Phase I study of CPT-11 and bolus 5-FU/<Emphasis Type="Italic">l</Emphasis>-leucovorin in patients with metastatic colorectal cancer

Background Irinotecan (CPT-11) and bolus 5-fluorouracil (5-FU)/leucovorin (LV) administered weekly for 4 weeks every 42 days (Saltz regimen) is active but substantially toxic in patients with metastatic colorectal cancer (CRC). The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC.Methods We investigated the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) for CPT-11 given i.v. (90-min infusion) and bolus 5-FU plus biologically active l-LV administered weekly for 3 weeks every 28 days (modified Saltz regimen) in Japanese patients with metastatic CRC. Eighteen patients with measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and adequate organ functions were enrolled.Results At dose level 2 (CPT-11, 100mg/m²; 5-FU, 400mg/m²; and l-LV, 25mg/body), 1 of 6 patients had DLT (febrile neutropenia). At dose level 3 (CPT-11, 100mg/m²; 5-FU, 500mg/m²; and l-LV, 25mg/body), 2 of 6 patients had DLT (febrile neutropenia and grade 4 neutropenia lasting more than 4 days). To determine whether level 3 was the MTD level, an additional 3 patients were treated at this level, but no DLT was observed. Consequently, 2 of 9 patients had DLT at level 3, this level thus being considered as the RD. At this level, grade 3–4 neutropenia was common but manageable. Nonhematological toxicities were mild. Seven partial responses were observed in the 18 enrolled patients (response rate [RR], 39%), and 8 patients (44%) experienced stable disease.Conclusion This CPT-11/5-FU/l-LV regimen administered weekly for 3 weeks every 28 days has substantial antitumor activity, with manageable toxicities. A multicenter phase II study is currently underway.     

Oxaliplatin plus irinotecan and leucovorin-modulated 5-fluorouracil triplet regimen every other week: a dose-finding study in patients with advanced gastrointestinal malignancies.

BACKGROUND: Oxaliplatin (OXA) and irinotecan (IRI) are active drugs in first-line as well as second-line treatment of advanced colorectal cancer patients, their toxicity profiles are not overlapping, and both drugs have shown synergism with folinic acid-modulated 5-fluorouracil (5-FU). We planned this phase I study to define the dose-limiting toxicities (DLTs), the maximum tolerated doses (MTDs), and the recommended doses (RDs) for a triplet regimen including OXA plus IRI on day 1, and 6S-folinic acid (LFA) plus 5-FU on day 2, every 2 weeks. PATIENTS AND METHODS: At least three patients had to be treated at each dose level, and the trial proceeded if no more than 33% of patients showed a DLT after the first cycle. Starting from OXA 85 mg/m(2) (over 2 h) and IRI 150 mg/m(2) (over 1 h), an alternated escalation was planned up to 110 mg/m(2) and 200 mg/m(2), respectively. Thereafter, a fixed dose of LFA, 250 mg/m(2) (as 2-h infusion), plus an escalating dose of 5-FU (from 650 to 800 mg/m(2) as an intravenous bolus) was added on day 2 to the previous dose level of OXA and IRI. RESULTS: Forty-six patients, all but four affected by advanced colorectal primaries, entered this study. The MTDs for OXA and IRI given on the same day were 110 and 200 mg/m(2): these doses caused a DLT in three of six patients. The previous dose level (110 and 175 mg/m(2), respectively) on day 1 was safely followed on day 2 by LFA plus 5-FU up to 800 mg/m(2). Indeed, only one of three patients treated at this last level had a DLT. This cohort was then expanded including a total of 14 patients, and on the whole series five cases of DLT occurred: WHO grade 4 neutropenia (two patients), grade 3 or 4 diarrhoea (three patients). Cumulative toxicity was analysed in 43 patients for a total of 347 cycles: grade 4 neutropenia was detected in 13 patients (30%); it was not dose-related, nor was it exacerbated by the addition of modulated 5-FU. Febrile neutropenia occurred in four patients. Grade 3 or 4 diarrhoea was suffered by nine (21%) and five (12%) patients, respectively. Two complete and nine partial responses were reported on 40 evaluable patients (six patients were disease-free at study entry), giving a response rate of 27.5% (95% confidence interval 15% to 44%); nine of 18 (50%) assessable patients of the two last cohorts treated with the triplet regimen achieved a complete response (two patients) or a partial response (seven patients). CONCLUSIONS: The RDs for this biweekly regimen were: OXA 110 mg/m(2) plus IRI 175 mg/m(2) on day 1, and LFA 250 mg/m(2) plus 5-FU 800 mg/m(2) on day 2. This regimen appeared active in pretreated gastrointestinal malignancies, and it is worthy of being evaluated in advanced colorectal carcinoma after failure of 5-FU-based adjuvant or palliative treatment.     

Bimonthly Chemotherapy with Oxaliplatin,Irinotecan, Infusional 5-Fluorouracil/Folinic Acid in Patients with Metastatic Colorectal Cancer Pretreated with Irinotecan- or Oxaliplatin-Based Chemotherapy

Abstract

This study was conducted to assess the tolerability and efficacy of a ternary bi-monthly irinotecan (CPT-11) - oxaliplatin (OHP) - infusional 5-fluorouracil (5-FU)/folinic acid (FA) combination in advanced colorectal cancer patients who had received prior CPT-11 and/or OHP-based chemotherapy regimen. Colorectal cancer patients were given bimonthly CPT-11 as a 90-min infusion, followed by OHP (85 mg/m²), FA (200 mg/m²) 2-h infusions and 5-FU (48-h infusion). CPT-11 and 5-FU doses were escalated as reported below. 26 patients were recruited. Fourteen patients had received a prior CPT-11-, 6 patients a prior OHP-based chemotherapy regimen and 6 patients both regimens. Three dose levels were investigated: CPT-11 100, 120 and 140 mg/m² and 5-FU 1500, 1800 and 2100 mg/m² in 6, 12 and 8 patients, respectively. All patients were evaluable for toxicity, 24 for antitumor activity. At all dose levels toxicity was ac-ceptable. Grade 4 toxicity occurred in two patients only (neutropenia in one case and stomatitis in another one, 3.8%). Grade 3 toxicities included nausea and vomiting (34.6%), asthenia (26.9%), neurosensory toxicity (15.4%), neutropenia (3.8%) and di-arrhea (3.8%). Hematological toxicity was infrequent and generally mild. At the third dose level, a higher, although not significantly different incidence of hematological and neurosensory toxicity (both occurring in 62.5% of cases, all grades) was observed compared to the other two, while nausea and vomiting were significantly less frequent (37.5% vs 100%). Overall, we observed 2 complete responses, 9 partial responses (OR 45.8%), 8 stable disease (33.3%), and 5 disease progression (20.8%). Median overall survival was 18 months and median time-to-progression 5.5 months. This combination showed moderate toxicity and promising antitumor activity in CPT-11 and/or OHP pretreated colorectal cancer patients. The second dose level using CPT-11 at 120 mg/m² and 5-FU at 1800 mg/m² is recommended for further phase II studies in this patient population.     

Dose escalation of CPT-11 in combination with oxaliplatin using an every two weeks schedule: A phase I study in advanced gastrointestinal cancer patients

Background:To determine the dose-limiting toxicity of CPT-11 incombination with oxaliplatin, and the maximal tolerated dose (MTD) and therecommended dose (RD) of CPT-11 using an every two weeks schedule. Patients and methods:The study was designed to evaluate escalateddoses of CPT-11 starting at 100 mg/m² with a fixedclinically-relevant dose of 85 mg/m² oxaliplatin given every twoweeks. Results:Twenty-three patients and 186 cycles were evaluable fortoxicity (median per patient: 7, range: 1–13). Grade 3oxaliplatin-induced neurotoxicity was cumulative and limiting in 39%(9 of 23) of patients. The MTD of CPT-11 was 200 mg/m², withincomplete neutrophil recovery at day 15 as limiting toxicity. At the RD (175mg/m² of CPT-11): no grade 4 neutropenia was seen in the two firstcycles; 30% of patients experienced grade 3–4 diarrhea. Febrileneutropenia (3.2% of all cycles) was 3-fold more frequent inperformance status (PS) 2 than in PS 0–1 patients. Among elevencolorectal cancer (CRC) patients, three complete and four partial responseswere documented, including in three 5-fluorouracil (5-FU) refractory patients. Conclusion:To combine CPT-11 175 mg/m² and oxaliplatin85 mg/m² every two weeks is feasible in an outpatient setting, andvery active in 5-FU resistant CRC patients. A dose of 150 mg/m²CPT-11 is recommended in PS 2 patients.     

Retrospective Comparison of Single-Agent Chemotherapy with Weekly 5-Fluorouracil or Weekly Irinotecan in Previously Treated Patients with Metastatic Colorectal Cancer

Abstract

This study is a retrospective analysis of response, toxicity and freedom from progression of two single-agent chemotherapy regimens in patients with previously treated metastatic colorectal cancer. Thirty-five patients with histological-ly confirmed measurable metastatic colorectal cancer received chemotherapy after failure of first-line 5-fluorouracil (5-FU) and leucovorin treatment. The median age was 61 years. Twenty-seven patients had liver metastases, 6 had local recurrence, 1 had retroperitoneal lymph node metastases and 1 had lung metastases. Eighteen patients received weekly 2600 mg/m² 5-FU and 17 patients received weekly 125 mg/m² irinotecan (CPT-11). Treatment was given until disease progression. Total number of cycles was 202 for 5-FU and 248 for CPT-11. The relative dose intensity was 1.0 for 5-FU and 0.84 for CPT-11. No grade 3-4 toxicity was registered in patients who received 5-FU. Grade 3- 4 toxicity rates were as follows in those who received CPT-11: vomiting 1 (5.9%) patient in 1 cycle, diarrhea 3 (17.7%) patients in 3 cycles and neutropenia in 3 (17.7%) patients in 3 cycles. No patients manifested febrile neutropenia. Two patients (11.8%) needed hospital admission because of toxicity: 1 for vomiting and 1 for diarrhea. No objective responses were observed in the 5-FU group of patients. Three patients (17.6%) who received CPT-11, achieved partial response with a median duration of 8 months. Stable disease was registered in 3 (17.6%) and 9 (52.9%) patients in 5-FU and CPT-11 groups respectively (p=0.05). Median time to progression was 3.3 months for patients who received 5-FU and 4.2 months for those treated with CPT-11 (not significant). One-year survival was 22.2% and 54.3% respectively (p=0.05).     

A phase I, dose-finding study of irinotecan (CPT-11) short i.v. infusion combined with fixed dose of 5-fluorouracil (5-FU) protracted i.v. infusion in adult patients with advanced solid tumours

Purpose Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy.Patients and methods Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m²) plus a fixed dose of 5-FU CI 250 mg/m² per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m². In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m², and then followed by 2–5 weeks rest.Results Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m² + 5-FU 250 mg/m² CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m² due to toxicity. The weekly schedule of CPT-11 75 mg/m² + 5-FU 250 mg/m² CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.Conclusion CPT-11 300 mg/m² + 5-FU 250 mg/m² protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.     

Biweekly irinotecan or raltitrexed plus 6S-leucovorin and bolus 5-fluorouracil in advanced colorectal carcinoma: a Southern Italy Cooperative Oncology Group phase II-III randomized trial.

Purpose:The aim of this randomised trial was to evaluate theactivity and toxicity of a biweekly regimen including 6S-leucovorin-modulated5-fluorouracil (LFA–5-FU), combined with either irinotecan (CPT-11 +LFA–5-FU) or raltitrexed (Tomudex®) (TOM + LFA–5-FU), inadvanced colorectal cancer patients, and to make a preliminary comparison ofboth these experimental regimens with a biweekly administration ofLFA–5-FU modulated by methotrexate (MTX + LFA–5-FU). Patients and methods:One hundred fifty-nine patients withadvanced colorectal carcinoma previously untreated for the metastatic disease(34 of them previously exposed to adjuvant 5-FU) were randomly allocated toreceive: CPT-11, 200 mg/m² i.v. on day 1, followed on day 2 by LFA,250 mg/m² i.v. infusion and 5-FU, 850 mg/m² s i.v. bolus(arm A); TOM, 3 mg/m² i.v. on day 1, followed on day 2 by LFA, 250mg/m² i.v. infusion and 5-FU, 1050 mg/m² i.v. bolus (armB); or MTX, 750 mg/m² i.v. on day 1, followed on day 2 by LFA, 250mg/m² i.v. infusion and 5-FU, 800 mg/m² i.v. bolus (armC). Courses were repeated every two weeks in all arms of the trial. Responserate (RR) was evaluated after every four courses. The sample size was definedto have an 80% power to detect a 35% RR for each experimentaltreatment, and to show a difference of at least 4% in RR with thestandard treatment if the true difference is 15% or more. Results:The RRs were: 34% (95% confidence interval(95% CI): 21%–48%) in arm A, including 3 completeresponses (CRs) and 15 partial responses (PRs), 24% (95% CI:14%–38%) in arm B, including 2 CRs and 11 PRs, and24% (95% CI: 14%–38%), with 2 CRs and 11PRs, in arm C. After a median follow-up time of 62 (range 18–108) weeks,the median time to progression was 38, 25, and 27 weeks for arm A, B, and C,respectively. With 94 patients still alive, the one-year probability ofsurvival was 61%, 54%, and 59%, respectively. WHO grade3 or 4 neutropenia and diarrhoea affected 46% and 16%,respectively, of patients treated with CPT-11 + LFA–5-FU. Medianrelative dose intensity over eight cycles (DI₈) was 78% forCPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA–5-FU wereneutropenia (16%) and diarrhoea (16%), but median relativeDI₈ was 93% for TOM, and 82% for 5-FU. Conclusions:CPT-11 + LFA–5-FU compares favorably in termof activity and toxicity with other combination regimens including CPT-11 andcontinuous infusional 5-FU. The hypothesis of a RR 15% higher than theMTX + LFA–5-FU treatment can not be ruled out after this interimanalysis. The TOM + LFA–5-FU regimen showed a RR and a toxicity profilevery close to the MTX + LFA–5-FU combination, and dose not deservefurther evaluation in advanced colorectal cancer patients.     

S-phase modulation by irinotecan: pilot studies in advanced solid tumors

Two studies of irinotecan (CPT-11) followed 24 h later by an antimetabolite were conducted. The objectives of the studies were: (1) to determine whether the increase in S-phase in tumor cells seen 24 h after CPT-11 administration in animal studies is seen in advanced solid tumors in patients, (2) to determine the dose of CPT-11 required to produce this effect, (3) to compare two methods (immunohistochemistry, IHC, for cyclin A, and DNA flow cytometry, FC) for evaluating S-phase in tumor biopsies from patients, and (4) to establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of CPT-11, given 24 h before gemcitabine (GEM, 1000 mg/m²). In one study CPT-11 was followed 24 h later by 5-fluorouracil (5-FU), 400 mg/m² per week for 4 weeks every 6 weeks. Tumor biopsies were obtained before and 24 h after CPT-11 administration before administration of 5-FU and assayed for S-phase by IHC for cyclin A and by FC. The starting dose of CPT-11 was 80 mg/m² per week with subsequent exploration of 40 and 60 mg/m² per week to establish the dose-effect relationship of the increase in tumor cells in S-phase. In the second study, CPT-11 was given 24 h before GEM 1000 mg/m² per week for 2 weeks every 3 weeks. Doses of 20–80 mg/m² were explored to establish the MTD and DLT and to study tumor cell S-phase in selected patients. CPT-11 80 mg/m² produced a mean increase in S-phase by IHC for cyclin A of 137%. Lesser increases were seen with 40 and 60 mg/m². CPT-11 followed 24 h later by 5-FU 400 mg/m² per week for 4 weeks was well tolerated. In the study of CPT-11 followed by GEM 1000 mg/m², 60 mg/m² of CPT-11 was the MTD.This work was presented in part at the 14th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Frankfurt, Germany, November 2002.     

CPT-11联合CF/5-FU方案治疗胃肠道癌的Ⅰ期临床研究

目的探索CPT-11(开普拓)联合CF/5-FU治疗胃肠道癌的最大耐受剂量(MTD)和剂量限制性毒性(DLT).方法 CPT-11初始剂量为120mg/m2,然后150mg/m2,180mg/m2和200mg/m2 iv d1,递增剂量直至出现DLT.CF 200mg/m2iv 2h,然后5-FU 400mg/m2快速静滴,接着5-FU 600mg/m2持续静滴22h,第1天、第2天给药,2周重复.结果 20例胃肠道癌患者共完成化疗111周期,中位数6周期.MTD为200mg/m2,DLT为腹泻和WBC减少.结论我们推荐CPT-11180mg/m2联合CF/5-FR每2周重复的方法,作为国内PS为0～1胃肠癌患者的一线二线化疗方案.     

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.     

Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors.

PURPOSE: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. PATIENTS AND METHODS: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. RESULTS: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P =.048), but objective neurotoxicity was not seen. CONCLUSION: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.     

Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer

The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m²/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m²) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m²) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m²) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4–6.6 months) and median survival was 11 months (95% CI: 7.9–14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m² i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m² p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m² and UFT 300 mg/m².     

Irinotecan (CPT-11) as first-line monotherapy in patients with advanced, metastatic colorectal cancer refractory to 5-fluorouracil adjuvant chemotherapy: a multicenter phase II study

Irinotecan (CPT-11) is active against colorectal cancer (CRC) refractory to 5-fluorouracil. Further information is needed to confirm whether CPT-11 monotherapy is more effective against tumors than 5-FU monotherapy or if there is cross-resistance of CPT-11 with 5-FU. This study assessed the efficacy and toxicity of CPT-11 350 mg/m² iv, once every 3 weeks, in patients with unsuccessfully pretreated advanced CRC. Thirty-two patients were enrolled and overall 152 cycles were administered. The total objective response rate was 17.9% and the disease stabilized in 11 patients (39.3%). Median time to progression was 3.8 months and me-dian survival was 8.2 months. Grade 3/4 diarrhea was observed in 9 cycles (5.9%) and 6 patients (18.8%), and grade 3/4 neutropenia in 5 cycles (3.3%) and 4 patients (12.5%). CPT-11 monotherapy is an active and well-tolerated first-line chemotherapy for CRC in 5-FU pretreated patients.     

Phase I study of CPT-11 and continuous 5-FU / l-leucovorin combination therapy(modified AIO regimen)in patients with metastatic colorectal cancer

A combination of CPT-11, continuous 5-fluorouracil(5-FU)and leucovorin(LV), the Arbeitsgemeinschaft für Internistische Onkologie(AIO)regimen, is widely used for the treatment of metastatic CRC. The efficacy and toxicity of this regimen, however, have not been determined in Japanese patients with metastatic CRC. Our objective was to evaluate the safety of the AIO regimen plus CPT-11 in Japanese colorectal carcinoma(CRC)patients. We investigated the maximum tolerated dose(MTD), dose-limiting toxicity(DLT), and recommended dose(RD)for CPT-11 and continuous 5-FU. CPT-11, 5-FU, and l-LV were administered on days 1, 8, and 15 of a 28-day cycle. The dose of CPT- 11 was escalated from 40 mg/m2 (level 1)to 80 mg/m2 (level 3). The 5-FU dose was then escalated from 1,000 mg/m2 (level 4)to 2,000 mg/m2 (level 5). If neither level met the criteria for the MTD, the recommended dose was defined as level 5, and the dose escalation was discontinued, because the maximum approved weekly dose of CPT-11 alone in Japan is 80 mg/m2 and the dose of 5-FU in the original AIO regimen was 2,000 mg/m2. A total of 18 patients were enrolled in this study. Hematological and non-hematological toxicity were infrequent and mild. There were no toxicities greater than grade 2 at each dose level. Level 5 did not meet the MTD criteria. Our results confirm that the modified AIO plus CPT-11 regimen is safe for Japanese patients. The recommended doses in the present study were CPT-11 80 mg/m2, 5-FU 2,000 mg/m2, and l-LV 250 mg/m2.     

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.     

Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: a phase I-II trial of the Southern Italy Cooperative Oncology Group (SICOG).

Background:The combination of cisplatin (CDDP) and 5-fluorouracil(5-FU) can be regarded as a reference regimen in squamous cell carcinoma ofthe head and neck (SCCHN). Raltitrexed (Tomudex) is a direct and specificthymidilate synthase (TS) inhibitor, which has shown clinical activity againstSCCHN in a previous phase I study, when combined with 5-FU and levo-folinicacid (LFA). Preclinical data support the combination of CDDP and raltitrexed.The aim of the present study was to evaluate the combination of cisplatin,raltitrexed, LFA and 5-FU in a phase I–II study. Patients and methods:Patients with locally advanced or metastaticSCCHN were treated with a combination of cisplatin at the starting dose of 40mg/m², followed by raltitrexed at the starting dose of 2.5mg/m² on day 1; levo-folinic acid at fixed dose of 250mg/m², followed by 5-fluorouracil at the starting dose of 750mg/m² on day 2. Doses of the three cytotoxic agents werealternately escalated up to dose-limiting toxicity (DLT). Treatment wasrecycled every two weeks and given up to a maximum of eight courses; afterchemotherapy, patients with locally advanced disease received a locoregionaltreatment. Results:Forty-five patients were entered into the study. Six doselevels were tested. At CDDP 50 mg/m², raltitrexed 3mg/m², 5-FU 900 mg/m², four out of six patients showedDLT, which was in all cases grade 4 neutropenia. Therefore, this dose levelwas defined as maximum tolerated dose (MTD). CDDP 60 mg/m²,raltitrexed 2.5 mg/m², LFA 250 mg/m², 5-FU 900mg/m² was the dose level recommended for phase II. CDDP,Raltitrexed and 5-FU mean actually delivered dose intensities at the selecteddose level were 26, 1.05, and 378 mg/m²/week, respectively.Neutropenia was the main side effect and was observed even at the lowest doselevels. Non-hematologic side effects were mild. Nine complete responses(20%) and twenty-one partial responses (47%) were observed, foran overall response rate of 67% (95% confidence interval(95% CI): 51%–80%), according to intention to treatanalysis. Fifteen of fifteen patients (100%) treated at the dose levelselected for phase II had an objective response (5 complete responses, 10partial responses). Conclusions:The results of our dose escalation clearlydemonstrate that it is possible to combine CDDP, raltitrexed, and modulated5-FU at effective doses, without unexpected toxicities. The response datapoint to an impressive clinical activity, which will be better defined by anongoing large phase II study.     

Combination Phase I/II Study of Irinotecan Hydrochloride (CPT-11) and Carboplatin in Relapsed or Refractory Non-Hodgkin's Lymphoma

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecinwhich inhibits topoisomerase I. Phase II studies have demonstratedthat CPT-11 is active against a broad spectrum of neoplasmsincluding intractable non-Hodgkin's lymphoma. An early phaseII study in lymphoma suggested that a schedule of daily infusionsof 40 mg/m²/day for three or five consecutive days is more effectivethan a single infusion of 200 mg/m² every three to four weeks.Carboplatin is also an active agent against lymphoma, and preclinicalstudies have shown that CPT-11 and its active metabolite havea synergistic effect with platinum compounds. To evaluate themaximal tolerated dose (MTD) and the therapeutic efficacy ofCPT-11 in combination with carboplatin in relapsed or refractorynon-Hodgkin's lymphoma, we conducted a combination phase I/IIstudy. The starting dose of CPT-11 was 20 mg/m²/day (days 1through 3 and 8 through 10), and dose escalations of 5 mg/m²/dayincrements were planned, with a fixed dose of carboplatin (300mg/m², day 1). Six of the eight patients receiving both agentsat the starting dose level developed critical toxicities suchas grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8)and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminaseelevation 1/8). Further dose escalation of CPT-11 was halted,and the starting doses were judged to be the MTDs. The responserate (25%, 2/8) to the combination of the MTDs was not superiorto that of CPT-11 alone in a previous phase II study (38%, 26/69),and the MTD of CPT-11 in combination with carboplatin was lessthan half the single-agent dose. We conclude that carboplatinis not recommendable for combination with CPT-11 in lymphomapatients. Other suitable agents for such a combination shouldbe sought.     

Increased tolerability of bimonthly 12-hour timed flat infusion 5-fluorouracil/irinotecan regimen in advanced colorectal cancer: A dose-finding study

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.     

A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer

OBJECTIVES: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks. PATIENTS AND METHODS: A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD. RESULTS: A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels. CONCLUSION: Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.     

Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.