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/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.     

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.     

Phase I dose escalation study of docetaxel with a fixed dose of S-1 in combination chemotherapy for advanced gastric cancer

Background  The primary objectives of this study were to estimate the maximum-tolerated dose (MTD) of docetaxel in combination with a fixed dose of S-1 and to determine the recommended dose (RD). Patients and methods  Patients with histologically proven gastric carcinoma with metastatic or locally advanced inoperable disease were eligible. Patients received intravenous docetaxel starting at 40 mg/m² (dose level 1), and stepwise dose increases to 50, 60, and 70 mg/m² were planned for successive patient cohorts (dose levels 2, 3, and 4, respectively) over 1 h on day 1 and oral S-1 administered at a fixed dose of 40 mg/m² twice daily on days 1–14, both drugs every 21 days. Results  A total of 13 patients were enrolled into this trial. All three patients at dose level 3 developed dose-limiting toxicities (DLT), and this level was declared to be the MTD. Hence, level 2 (docetaxel 50 mg/m²) was declared to be the RD for the next study. As 9 of the 13 enrolled patients responded to treatment, the overall objective response rate was 69.2% (95% CI, 44.1–94.3%). The median time to progression was 8.38 months (range 1.44–8.51) and the overall survival duration was 9.9 months (range 0.62–11.57). The most common grade 3/4 toxicity of docetaxel plus S-1 was neutropenia, which was tolerable and manageable. Conclusion  This regimen showed encouraging activity and a manageable safety profile in advanced gastric carcinoma and could be used in further randomized studies.     

Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients

Purpose  This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients. Methods  Five dose level combinations with irinotecan (from 180 to 240 mg/m², day 1, q21), capecitabine (1,500–2,000 mg/m² per day, days 2–15, q21) and erlotinib (50–150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Results  Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed. Conclusions  The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m² and capecitabine 1,500 mg/m² per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.     

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

Introduction Vinorelbine alone and irinotecan alone have been shown to have efficacy against non-small cell lung cancer (NSCLC); each drug has different mechanisms of action. A phase I study using a combination of vinorelbine and irinotecan as first-line treatment for advanced NSCLC was done to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT). Methods Previously untreated patients (≤75 years old) with Stage IIIB or IV NSCLC were enrolled. Based on a 4-week cycle, vinorelbine was given on days 1 and 8, and irinotecan was given on days 1, 8, and 15 intravenously. To prevent an injection site reaction to vinorelbine, the site was treated with topical clobetasol ointment, and the patients were given intravenous dexamethasone prior to vinorelbine treatment. DLT was defined as grade 4 neutropenia lasting ≥4 days or febrile neutropenia, grade 4 thrombocytopenia, ≥grade 3 non-hematological toxicities, or the need to cancel drug administration on both days 8 and 15. Results A total of 23 patients were enrolled. DLT was observed in 1 of 6 patients at level 3 (20 mg/m² vinorelbine, 50 mg/m² irinotecan), in 2 of 3 at level 4 (25 mg/m², 50 mg/m²), and in 2 of 5 at modified level 4 (20, 60 mg/m²). Level 4 and modified level 4 were considered to be the MTD; dose level 3 was therefore recommended. DLTs included liver dysfunction, pneumonitis, colitis, and arrhythmia. Injection site reactions were mild. Hematological and non-hematological toxicities were mild and easily controlled. Conclusion Use of 20 mg/m² vinorelbine on days 1 and 8 followed by 50 mg/m² irinotecan on days 1, 8, and 15 every 4 weeks warrants a phase II 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).     

A phase I trial of S-1 with concurrent radiotherapy in patients with locally recurrent rectal cancer

Background

The purpose of this phase I trial of S-1 chemotherapy in combination with pelvic radiotherapy for locally recurrent rectal cancer was to determine the maximum tolerated dose (MTD), recommended dose (RD), and dose-limiting toxicity (DLT) of S-1.

Methods

We enrolled 9 patients between April 2005 and March 2009. Radiotherapy (total dose, 60 Gy in 30 fractions) was given to the gross local recurrent tumor and pelvic nodal metastases using three-dimensional radiotherapy planning. We administered oral S-1 twice a day on days 1–14 and 22–35 during radiotherapy. The dose of S-1 was initially 60 mg/m²/day and was increased to determine the MTD and RD for this regimen.

Results

DLT appeared at dose level 2 (70 mg/m²/day) in 2 patients, who experienced grade 3 enterocolitis and consequently required suspension of S-1 administration for longer than 2 weeks. Hematological toxicity was mild and reversible. At the initial evaluation, complete regression and partial regression were seen in 1 patient (11%) and 2 patients (22%), respectively.

Conclusion

This phase I trial of S-1 chemotherapy with pelvic radiotherapy for locally recurrent rectal cancer revealed that the MTD for S-1 was 70 mg/m²/day and the RD was 60 mg/m²/day.     

Phase I trial of neoadjuvant preoperative chemotherapy with S-1 and irinotecan plus radiation in patients with locally advanced rectal cancer

PURPOSE: To determine the maximum tolerated dose (MTD) and recommended dose (RD) of irinotecan combined with preoperative chemoradiotherapy with S-1 in patients with locally advanced rectal cancer. PATIENTS AND METHODS: We gave preoperative radiotherapy (total dose, 45 Gy) to 23 patients with locally advanced (T3/T4) rectal cancer. Concurrently, S-1 was given orally at a fixed dose of 80 mg/m2/day on Days 1-5, 8-12, 22-26, and 29-33, and irinotecan was given as a 90-min continuous i.v. infusion on Days 1, 8, 22, and 29. The dose of irinotecan was initially 40 mg/m2/day and gradually increased to determine the MTD and RD of this regimen. RESULTS: Among the 4 patients who received 90 mg/m2 irinotecan, 2 had Grade 4 neutropenia and 1 had Grade 3 diarrhea. Because dose-limiting toxicity (DLT) occurred in 3 of the 4 patients, 90 mg/m2 irinotecan was designated as the MTD. Consequently, 80 mg/m2 irinotecan was given to 7 additional patients, with no DLT, and this was considered the RD. Of the patients who received irinotecan at the RD or lower doses, 6 (31.6%) had a complete pathologic response (Grade 3) and 9 (47.4%) underwent sphincter-preserving surgery. CONCLUSIONS: With our new regimen, the MTD of irinotecan was 90 mg/m2, and the RD of irinotecan for Phase II studies was 80 mg/m2. Although our results are preliminary, this new neoadjuvant chemoradiotherapy was considered safe and active, meriting further investigation in Phase II studies.     

Phase I study of weekly cisplatin, vinorelbine, and concurrent thoracic radiation therapy in patients with locally advanced non-small-cell lung cancer

Background The combination of chemotherapy and thoracic radiation therapy (TRT) is considered as a standard treatment for locally advanced non-small-cell lung cancer (NSCLC). Although the frequent interaction of anticancer agents and irradiation may produce stronger radio-sensitizing effects, the daily administration of these agents is complicated. We therefore used weekly administration of these agents, and conducted a phase I study of weekly cisplatin, vinorelbine, and concurrent TRT. The purpose of this study was to identify the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the recommended dose of this treatment. Methods Patients with locally advanced NSCLC were enrolled in this study. Both cisplatin and vinorelbine were given intravenously on a weekly schedule for 6 weeks, starting on the first day of TRT, i.e., on days 1, 8, 15, 22, 29, and 36. The total dose of TRT was 60 Gy. The dose of cisplatin was fixed at 20 mg/m² per week. The starting dose of vinorelbine was 15 mg/m² per week (dose level 1). Results Nine patients were enrolled in this study. All three patients at dose level 1 experienced DLTs. We decreased the dose of vinorelbine to 10 mg/m² per week (dose level 0). Two of the six patients at dose level 0 experienced DLTs. Therefore, dose level 1 was considered as the MTD, and dose level 0 as the recommended dose. The DLTs of this treatment were esophagitis, fatigue, infection, and hyponatremia. Conclusion The recommended dose of cisplatin is 20 mg/m² per week and that of vinorelbine is 10 mg/m² per week with standard TRT. A phase II study of this treatment is warranted. The results of this study were presented in part at the 43rd Annual Meeting of the Japan Lung Cancer Society in Fukuoka, Japan, November 21–22, 2002.     

Weekly docetaxel for patients with platinum/paclitaxel/irinotecan-resistant relapsed ovarian cancer: a phase I study

Background This study was designed to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RD) of weekly docetaxel treatment in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.Methods Patients were enrolled on the basis of inclusion and exclusion criteria. Docetaxel was administered intravenously over a 60-min period on days 1, 8, and 15. Four dosage levels, 30, 35, 40, and 45mg/m², were employed, and the dosage was escalated from level 1 to level 4. DLT criteria were established, and the DLT was used as the criterion for deciding the MTD and RD.Results Twelve patients were enrolled. No grade 3/4 hematological toxicities were manifested at any dosage level. Grade 3/4 nonhematologic toxicities were manifested at level 4, consisting of fatigue/asthenia in 2 patients and neuropathy/sensory toxicity in 1 patient. Level 4 (45mg/m²) was thus judged to be the MTD, and the RD was concluded to be one level lower, i.e., level 3 (40mg/m²).Conclusions It was concluded that the RD for weekly docetaxel therapy is 40mg/m² per week in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.     

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.     

Phase I/II study of 3-week combination of S-1 and cisplatin chemotherapy for metastatic or recurrent gastric cancer

Purpose To define the maximum-tolerated dose (MTD) of S-1, given daily for 2 weeks followed by a 1-week rest, with a fixed dose of cisplatin on the initial day, and to determine the activity and safety of this regimen at the recommended dose (RD) when used as first line treatment of advanced gastric cancer (AGC). Patients and methods Cisplatin was fixed at a dose of 60 mg/m² on day 1 (D1) and the starting dose of S-1 was 60 mg/m²/day (30 mg/m² bid) (level I) on D1 to D14, every 3 weeks. The dose of S-1 was increased by 5 mg/m² bid up to 100 mg/m²/day (level V) unless the MTD was achieved. Results Sixty-two eligible patients were enrolled. MTD was set at level V with two of three patients developing grade 3 diarrhea or febrile neutropenia. The RD was determined at level IV (90 mg/m²/day). After the first 20 patients were enrolled in phase II, the protocol was amended; the S-1 dose was reduced to 80 mg/m²/day (N = 23) because of poor bone marrow recovery. The objective response was observed in 20 of 42 evaluable patients (48%). SD was achieved in 15 (36%). The median PFS was 5.3 months (95% CI, 4.6–6.0 months) with a median OS of 10.0 months (95% CI, 5.1–14.8 months). Grade 3–4 toxicities included neutropenia (33%), anemia (31%), and anorexia (24%). Conclusions The 3-week combination of cisplatin plus S-1 is active against AGC with favorable toxicitiy profiles. The phase II schedule or doses may need further refinements.     

Phase I/II study of cisplatin, ifosfamide and irinotecan with rhG-CSF support in patients with stage IIIB and IV non-small-cell lung cancer

Purpose: We conducted a phase I/II study in previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) to: (1) determine the maximum tolerated dose (MTD) of cisplatin combined with a fixed schedule of ifosfamide and irinotecan with rhG-CSF support; and (2) to determine the overall response rate and median survival of patients entered on this study. Methods: Ifosfamide (1.5 g/m²) and irinotecan (60 mg/m²) were administered at fixed doses on days 1–4 and on days 1, 8 and 15, respectively. Cisplatin was given on day 1 at 60 mg/m² and was increased in 10-mg/m² increments. This regimen was repeated every 4 weeks. rhG-CSF (nartograstim) was administered subcutaneously at a dose of 1 μg/kg on days 5–18 except on the day of irinotecan treatment. Results: Between June 1995 and April 1998, 46 patients were registered onto this phase I/II study. The MTD of cisplatin was defined according to toxicity and the dose during three courses was increased. Since at the 80 mg/m² dose level more than one-third of the patients were treated with dose modification, the dose of 70 mg/m² was recommended for phase II study. The dose-limiting toxicity was leukopenia. The overall response rate was 62.2% (95% CI 48.0–76.4%), the median response duration was 144 days, and the median survival time was 393 days. Conclusion: For phase II study, we recommend doses of cisplatin 70 mg/m² on day 1 combined with ifosfamide and irinotecan with rhG-CSF support. Both the response rate and preliminary survival data in this study suggest a high degree of activity of this combination in previously untreated NSCLC. Received: 29 April 1999 / Accepted: 15 September 1999     

Phase I study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer

Purpose This trial was conducted to determine the maximum tolerated dose (MTD), principal toxicity, and recommended dose for phase II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). Methods Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The respective doses of nedaplatin (day 1) and weekly paclitaxel (days 1, 8, and 15) studied were 80/60, 80/70, 80/80, 80/90, and 100/90 (mg m⁻²), repeated every 4 weeks. Results From May 2004 through June 2005, 21 patients (18 men and 3 women; median age, 63 years; age range, 53–75 years) were enrolled. The MTD was determined to be 100 mg m⁻² of nedaplatin and 90 mg m⁻² of weekly paclitaxel. Dose-limiting toxicities at the MTD were neutropenic fever and hepatic dysfunction. We recommend doses of 80 mg m⁻² of nedaplatin and 90 mg m⁻² of weekly paclitaxel for phase II study. Grade 3–4 hematologic toxicities included neutropenia in 29% of patients, thrombocytopenia in 0%, and anemia in 5%. Although the most frequent non-hematologic toxicity was hepatic dysfunction, all cases were only mildly to moderately severe. Although two patients had grade 3 or 4 pulmonary toxicity due to Pneumocystis carinii pneumonia, these patients recovered after receiving trimetoprim-sulfamethoxazole, steroid therapy, and supplemental oxygen. There were no treatment-related deaths. The overall response rate was 19.0% (95% confidence interval, 5.4–41.9%), and all responses were in patients receiving the recommended doses. The median dose-intensities for nedaplatin and paclitaxel were 91.6 and 87.1%, respectively, of the planned doses. Conclusion This combination chemotherapy is active and well tolerated and warrants phase II study.     

Phase I and pharmacokinetic study of S-1 administered for 14 days in a 21-day cycle in patients with advanced upper gastrointestinal cancer

Purpose S-1 is a novel oral fluoropyrimidine that combines tegafur with CDHP and oxonic acid. To decrease the incidence of late onset, severe diarrhea observed in a previous study, a phase I study was conducted to determine the maximum tolerated dose (MTD) of S-1 utilizing a 14-day schedule, repeated every 21 days, in patients with chemotherapy–refractory upper gastrointestinal malignancies. Methods S-1 was administered orally, twice-daily, at an initial dose level of 30 mg/m²/dose; doses were escalated by 5 mg/m² at each level. A minimum of three patients were enrolled at each dose level. S-1 toxicity, antitumor activity, and pharmacokinetics were assessed. The MTD was based on the dose limiting toxicity (DLT) during the first treatment cycle. Results At 30 mg/m² no DLT was observed in the first three evaluable patients. Two of the first three patients at the 35 mg/m² dose level developed DLTs (grade 3 rash and dehydration). An additional nine patients were subsequently treated at 30 mg/m² without DLT and this dose was established as the MTD. Common toxicities at 30 mg/m² included diarrhea, nausea, skin rash, anorexia, and fatigue. No grade 4 toxicities were observed. One partial response was seen in a patient with gemcitabine-refractory pancreatic adenocarcinoma and ten patients with pancreatic, gastric, or gallbladder carcinomas achieved stable disease as their best response to therapy. The AUC_(0–8) of 5-FU at the 30 and 35 mg/m² dose levels were 875 ± 212 and 894 ± 151 h ng/ml, respectively. Conclusions In a 14-day dosing schedule, the MTD of S-1 was 30 mg/m² and preliminary evidence of antitumor activity was seen in a North American population with refractory upper gastrointestinal malignancies. Supported in part by a grant from Taiho Pharma USA Inc., Princeton, NJ, USA.     

Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma

We determined the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of the oral vascular endothelial growth factor receptor (VEGFR) inhibitor, sunitinib, when administered with irinotecan among recurrent malignant glioma (MG) patients. For each 42-day cycle, sunitinib was administered once a day for four consecutive weeks followed by a 2 week rest. Irinotecan was administered intravenously every other week. Each agent was alternatively escalated among cohorts of 3–6 patients enrolled at each dose level. Patients on CYP3A-inducing anti-epileptic drugs were not eligible. Twenty-five patients with recurrent MG were enrolled, including 15 (60%) with glioblastoma (GBM) and 10 (40%) with grade 3 MG. Five patients progressed previously on bevacizumab and two had received prior VEGFR tyrosine kinase inhibitor therapy. The MTD was 50 mg of sunitinib combined with 75 mg/m² of irinotecan. DLT were primarily hematologic and included grade 4 neutropenia in 3 patients and one patient with grade 4 thrombocytopenia. Non-hematologic DLT included grade 3 mucositis (n = 1) and grade 3 dehydration (n = 1). Progression-free survival (PFS)-6 was 24% and only one patient achieved a radiographic response. The combination of sunitinib and irinotecan was associated with moderate toxicity and limited anti-tumor activity. Further studies with this regimen using the dosing schedules evaluated in this study are not warranted.     

Phase I dose escalation study of weekly ixabepilone, an epothilone analog, in patients with advanced solid tumors who have failed standard therapy

Purpose  To establish the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and recommended Phase II dose of ixabepilone, administered weekly as an intravenous (IV) infusion to patients with solid tumors who have failed standard therapy. Method  This was an open-label, single-arm, Phase I, dose-escalation study. Results  The MTD of ixabepilone [30-min, weekly IV infusion on a 21-day schedule (N = 33)] was established at 25 mg/m². Grade 3 fatigue was the DLT in 2/4 patients treated at 30 mg/m². Ixabepilone was well tolerated at the MTD. Myelosuppression was rare, with no Grade 3/4 neutropenia. Due to the potential for cumulative neurotoxicity, the protocol was amended to a 1-h infusion, weekly for 3 weeks with a 1-week break. No DLT occurred at starting doses of 15, 20 and 25 mg/m² on this modified schedule (N = 51), although overall toxicity was less at 15 and 20 mg/m² than 25 mg/m². Five patients (2 on the 30-min/21-day schedule and 3 on the 60-min/28-day schedule) achieved durable objective partial responses across a variety of tumor types. Conclusions  Ixabepilone had an acceptable safety profile at the MTD of 25 mg/m² (as a 30-min weekly infusion on a continuous 21-day schedule) and at 20 mg/m² (as a 1-h weekly infusion on a modified 28-day schedule). The clinical activity and acceptable tolerability profile warrant further single- or combination-agent evaluation.     

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.     

Phase I study of docetaxel plus S-1 combination chemotherapy for recurrent non-small cell lung cancer

S-1 is a novel oral fluorouracil prodrug that plays a role in non-small cell lung cancer (NSCLC). Docetaxel (DTX) is one of the standard agents for relapsed NSCLC. We performed a phase I study of DTX plus S-1 combination therapy as second-line treatment for NSCLC to determine the maximum tolerated dose (MTD) and recommended dose (RD). Patients with recurrent NSCLC, aged 20-74 years with an Eastern Cooperative Oncology Group performance status of 0-1 and measurable lesions, were enrolled. The treatment consisted of four dose levels. The patients received DTX (40-60 mg/m(2) intravenously on day 1) and S-1 (65-80 mg/m(2) orally, daily on days 1-14) for each 21-day cycle. Three to six patients were treated at each dose level with the two drugs, with MTD defined as the dose level at which dose-limiting toxicity (DLT) occurred in 33% of the patients. A total of 17 patients were enrolled. At dose level 4 (DTX, 60 mg/m(2); S-1, 80 mg/m(2)) 3 of 5 patients experienced DLT and this level was regarded as the MTD. Therefore, dose level 3 (DTX, 60 mg/m(2); S-1, 65 mg/m(2)) was selected as the RD for subsequent studies. The DLTs were neutropenia (grade 4) and mucositis (grade 3). The response rate was 5.9% (1 of 17 patients achieved a partial response) and 14 of 17 patients achieved stable disease. This combination regimen showed a tolerable and manageable profile in recurrent NSCLC and therefore warrants further evaluation.