Phase I study of gemcitabine (GEM) and docetaxel (TXT) combination chemotherapy for unresectable non-small-cell lung cancer

A phase I study of gemcitabine (GEM) and docetaxel (TXT) combination chemotherapy was performed for unresectable non-small-cell lung cancer. Chemotherapy consisted of a fixed dose of GEM (1,000 mg/m2) on day 1, 8 and an escalated dose of TXT (50, 60, 70 mg/m2) on day 8 every 21 days, > or = 2 courses. Nine patients were entered (each dose level: 3 patients). Leukopenia, neutropenia, GOT increase, GPT increase, anorexia, fatigue, fever, and alopecia occurred, but no dose-limiting toxicity was found at any dose level and no MTD was reached. The recommended dose for the phase II study is GEM 1,000 mg/m2 and TXT 70 mg/m2 with consideration of application to outpatients and continuing courses.     

Phase I study of gemcitabine (GEM) and UFT combination chemotherapy for unresectable/recurrent pancreatic cancer

A phase I study of gemcitabine (GEM) and UFT combination chemotherapy was performed for unresectable pancreatic cancer. The regimen included UFT orally from day 1 through day 6 and from day 8 through 13, GEM intravenously on day 7 and 14, and 1 week rest as 1 course. Administration of more than 2 courses was attempted for each patient, with the same dosage levels at all 3 scheduled steps. Nine patients were enrolled in the study. Leukopenia and neutropenia of grade 3 occurred in 2 of 6 patients at level 2, and maximum tolerated dose (MTD) was considered to be 800 mg/m2 for GEM and 250 mg/m2 for UFT. Clinical effects of the patients included: 2 PR, 4 NC, and 3 PD, for a response rate of 22% (2/9 patients). Reduced CA19-9 level of less than half of that at starting time was observed in 4 of 9 (44%) patients. The recommended dose for the phase II study is GEM 800 mg/m2 and UFT 250 mg/m2 with consideration of application to outpatients and continuing courses.     

Phase I Trial ofU racil-Tegafur (UFT) plus Oral Leucovorin: 28-Day Schedule

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m²/day, with planned escalations to 250, 300, 350, and 400 mg/m²/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m²/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m² level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m²/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and “hand-foot syndrome“ were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.     

Phase I study with dose escalation of gemcitabine and cisplatin in combination with ifosfamide (GIP) in patients with non-small-cell lung carcinoma

Gemcitabine (G) and cisplatin (P) are active reference agents in patients with non-small-cell lung cancer (NSCLC). Ifosfamide (I) has also been approved for NSCLC treatment. This phase I trial aimed to determine the dose-limiting toxicity (DLT), maximum tolerated dose [maximum tolerated dosage (MTD)], and recommended dose (RD) of a GIP combination in patients with advanced/metastatic NSCLC. In this study, one cycle of chemotherapy combined the following: ifosfamide: 3 g/m2 fixed dose (24-hour intravenous infusion) combined with mesna, day 1; gemcitabine: starting dose 1,000 mg/m2/d, escalating by 250 mg/m2 increments, days 1 and 15; cisplatin: starting dose 80 mg/m2, subsequently 100 mg/m2, day 15; in cohorts of at least 3 patients. Cycles were repeated every 28 days and no hematopoietic growth factors were administered. DLT was evaluated after the first chemotherapy cycle. Thirty-three patients (30 men, 3 women) with stage III (14 patients)/IV (19 patients) NSCLC were treated at eight dose levels, receiving 109 cycles of chemotherapy. Neutropenia was the only DLT reported. Although the MTD was not reached at the highest tested dose level, the RD chosen corresponds to the full doses of the GP3000 doublet standard (G: 3,000 mg/m2; P: 100 mg/m2 per cycle) every 28 days. Nonhematologic toxicities were mainly grade I-II. Relative dose intensities of G, I, and P at the RD were 96%, 98%, and 96%, respectively. Sixteen of 33 patients with measurable/evaluable disease had an objective response including two complete responses. In conclusion, GIP chemotherapy is safe and appears to be active in patients with NSCLC. The RD is gemcitabine: 1,500 mg/m2 days 1 and 15; ifosfamide: 3 g/m2 day 1; cisplatin: 100 mg/m2 day 15. A confirmatory phase II study is currently under way, before a phase III trial of GIP versus GP.     

A phase I study of combination chemotherapy with gemcitabine and oral UFT for advanced non-small cell lung cancer

A phase I study was carried out to determine the optimal dose and administration schedule for combined UFT plus gemcitabine therapy in patients with non-small cell lung cancer. Twenty-four patients (including 11 patients previously treated with cisplatin as the key drug) received oral UFT 400 mg x m(-2) on days 1 to 14 with intravenous infusions of gemcitabine (800 mg x m(-2) on days 8 and 15, or 900 mg x m(-2) on days 8 and 15, or 900 mg x m(-2) on days 1, 8 and 15). The most appropriate dosing option appeared to be 400 mg x m(-2) per day of oral UFT for 14 consecutive days with 900 mg x m(-2) gemcitabine on days 8 and 15. Eight of the 24 patients achieved partial response. The combination chemotherapy UFT and gemcitabine was well tolerated and may benefit patients with advanced non-small cell lung cancer. A multicentre phase II study using a 3-weekly regimen is in progress.     

Phase I study of gemcitabine and liposomal doxorubicin in relapsed ovarian cancer

Twenty-three patients were enrolled in a phase I study conducted to determine the maximum tolerated doses (MTD) of combined liposomal doxorubicin (CAE) and gemcitabine (GEM) in relapsed ovarian cancer patients. A total of 82 courses are evaluable, with a median number of three cycles administered per patient (range 2-8). GEM was administered on days 1 and 8 by 30-min intravenous infusion immediately after CAE given by 60-min intravenous infusion on day 1; cycles were repeated every 21 days. The starting doses were CAE 20 mg/m(2) and GEM 600 mg/m(2). Following dose levels were 20/800; 20/1,000; 30/800; 30/1,000; 35/800, and 35/1,000 for CAE and GEM, respectively. The MTD was reached at dose level 5, with febrile neutropenia and thrombocytopenia as dose-limiting toxicities. After the MTD, granulocyte-colony stimulating factor was administered in 15% of cycles. Non-hematological toxicity was mild and manageable. All patients are so far evaluable for response. Among them, 5 partial responses (21.7%; 95% confidence interval, CI: 4.9-38.5), 5 disease stabilizations (21.7%, 95% CI: 4.9-38.5) and 13 progressions (56.6%, 95% CI: 36.4-76.8) have been registered. These results warrant further research in a phase II study.     

Phase II study of gemcitabine (GEM) and docetaxel (TXT) combination chemotherapy for unresectable non small cell lung cancer

A phase I study of gemcitabine (GEM) and docetaxel (TXT) combination chemotherapy had been performed for unresectable non-small-cell lung cancer, and the dose level of GEM (1,000 mg/m2) on days 1 and 8, and TXT (70 mg/m2) on day 8 every 21 days had been recommended. The combination chemotherapy was repeated> or =2 courses in this phase II study, and the efficacy and safety were evaluated. 31 patients were entered, and the mean number of courses was 3.1. Leukopenia, neutropenia, anemia and fatigue were observed as major adverse reactions. The severe adverse reactions (> or =Grade 3) were leukopenia 48.4% and neutropenia 70.9%. With G-CSF support, all except 2 patients were administered as per schedule, and the TXT dosage in 2 patients was reduced. Other toxicities were mild. The overall response rate was 71.0%, and MST was 515 days. All except the 2 fatal cases on initial hospital admission made the shift to outpatient therapy. These results indicate the efficacy and safety of GEM and TXT combination chemotherapy.     

Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.     

A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1. RESULTS: A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients. CONCLUSION: UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.     

A triplet chemotherapy with cisplatin, docetaxel and gemcitabine in patients with advanced non-small-cell lung cancer: a phase I/II study

Purpose We conducted a phase I/II study of triplet chemotherapy consisting of cisplatin (CDDP), docetaxel (DCT) and gemcitabine (GEM) in patients with advanced non-small-cell lung cancer (NSCLC). Methods Fifty-three untreated patients with stage IIIB or IV NSCLC were enrolled. All drugs were given on days 1 and 8. The doses of CDDP and DCT were fixed at 40 mg/m² and 30 mg/m², respectively. In the phase I portion, a dose escalation study of GEM with starting dose of 400 mg/m² was conducted and primary objective in the phase II portion was response rate. Results The maximally tolerated dose (MTD) and recommended dose (RD) of GEM were determined as 800 mg/m² because grade 3 non-hematological toxicity (liver damage, diarrhea, and fatigue) developed in three of nine patients evaluated at that dose level. In pharmacokinetic analysis, C _max and AUC of dFdC and dFdU were increased along with the dose escalation of GEM. However, no relationship between pharmacokinetic parameters and toxicity or response was observed. Objective response rate was 34% and median survival time was 11.7 months. Though major toxicity was myelosuppression, there were no life-threatening toxicities. Conclusion These results indicate that this triplet chemotherapy is feasible and effective in patients with advanced NSCLC.     

Phase I/II study of oxaliplatin with oral S-1 as first-line therapy for patients with metastatic colorectal cancer

Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35-40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m(-2) (level 1) or 130 mg m(-2) (level 2) on day 1, and S-1 (80-120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2-14), RR of 50% (1 CR and 13 PR: 95% CI 31-69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access.     

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (SCOUT) in metastatic colorectal cancer

Tegafur-uracil (UFT) plus leucovorin (LV, folinic acid) with alternating irinotecan and oxaliplatin were effective and well tolerated in patients with metastatic colorectal cancer (mCRC) in a phase I study. This study expanded the maximum tolerated dose group. Patients aged >or=18 years had histologically confirmed, inoperable, previously untreated, measurable mCRC. Patients received irinotecan 180 mg m(-2) on day 1, oxaliplatin 100 mg m(-2) on day 15 and UFT 250 mg m(-2) plus LV 90 mg on days 1-21 every 28 days. The phase I/II study comprised 45 patients, 29 at the maximum tolerated dose (MTD). The response rate in 38 evaluable patients was 63% (95% confidence interval (CI): 49-80). Median time to progression and overall survival were 8.7 months (95% CI: 7.9-10.4) and 16.8 months (95% CI: 9.6-25.3), respectively. In the MTD group, one patient had grade 3 leucopenia; one had grade 3 neutropaenia; three had grade 3 diarrhoea; and one had grade 3 neurotoxicity. No hand-foot syndrome grade >1 was seen. In total, 67% of eligible patients received second-line therapy. UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for mCRC, with minimal neurotoxicity and hand-foot syndrome.     

Multicenter phase II study of pre-administered uracil/tegafur (UFT) plus gemcitabine for unresectable/recurrent pancreatic cancer

Our objective was to evaluate the efficacy and toxicity of the pre-administration of UFT (uracil/tegafur: prodrug of 5-FU) and GEM combination therapy for unresectable/recurrent pancreatic cancer in the outpatient setting. UFT (250mg/m(2)/day) was orally administered from day 1 through day 6 and from day 8 through 13, and GEM (800mg/m(2), div/30 min) was administered on day 7 and 14, with a one-week rest every 3 weeks based on results of the previous phase I study. Thirty-six pts (24 male, 12 female) were enrolled (median age, 63.8 yrs). There were 8 partial responses (25%). Eighteen pts (56%) had stable disease, and 6 pts (19%) had a progression. The median survival time was 7. 0 months( range 1.5 -66). Grade 3 toxicities were leucopenia (17%), thrombocytopenia (3%), nausea (3%), and liver dysfunctions(3%). There were no Grade 4 toxicities. Pre-administered UFT plus GM is a promising treatment for unresectable/recurrent pancreatic cancer in the outpatient setting.     

Phase I study of paclitaxel,carboplatin and UFT in chemo-naive patients with advanced non-small cell lung cancer (NSCLC)

Objective We conducted a phase I study of paclitaxel (PTX), carboplatin (CBDCA), and UFT in chemo-naive patients with advanced non-small cell lung cancer (NSCLC). Method Twenty-one chemo-naive patients with advanced NSCLC were enrolled. The study was conducted as a phase I dose-escalation study of various doses of systemic PTX followed by CBDCA on day 1 and oral UFT (400 mg/m²) on days 1–5 and 8–12, with the cycle repeated at 21-day intervals. At least three patients were enrolled in each step. Results The main toxicities were neutropenia and paresthesia, but were tolerable and reversible in all cases. Overall response rate was 57% (12 out of 21). The MTD was not reached at the highest dose level after the first cycle. Given previous recommends of PTX at 225 mg/m² and CBDCA AUC 6 for two-drug therapy, the recommended dose for the phase II study under our regimen was set at PTX 225 mg/m² on day 1, CBDCA AUC 6 on day 1, and UFT 400 mg/m² on days 1–5 and 8–12. Conclusion The combination of PTX, CBDCA, and UFT showed promising activity and acceptable toxicity in these chemo-naive patients, supporting the development of this combination as a feasible chemotherapeutic option for advanced NSCLC.     

A phase I trial of gemcitabine and infusional 5-fluorouracil (5-FU) in patients with refractory solid tumors: Louisiana Oncology Associates protocol no. 1 (LOA-1)

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine (GEM) (Gemzar) and 5-fluorouracil (5-FU) combination therapy when administered to patients with advanced solid tumors. GEM was administered intravenously over 30 minutes on days 1, 8, and 15, and 5-FU was administered as a continuous intravenous infusion from day 1 through day 15 of each 28-day treatment course. Seventeen patients (13 men and 4 women, median age 57, all previously treated with chemotherapy) were treated with 68 courses at 3 dose levels: 800/200, 1,000/200, and 1,000/300 [GEM (mg/m2/week)/ 5-FU (mg/m2/day)]. Two further patients were not fully evaluable for toxicity; one died from a probable pulmonary embolism, and one refused further treatment after developing grade II mucositis and dermatitis after her day 1 to 7 treatment. At the third dose level, 2 of 4 patients developed grade III mucositis; one also developed grade IV neutropenia with fever and grade III thrombocytopenia. Patient accrual then resumed at the second dose level. At this level, 10 patients were treated, with two developing grade III mucositis. One of these patients also developed grade IV dermatitis. No other patient developed grade III or IV side effects. Prophylactic dexamethasone was initiated after 4 of the first 7 patients (including 1 of the not fully evaluable patients) developed dermatitis-grade IV in 1 patient and grade II in the remaining 3 patients. After the steroids were initiated, 4 of the last 11 patients treated developed dermatitis, but grade 1 in all cases. One patient with metastatic gastric cancer achieved a near-complete response of his gastric mass and adrenal metastasis. Minor responses were achieved in a patient with colon carcinoma and a patient with an ethmoid sinus adenoid cystic carcinoma. The MTD and recommended dose for phase II clinical trials of GEM and 5-FU on the above schedule is 1,000 mg/m2 and 200 mg/m2 respectively, with mucositis as the DLT.     

Phase II Study of UFT in Patients With Advanced Non-Small Cell Lung Cancer

A phase II study of UFT (a mixture of uracil and tegafur; molarratio of uracil to tegafur = 4) was undertaken in 21 patientswith advanced non-small cell lung cancer (NSCLC). UFT was administeredorally at a dose of 400 mg/m² every day, for more than fourweeks. Of 16 adequately treated patients, one (6.3%) showed a partialresponse. Toxic effects included minimal myelosuppression, anorexia,nausea, vomiting and epigastralgia. Gastrointestinal toxicitywas well tolerated. Considering the poor response and mild toxicity,a further phase II study of higher-dose UFT is necessary forpatients without prior therapy.     

Phase I/II study of CPT-11 plus UFT in patients with advanced/recurrent colorectal cancer: Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG): Protocol 0102

OBJECTIVE: The primary objective of this study was to explore the efficacy and safety of combined chemotherapy with CPT-11 and UFT in patients with advanced/metastatic colorectal cancer. METHODS: Twenty-two patients with metastatic colorectal cancer were enrolled in the phase I trial and 35 patients (including eight patients treated at level 4 during phase I) were evaluated in the phase II trial. Treatment consisted of two 35-day cycles of combination chemotherapy with CPT-11 and UFT. During phase I, CPT-11 was administered on days 1 and 15 as an intravenous infusion over 90 min at four different dose levels, starting from a dose of 80 mg/m2 (level 1). During phase II, the dose of CPT-11 was fixed at 150 mg/m2 based on the results of the phase I study. UFT was administered orally at a fixed dose of 300 mg/m2 on days 1-28, followed by a 1-week drug holiday, during each course (35 days). RESULTS: The maximum tolerated dose (MTD) of CPT-11 was determined to be 150 mg/m2 during the phase I trial. The major toxicities detected during phase II in 35 patients receiving CPT-11 at this recommended dose were grade 3/4 neutropenia in nine patients (25.7%) and grade 3/4 anorexia in six patients (11.4%). No severe adverse events occurred. The overall response rate and the median overall survival time was 22.9% (8/35) and 23.9 months for all patients, respectively. For pre-treated patients they were 26.3% (5/19) and 25.1 months, respectively. CONCLUSION: This combination of CPT-11 and UFT is considered to be both feasible and relatively safe. The response rate of the patients receiving CPT-11 at a dose of 150 mg/m2 was comparable to that reported previously for 5-FU-based regimens coupled with CPT-11, and this regimen can probably be beneficial for patients with pre-treated advanced colorectal cancer on an outpatient basis.     

A phase I study of combined UFT plus leucovorin and radiotherapy for pancreatic cancer

PURPOSE: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. METHODS: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. RESULTS: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. CONCLUSION: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.     

A phase I study of oral uracil-ftorafur plus folinic acid in combination with weekly paclitaxel in patients with solid tumors.

INTRODUCTION: Ftorafur is an orally available prodrug of 5-fluorouracil (5-FU). Its combination with uracil in a molar ratio of 1:4 (UFT) increases the 5-FU concentration in tumor cells compared with ftorafur alone. Paclitaxel has a broad spectrum of activity against solid tumors and synergic effects with UFT have been demonstrated in vitro. A phase I study was performed to determine the maximum tolerated dose of the combination of UFT and paclitaxel in patients with advanced solid tumors. STUDY DESIGN: UFT and folinic acid were applied at 300 mg/m2/day and 90 mg/day, respectively, on days 1-28, repeated on day 36. Paclitaxel was applied on days 1, 8, 15 and 22 of each cycle. The starting dose of paclitaxel was 50 mg/m2 and escalation in 10 mg/m2 steps was performed up to 100 mg/m2 weekly. RESULTS: Forty-seven consecutive patients with various solid tumors have been included in six different dose levels. One hundred and thirty cycles have been applied. The treatment was well tolerated overall. Most frequently encountered adverse effects were gastrointestinal and hematological toxicity (diarrhea CTC 3/4 in 6% of patients, anemia in 11%, leukocytopenia in 9%, polyneuropathy in 9%, fatigue in 11%, other in 6%). Partial remissions were observed in 28% of patients. CONCLUSION: Owing to the lack of overlapping toxicities, UFT/folinic acid plus paclitaxel can be combined at doses of proven single agent activity. Side effects are mainly attributable to the gastrointestinal toxicity of UFT and to the neuro- and hematotoxicity of paclitaxel. The recommended doses for phase II studies are 300 mg/m2 of UFT plus 90 mg of folinic acid on days 1-28, and 90 mg/m2 of paclitaxel weekly.     

Phase I/II clinical trial of induction chemotherapy with nedaplatin (CDGP), docetaxel (DOC) and 5-fluorouracil (5-FU) for squamous cell carcinoma of head and neck

In a phase I study, we determined the maximum tolerated dose (MTD) and the recommended dose (RD) of nedaplatin (CDGP) in combination chemotherapy with Docetaxel (DOC) and 5-fluorouracil (5-FU) for treatment of carcinoma of the head and neck. Then, in a phase II study, we examined the efficacy and safety of the RD of chemotherapy. Fresh patients with squamous cell carcinoma of the head and neck were enrolled in the study. The dosage of chemotherapy was as follows: DOC 60 mg/m(2) on day 1 by infusion over 2 hours; CDGP 20-30 mg/m(2)/day on day 1 to 5 by infusion over 1 hour, and 5-FU 600 mg/m(2)/day on day 1 to 5 by 5 days continuous infusion. For CDGP, an initial dose level was set at 20 mg/m(2), and 3 patients were enrolled for each level of dose escalation. The DLT was defined here as grade 4 neutropenia or grade> or =3 non-hematotoxic reactions. The dose at which DLT was observed in overall 33% cases was taken as MTD. The RD for phase II study was estimated to be DOC 60 mg/m(2), CDGP 20 mg/m(2)/day, 5-FU 600 mg/m(2)/day. Forty patients were enrolled in the phase II study. DLT of neutropenia was noted in 2 of 38 cases. DLT of non-hematotoxic reactions was found in less than 33% of the cases; 17 cases showed CR, and 12 cases showed PR. The response rate was 76.3%. The overall response rate in histological assessment was 55.3%. The combination chemotherapy with Low-Divided Dose of CDGP, DOC and 5-FU was suggested to be safe and effective.