine patients with histologically confirmed advanced NSCLC, Eastern Cooperative Oncology Group performance status 0–1, prior platinum-based first-line chemotherapy, and measurable or evaluable lesions. Treatment consisted of five dose levels, with amrubicin 35–45 mg/m² administered as a 5-min intravenous infusion on days 1–3 and vinorelbine 15–25 mg/m² given as a 1-h intravenous infusion on days 1 and 8, every 3 weeks. Results  All patients had received carboplatin and paclitaxel as first-line therapy. Dose-limiting toxicity (DLT) was seen in two of six patients (febrile neutropenia and deep vein thrombosis ) at level 1, allowing us to conduct level 2. At level 2, all three patients experienced DLT (leucopenia ≥4 days in one patient; febrile neutropenia in three patients; and infection in two patients), and this level was determined as the MTD. Subsequently, level 1 (amrubicin 35 mg/m² and vinorelbine 15 mg/m²) was defined as the RD. Responses in the nine patients included a partial response in one patient and stable disease in four patients. Conclusion  As second-line therapy, the RD of the combination of amrubicin and vinorelbine is 35 mg/m² and 15 mg/m², respectively. Further study should proceed to clarify the efficacy of this regimen.     

Phase I study of daily S-1 combined with weekly irinotecan in patients with advanced non-small cell lung cancer

Background  S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan. Methods  Patients with advanced NSCLC received S-1 (80 mg/m²) on days 1–14 and irinotecan (50–80 mg/m²) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients. Results  At doses of 50–70 mg/m², no patients experienced any DLT, whereas, at a dose of 80 mg/m², two of four patients experienced DLTs. Two patients experienced grade 3 toxicities — neutropenia and diarrhea. Conclusion  The MTD of weekly irinotecan was 80 mg/m², making its RD for phase II trials 70 mg/m².     

Cisplatin plus continuous infusion vinorelbine for the treatment of advanced non-small cell lung cancer: a phase I-II study

Backbround In this Phase I/II trial, the maximum-tolerated dose (MTD) and activity of cisplatin plus vinorelbine (VRL) administered in continuous in-fusion as first-line treatment of advanced non small cell lung cancer (NSCLC) was determined in 12 consecutive chemotherapy-naive patients with advanced NSCLC. Patients and methods The dose of cisplatin was 100 mg/m² in all patients, and vinorelbine was administered as an initial intravenous (iv) bolus of 8 mg/m² on day 1 followed by a 4-day continuous iv infusion at 4 different 24 h dose levels (DLs) to be repeated every 21 days. All 12 patients (47 cycles) were evaluable for response and toxicity. Results The MTD was 8 mg/m² bolus followed by a continuous iv infusion of 8 mg/m² per day over 4 days. The dose limiting toxicities (DLT) were febrile neutropenia in 4 patients and grade 3 mucositis in 1 patient. There was less neuro-toxicity and compared to the weekly bolus scheme. There was no significant cumulative toxicity after 3 cycles. Partial responses were observed in 6 patients; an overall response rate of 50% (95% CI: 30–65%). Median time to progression was 5,5 months (95% CI: 1,5–11 months) and median survival was 11 months (95% CI: 5–20 months). Conclusions The results demonstrate that, in this setting of first-line treatment of NSCLC, cisplatin plus vinorelbine at 8 mg/m² bolus followed by a continuous infusion of 8 mg/m² per day over 4 days is the recommended schedule. Further trials would be useful to establish activity of this combination.     

Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies

Purpose  To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine. Methods  Eligible adults (advanced solid tumor; performance status ≤2) received capecitabine 500 mg/m² PO BID days 1–14 and FDR gemcitabine (400–1,000 mg/m² escalated by 200 mg/m² increments) at 10 mg/m²/min days 1 and 8 on a 21-day cycle. A traditional 3 + 3 cohort design was used to determine the MTD. Results  Thirty patients (median age 59 years) were enrolled. The predominant grade ≥3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m² gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia ≥7 days). At dose level 3 (800 mg/m² gemcitabine), one patient had a DLT (grade 3 neutropenia ≥7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m² PO BID days 1–14 with 800 mg/m² FDR gemcitabine days 1 and 8 infused at 10 mg/m² per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas. Conclusions  This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas. The results of this research appeared as abstract ID 13509 at the 2008 American Association of Clinical Oncology meeting in Chicago, IL, USA.     

Inability to escalate vinorelbine dose intensity using a daily × 3 schedule with and without filgrastim in patients with metastatic breast cancer

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support. Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC >1500/mm², PLT >100 000 m³, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m² per day and dose escalations of 5 mg/m² were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm³ for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm³. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m². Results: At DUMC, DLT was seen at 20 mg/m² in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m² and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients at DFCI were treated with vinorelbine at a dose of 25 mg/m² with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer. Received: 27 October 1997 / Accepted: 16 April 1998     

Phase I study of docetaxel and irinotecan in patients with advanced non-small-cell lung cancer

The role of non-platinum combination chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has not yet been clarified. In this phase I study, the dose-limiting toxicity (DLT), the maximum tolerable dose (MTD) and the antitumor activity of a two-drug combination of docetaxel (DCT) and irinotecan (CPT) in patients with advanced NSCLC were evaluated. Previously untreated patients with NSCLC in stage IIIB with malignant pleural effusion or stage IV were eligible. Both drugs were administered by 1-h intravenous infusion on day 1, and repeated every 3 weeks. DCT was given before CPT administration. Five escalating dose levels of DCT/CPT (40/135, 50/135, 50/150, 60/150, and 60/165 mg/m2) were studied. Eighteen patients received 44 courses. The DLT was considered to be neutropenia, because grade 4 neutropenia lasting for 3 days or more was observed in three patients, which was accompanied with three episodes of febrile neutropenia. As a non-hematological toxicity, grade 3 diarrhea occurred in three patients. Since all the three patients treated at the fifth dose level (DCT at 60 mg/m2 and CPT at 165 mg/m2) experienced DLT (grade 4 neutropenia in two patients and grade 3 hepatic toxicity in one), this dose level was determined to be the MTD. The objective response rate was 33.3%, and the median survival time was 13.6 months. To confirm the effectiveness of this combination for advanced NSCLC which was suggested in the present study, a phase II study with the recommended doses (150 mg/m2 for CPT and 50-60 mg/m2 for DCT) is warranted.     

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.     

Phase I study of high-dose epirubicin and vinorelbine in previously untreated non-small-cell lung cancer stage IIIB-IV.

The aim of the study was to determine the maximum tolerated dose (MTD) for the combination of high-dose epirubicin and vinorelbine in chemotherapy-naive patients with inoperable non-small-cell lung cancer (NSCLC). Twenty-one patients with stage IIIB and IV NSCLC were treated in a single-centre study with escalating doses of epirubicin and vinorelbine given on an outpatient basis. The first dose level comprised epirubicin 100 mg m-2 on day 1 and vinorelbine 20 mg m-2 (days 1 and 8) given intravenously every 3 weeks. Escalating doses for epirubicin and vinorelbine were respectively 120 (day 1) and 20 (days 1 and 8), 120 (day 1) and 25 (days 1 and 8) and 135 (day 1) and 25 (days 1 and 8) mg m-2. Inclusion criteria were age < or = 75 years, ECOG performance score < or = 2 and normal renal, hepatic and bone marrow functions. Dose-limiting toxicities were thrombocytopenia grade II and neutropenia grade III on day 8, febrile neutropenia, and neutropenia lasting > 7 days. No dose-limiting toxicity (DLT) was observed at the first dose level; at the 135/25 mg m-2 dose level three out of six patients had a DLT which was considered as unacceptable. The only non-haematological toxicity reaching grade III was nausea/vomiting. One patient showed cardiac toxicity. No neurotoxicity and no treatment-related deaths were seen. The maximum tolerated dose of epirubicin and vinorelbine is 135 mg m-2 (day 1) and 25 mg m-2 (days 1 and 8) respectively, causing mainly haematological toxicity. The recommended dose of epirubicin and vinorelbine for phase II studies is found to be 120 mg m-2 and 20 mg m-2 respectively.     

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.     

A multicenter phase I trial of metronomic oral vinorelbine plus cisplatin in patients with NSCLC

The purpose of the present study was to determine the maximum-tolerated doses (MTDs) and the dose-limiting toxicities of a metronomic administration of oral vinorelbine and cisplatin in patients with advanced/metastatic NSCLC. Twenty-six patients with advanced/metastatic NSCLC were enrolled. Escalating doses of vinorelbine (40–70 mg p.o./trice per week) and cisplatin (70–85 mg/m² intravenous infusion) were administered on day 1 every 3 weeks. ΜΤDs were reached at 60 mg thrice/week p.o. for vinorelbine and 85 mg/m² for cisplatin. Grade 4 neutropenia, febrile neutropenia and grade 4 diarrhea were the dose-limiting events during the first cycle of chemotherapy. The most common grade III-IV hematologic toxicity was neutropenia occurring in seven (27%) patients, while non-hematological toxicities were relatively infrequent and mostly of grade I or II. Objective responses were observed in 20.8% of patients with measurable disease. The regimen of metronomic administration and cisplatin is feasible and active in patients with NSCLC.     

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Background

This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.

Methods

Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25–1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.

Results

Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.

Conclusion

The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.     

A phase I study of paclitaxel, cisplatin, and fluorouracil (TCF) for advanced gastric cancer

Purpose

A phase I study of TCF therapy, which consists of paclitaxel (TXL: Taxol^®) + cisplatin (CDDP) + 5-fluorouracil (5-FU), in advanced gastric cancer patients was performed to determine the recommended dose (RD) for a phase II study by checking the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of 5-FU above the fixed dose of TXL and CDDP.

Methods

The doses of TXL and CDDP were fixed at 80 and 25 mg/m², respectively, while that of 5-FU was increased by 100 mg/m² in each cohort from 300 mg/m² (level 1) to a maximum of 600 mg/m² (level 4). One cycle consisted of administration of these agents once per week for 3 weeks, every 4 weeks.

Results

A total of twelve eligible patients were included in this study. At level 1, two of three cases showed grade 3 leukopenia. At level 2, one of three cases showed grade 4 neutropenia (recovered within 3 days), and another one case showed grade 3 neutropenia. At level 3, one of three cases showed grade 3 neutropenia, and at level 4, one of three cases showed grade 4 neutropenia (recovered within 3 days), with grade 3 neutropenia in the other two cases. Even at the highest dose administered, none of the patients showed DLT. Moreover, no non-hematological toxicity judged to be DLT was observed through all levels. Six of the twelve patients had measurable disease, and the overall response rate was 83%.

Conclusions

Although the MTD level was not determined, based on the observed efficacy and the results of other clinical trials, the recommended doses of TXL, CDDP, and 5-FU for the TCF regimen were set as 80, 25, and 600 mg/m², respectively, and a phase II study to investigate the clinical effectiveness and safety of this regimen has now begun.     

Phase I and II trials of vinorelbine with carboplatin for patients 75 years of age or older with previously untreated non-small-cell lung cancer

BackgroundThe safety and efficacy of platinum-based combination chemotherapy for elderly patients with advanced non–small-cell lung cancer (NSCLC) remains unclear. We conducted phase I and phase II trials of a combination of vinorelbine and carboplatin for patients ≥75 years of age and with advanced NSCLC.Patients and MethodsPreviously untreated patients (≥75 years of age) with stage IIIB or IV NSCLC were enrolled. Based on a 4-week cycle, vinorelbine was given on days 1 and 8, and carboplatin was given on day 1. Dose-limiting toxicity was defined as grade 4 hematologic toxicity that lasted 4 days or more, febrile neutropenia; grade 3 or worse nonhematologic toxicities; or the omission of vinorelbine administration on day 8 in the first cycle.ResultsThirteen patients were enrolled in phase I. dose-limiting toxicity was grade 4 neutropenia that lasted 4 days or more, observed in 2 of 4 patients at level 4. Phase II study used the dose of level 3 (20 mg/m² vinorelbine, area under the curve of 4 mg/mL/min carboplatin). Forty-two patients were enrolled. The response rate was 14.6% of 41 assessable patients (95% CI, 3.8-25.4). The median time to progression was 98 days (95% CI, 61-135 days), and the median survival time was 366 days (95% CI, 321-411 days). All toxicities were mild and manageable.ConclusionUse of 20 mg/m² vinorelbine on days 1 and 8, followed by carboplatin area under the curve of 4 mg/mL/min on day 1 every 4 weeks warrants a phase III study for elderly patients with advanced NSCLC.     

Phase I and Pharmacologic Study of Weekly Bolus Topotecan for Advanced Non–Small-Cell Lung Cancer

PurposeWe conducted a phase I trial of the topoisomerase I inhibitor topotecan for the purpose of determining the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of topotecan when administered weekly to patients with advanced non–small-cell lung cancer.Patients and MethodsTwelve patients with stage IIIB or IV disease were treated with topotecan by 30-minute intravenous infusion on days 1, 8, and 15 every 4 weeks. The dose was escalated in 2-mg/m² increments from the starting dose of 4 mg/m² until the MTD was reached. After the MTD had been reached in previously treated patients, chemotherapy-naive patients were enrolled for treatment at that dose, and the dose was escalated to estimate the MTD in the treatment-naive group.ResultsThe MTD of topotecan was determined to be 6 mg/m² in the previously treated group and 8 mg/m² in the chemotherapy-naive group. All 3 previously treated patients experienced DLT at the 6-mg/m² dose level. Although only 1 of the 3 previously treated patients experienced DLT (grade 4 neutropenia for ≥ 3 days) at the 8-mg/m² dose level, skipping the topotecan dose on day 15 because of neutropenia was reported in 2 patients. Anorexia and general fatigue were the common nonhematologic toxicities.ConclusionThe recommended dose of topotecan for phase II studies in previously untreated patients is 6 mg/m² on days 1, 8, and 15, every 28 days, and 4 mg/m² appears to be a suitable dose for use in previously treated patients with this schedule.     

Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, which was administered to patients with advanced solid tumors on days 1 and 8 in 3-week courses

Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses. Methods Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy ≤2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status ≤1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2. Results Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m²) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m². In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m². Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m², at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response. Conclusions When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m² and was lower than the value of 2.4 mg/m² in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.     

A phase I and pharmacokinetic study of a powder-filled capsule formulation of oral irinotecan (CPT-11) given daily for 5 days every 3 weeks in patients with advanced solid tumors

Purpose: Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks. Patients and methods: Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC. Results: 20 patients (median age 61.5 years, range 40–75; M/F 12/8; ECOG PS 0=5, 1=11, 2=4) received oral irinotecan at dose levels of 30 (n=3), 40 (n=3), 50 (n=6), and 60 (n=8) mg/m²/day. Of the eight patients enrolled at 60 mg/m², three patients experienced DLT (≥ grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m² dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC_0-24) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated. Conclusion: Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m²/d.Supported in part by Pharmacia and National Cancer Institute Grants U01-CA69912, M01-RR00585, and CA15083-26     

A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer

Background:Gemcitabine is active in patients with otherwiseresistant or refractory ovarian cancer. As the drug is well tolerated, studiesusing gemcitabine combined with other antineoplastic agents are needed. Theaim of the study was to determine the maximum tolerated dose (MTD) ofepirubicin combined with gemcitabine, with and without support of G-CSF. Patients and methods:Patients with platinum-resistant orrefractory ovarian cancer were eligible. Gemcitabine (G) (starting dose 800mg/m² day 1 and 8; 200 mg/m² escalation per level) andepirubicin (E) (starting dose 60 mg/m² day 1; 15 mg/m²escalation per level) were given every 21 days for four to six cycles. G-CSF(filgrastim 5 µg/kg/die) was given in case of grade 4 neutropenia(levels without support) or from day 9 up to leukocyte count>10,000/mm³ after nadir (levels with support). Cohorts of threepatients were enrolled at each level, and another three patients were planned,if one dose-limiting toxicity (DLT) was registered. MTD was determined firstwithout and then with G-CSF. Results:Four levels were studied (G 800 + E 60; G 1000 + E 60;G 1000 + E 75; G 1000 + E 75 + G-CSF) with four, four, three and threepatients enrolled, respectively. DLT (grade 4 febrile neutropenia) wasobserved in two patients at level 3. Thus, G1000 + E 60 mg/m² wasthe MTD without G-CSF. The addition of prophylactic G-CSF did not allow afurther increase of the dose and grade 4 thrombocytopenia was the DLT at level4. Non-hematological toxicity was mild. Grade 2 mucositis was reported in fourpatients. Among the 13 patients with measurable or evaluable disease, 3partial responses were observed for an overall response rate of 23.1%. Conclusions:The combination of gemcitabine 1000 mg/m²(day 1, 8) and epirubicin at 60 mg/m² (day 1) is a feasibletherapy. Grade 4 neutropenia is frequent and G-CSF support is often required.With prophylactic support of G-CSF, the DLT is thrombocytopenia.     

A phase I/II study of vinorelbine, doxorubicin, and methotrexate with leucovorin rescue as first-line treatment for metastatic breast cancer

Purpose: This study was performed to determine the maximum tolerated dose (MTD) and toxicity of vinorelbine when used in combination with doxorubicin and methotrexate with leucovorin rescue in women with metastatic breast cancer. Methods: Enrolled in the study were 23 women with metastatic breast cancer who had not received prior chemotherapy for metastatic disease. Patients treated at the first dose level received vinorelbine 20 mg/m² on day 1, doxorubicin 40 mg/m² on day 1, methotrexate 100 mg/m² on day 1 and leucovorin 20 mg orally every 6 h for six doses beginning on day 2. Treatment was repeated every 21 days. The vinorelbine dose was escalated by 5 mg/m² for patients treated at subsequent dose levels. The MTD was defined as the dose level at which fewer than one-third of patients enrolled experienced dose-limiting toxicity (DLT). When the MTD of vinorelbine had been determined, the doxorubicin dose was then escalated by 10 mg/m² with the vinorelbine dose held at its MTD. Results: total of 98 courses of treatment (median of 4 per patient, range 2–8) were administered. The MTD of this regimen was found to be vinorelbine 25 mg/m², doxorubicin 40 mg/m², and methotrexate 100 mg/m² with leucovorin rescue. At higher doses of vinorelbine, neutropenia, fatigue, arm pain, malaise, nausea and vomiting were dose-limiting. Higher doses of doxorubicin resulted in universal dose limiting neutropenia, and frequent nonhematologic DLT consisting of arm pain, malaise, stomatitis, nausea and vomiting. Amongst the 20 patients with measurable disease, there were 3 complete responses (15%, 95% confidence interval 3%–38%), 5 partial responses (25%, 95% confidence interval 9%–49%) and an overall response rate of 40% (95% confidence interval 19%–64%). The median survival was estimated to be 25 months from the start of chemotherapy. Conclusions: Vinorelbine at 25 mg/m² can be safely administered with doxorubicin at 40 mg/m² and methotrexate at 100 mg/m² with leucovorin rescue. Response rates observed with this regimen suggest that this combination of chemotherapeutic agents may not be more effective than the combination of vinorelbine and doxorubicin. Received: 27 April 1998 / Accepted: 17 September 1998     

An escalating dose finding study of liposomal doxorubicin and vinorelbine for the treatment of refractory or resistant epithelial ovarian cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD) of liposomal doxorubicin (LD)-vinorelbine (V) in patients with refractory or resistant ovarian cancer. PATIENTS AND METHODS: Thirty patients were eligible. Seven levels were studied [LD 25-V20 (three patients enrolled); LD 30-V20 (three); LD 35-V20 (three); LD 20-V25 (three); LD 25-V25 (three); LD 30-V25 (10); LD 35-V25 (five)]. LD was given on day 1, while V was given on days 1 and 8 every 21 days. Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. RESULTS: DLT was observed in four patients: two febrile neutropenia, one grade 4 thrombocytopenia and one grade 3 palmar-plantar erythrodysesthesia (PPE) at level 7 (LD 35-V25). Thus, liposomal doxorubicin 30 mg/m(2) plus vinorelbine 25 mg/m(2) was the MTD. The most frequent toxicity was neutropenia. Fifteen patients (50%) experienced grade 3 neutropenia and 10 (33.3%) grade 4 neutropenia. Non-hematological toxicity was mild. Mucositis and PPE were the most frequent toxicities, but in most cases were grade 1. Out of 29 assessable patients, six (20.7%; 95% confidence interval 10%-39%) experienced an objective response, with one complete response. CONCLUSIONS: In patients with refractory or resistant ovarian cancer, the recommended doses for the combination studied are liposomal doxorubicin 30 mg/m(2) (day 1) plus vinorelbine 25 mg/m(2) (day 1 and 8). Neutropenia is the most frequent toxicity, while non-hematological toxicity is mild. Substantial activity was recorded and a phase II study is justified.     

Salvage chemotherapy with mitomycin, docetaxel, and irinotecan (MDI regimen) in metastatic pancreatic adenocarcinoma: a phase I and II trial

BACKGROUND: This study evaluates the maximum tolerated dose (MTD) and activity of mitomycin, docetaxel, and irinotecan (MDI) regimen on metastatic pancreatic adenocarcinoma, previously treated with gemcitabine-containing chemotherapy. PATIENTS AND METHODS: Patients with less than 76 years, Karnofsky performance status > or = 60, and adequate bone marrow, kidney, and liver function were eligible for this trial. Treatment consisted of mitomycin 6 mg/m2 day 1, docetaxel and irinotecan on days 2 and 8 with escalating doses, every 4 weeks. Dose levels were level 1:30 and 70 mg/m2; level 2:30 and 100 mg/m2; level 3:30 and 85 mg/m2; and level 4:35 and 85 mg/m2. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia > 7 days, febrile neutropenia, grade 4 thrombocytopenia, nausea and vomiting, or diarrhea, grade > or = 3 nonhematological toxicity, or failure to recover to grade < or = 1 toxicity by day 43, occurring during the first cycle of chemotherapy. RESULTS: Between September 2001 and October 2002, 15 eligible patients, three of whom had been previously treated with two lines of chemotherapy, received 33 cycles of MDI. Toxicity consisted of grade 3 to 4 neutropenia in 23% of cycles, fatigue, diarrhea, and vomiting in 10% of cycles, and one toxic death. DLT was observed in 2 of 6 level 2 patients (one toxic death and one grade 3 fatigue), and 2 of 3 level 4 patients (one neutropenic fever and one grade 3 fatigue). Thirteen patients were assessable for response. No objective response was observed among patients treated with MTD or higher doses. Three patients had stable disease; all other patients had progressive disease. The median time to tumor progression and median survival was 1.7 and 6.1 months, respectively. CONCLUSION: The MTD was mitomycin 6 mg/m2 day one, and docetaxel 30 and irinotecan 85 mg/m2 days 2 and 8. This regimen is inactive in metastatic pancreatic cancer.