Phase I–II trial of prolonged gemcitabine infusion plus paclitaxel as a biweekly schedule for advanced breast cancer patients pretreated with anthracyclines

Purpose

Paclitaxel (PACL) plus gemcitabine (GEM) is an effective regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged GEM infusion at a fixed dose rate (FDR) of 10 mg/m²/min produces higher levels of intracellular active metabolites of GEM when compared with a standard 30-min infusion. In the present phase I/II trial, we investigated the association of FDR GEM plus PACL.

Methods

1,200 mg/m² was the dose of GEM recommended for the phase II study, in which patients received PACL at 150 mg/m², followed by FDR GEM at 1,200 mg/m² (total GEM infusion time = 120 min), both drugs administered biweekly.

Results

Forty-two anthracycline-pretreated advanced breast cancer patients with disease recurrence following at least one line of chemotherapy were enrolled. Two (4.8%) and 12 (33.3%) patients experienced a complete and partial response, respectively, for an overall response rate of 38.1% (95% CI 23.4–52.8%). Median progression free survival and overall survival were 5 and 19.9 months, respectively. No statistically significant association was noted between in situ protein expression of RRM1 and BRCA1 (as assessed by immunofluorescence combined with automated quantitative analysis) and response to treatment in 15 patients with tissue available for analysis. Toxicity was mostly mild to moderate, mainly consisting of G3–G4 neutropenia (9.6%) and hypertransaminasemia (9.5%).

Conclusions

Biweekly FDR GEM in combination with PACL is an active and safe regimen for advanced breast cancer patients pretreated with anthracyclines. A prolonged infusion regimen of GEM does not seem to improve the efficacy of a standard 30-min infusion.     

Paclitaxel and gemcitabine combination in a biweekly schedule in patients with advanced non small-cell lung cancer: a phase i study

Purpose: This phase I study was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of the paclitaxel–gemcitabine combination in a biweekly schedule in chemotherapy-naive patients with advanced non small-cell lung cancer (NSCLC). Patients and methods: Treatment was administered on an outpatient basis every 2 weeks: paclitaxel over a 1-h IV infusion and gemcitabine as a 30-min IV infusion immediately following paclitaxel. Results: Twenty-nine patients were treated at six different dose levels, ranging from paclitaxel 135–175 mg/m² and gemcitabine 1,500–3,000 mg/m². A total of 198 cycles were administered (median 7, range 1–13). DLTs in the first two cycles were grade 4 neutropenia and myocardial ischemia at the dose level paclitaxel/gemcitabine 150/2,000 mg/m², febrile neutropenia and grade 4 neutropenia at the dose level paclitaxel/gemcitabine 175/2,500 mg/m², fatal pneumonitis, sudden death and grade 3 neutropenia at the dose level paclitaxel/gemcitabine 175/3,000 mg/m². The MTD was paclitaxel 175 mg/m² and gemcitabine 2,500 mg/m². The average dose intensity at this dose level was 98%. The overall intent-to-treat response rate was 35.7% (95% confidence interval [CI] 17.97% - 53.47%). Overall median survival was 36 weeks (95% CI, 24-48). Conclusion: Paclitaxel and gemcitabine can be safely administered at a high dose intensity on an every-other-week schedule. The recommended phase II dose is paclitaxel 175 mg/m² and gemcitabine 2,500 mg/m².     

Phase I and pharmacologic study of weekly gemcitabine and paclitaxel in chemo-na?ve patients with advanced non-small-cell lung cancer

Background:Gemcitabine (GEM) and paclitaxel (TAX) are active,non-cross-resistant drugs in non-small-cell lung cancer (NSCLC). We performeda phase I study to determine the maximum-tolerated dose (MTD), antitumoractivity and pharmacokinetics of GEM and TAX given weekly in chemo-naïvepatients with advanced NSCLC. Patients and methods:Escalating doses of GEM (800–2000mg/m²) and TAX (60–100 mg/m²) were administeredon days 1, 8, 15 every 4 weeks to 35 patients with advanced NSCLC. Plasmapharmacokinetics of TAX and GEM was assessed at the three higher dose-levels. Results:Dose-escalation was discontinued in absence of MTDbecause of increased cumulative toxicity leading to dose modification ortreatment delay at levels 6 and 7 (TAX 100 mg/m² plus GEM 1750 and,respectively, 2000 mg/m²). Hematological toxicity included grade4 neutropenia in 3% of cycles, grade 3 thrombocytopenia in one cycleand febrile neutropenia in three cycles. Maximal non-hemathological toxicitywas grade 3 elevation in serum transaminases and grade 2 neuro-sensorytoxicity in 8% and 5% of cycles, respectively. At the two higherdose-levels a non-linear pharmacokinetics of GEM was observed with aremarkable variability of C_max and AUC. No pharmacokineticinteractions were reported. Objectives responses were seen at all dose levels,with an overall response rate of 43% (95% confidence interval(95% CI): 25.5%–62.6%) in 30 evaluable patients. Conclusions:The weekly administration of GEM and TAX is very welltolerated, and has shown promising antitumor activity in NSCLC. In view of thecumulative toxicity and of the pharmacokinetic profile of GEM, doses of 1500mg/m² of GEM and 100 mg/m² of TAX are recommended forphase II studies.     

Weekly administration of bendamustine: A phase I study in patients with advanced progressive solid tumours

Background:The cytotoxic agent bendamustine combines apurine-like benzimidazol and alkylating nitrogen mustard group. The clinicallytolerated dose for single bolus bendamustine is 215 mg/m², forfractionated therapy on four consecutive days 85 mg/m². The maximumtolerated dose of a day 1 and 8 (q4w) 30 min infusion schedule was recentlyfound to be 160 mg/m², mouth dryness and fatigue weredose-limiting. Our current phase I trial was designed to define therecommended dose of a new weekly short infusion schedule. Patients and methods:Patients with refractory malignant tumoursqualified for the trial after written informed consent was obtained.Bendamustine was given as a 30-min i.v. infusion weekly for up to eightconsecutive weeks. Results:Twelve patients (8 male, 4 female, median age 57.5 years,range 42–64) were enrolled in this trial. At the starting dose of 80mg/m², two patients had dose-limiting toxicity (fatigue grade 3,mouth dryness grade 3, fever grade 4 Common Toxicity Criteria). Nodose-limiting events were observed in six patients treated at 60mg/m². An intermediate dose level of 70 mg/m² wasstudied in three younger, less heavily pre-treated patients, was welltolerated and not associated with dose-limiting events. Haematologicaltoxicity was mild except for grade 3–4 lymphocytopenia, occurring in 11of 12 patients. Bendamustine was found to induce long-lastingpanlymphocytopenia with predominant B-cell cytotoxicity. Conclusions:The maximum tolerated dose of weekly bendamustinegiven as a 30-min i.v. infusion is 80 mg/m², mouth dryness, fatigueand fever are dose-limiting. The recommended dose for phase II trials is 60mg/m².     

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.     

Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM)

Background:Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin–5-FU and gemcitabine combination. Patients and methods:This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m² in a two-hour infusion, followed by 5-fluorouracil 400 mg/m² bolus and 2 or 3 g/m² continuous infusion over 46 hours; gemcitabine 1 g/m² was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m² every two cycles up to 1500 mg/m²) in the absence of NCI-CTC toxicity >2. Results:Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%–37.8%) and 22.6% (95% CI: 12%–33.2%) in the intent-to-treat population; the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression-free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3–4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients. Conclusions:Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.     

Weekly gemcitabine and cisplatin chemotherapy: a well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

BACKGROUND: This phase II study was initiated to determine the activity and toxicity of a combination of gemcitabine (GEM) and cisplatin (CDDP) in patients with pancreatic cancer. PATIENTS AND METHODS: CDDP 35 mg/m(2) was given as a 30-min infusion and GEM 1000 mg/m(2) as a 30-min infusion. Both drugs were administered once weekly for 2 consecutive weeks out of every 3 weeks to chemonaive patients with locally advanced or metastatic pancreatic cancer. RESULTS: Forty-five advanced pancreatic cancer patients received this regimen for a total of 180 cycles of chemotherapy. One complete and four partial responses have been observed for an overall response rate of 9% (95% confidence interval 10% to 11%). Twenty-one patients (46%) had stable disease and 19 progressed on therapy. The median time to progression was 3.6 months, with a median survival of 5.6 months. A clinical benefit was obtained in nine of 37 patients (24%). Side-effects were mainly represented by hematological toxicity. Grade 3/4 WHO toxicities included neutropenia (6% of the patients) and thrombocytopenia (11%). The dose of GEM and CDDP was reduced in 14 patients (31%) and treatment was delayed in 10 patients (22%). CONCLUSIONS: Our results in terms of response rate, clinical benefit and survival do not support an advantage for the combination of GEM and CDDP given by this schedule.     

Oxaliplatin and protracted continuous 5-fluorouracil infusion in patients with pretreated advanced colorectal carcinoma

Background:Both OHP and 5-FU are clinically active as single agents in the treatment of metastatic colorectal cancer (MCRC). Clinical and laboratory studies suggest a synergistic interaction between these agents. This phase II study was performed to evaluate the activity of a schedule including OHP and protracted 5-FU infusion in 5-FU-resistant MCRC. Patients and methods:From October 1997 to January 2000, 50 patients with measurable progressive MCRC after one or more 5-FU-based regimens were treated. OHP (2–3-hour i.v. infusion) on day 1 and 5-FU (protracted i.v. infusion using elastomeric/electronic pump through a central venous catheter) on days 1–21 were administered every 3 weeks, at the following 4 dose levels: 1) OHP 100 mg/m² + 5-FU 200 mg/m² (21 patients); 2) OHP 100 mg/m² + 5-FU 250 mg/m² (3 patients); 3) OHP 130 mg/m² + 5-FU 200 mg/m² (10 patients); 4) OHP 130 mg/m² + 5-FU 250 mg/m² (16 patients). Results:Objective responses were 1 (2%) CR; 10 (20%) PR, for a median duration of 8 months; 23 (46%) stable diseases, for a median duration of 6 months; 16 (32%) progressions. CR + PR was higher in patients who had previously received no more than one line of chemotherapy for metastatic disease as compared with patients who had received two or more lines of therapy (33% vs. 5%, P < 0.01). The median time to progression was four months (one to nine). All dose levels (313 cycles) were well tolerated with mild toxicity. Major toxicity (grade 3 WHO) included: anaemia in 1 patient (2%), nausea and vomiting in 1 patient (2%), diarrhoea in 4 patients (8%) and stomatitis in 1 patient (2%); grade 1 and 2 peripheral neuropathy were encountered, respectively, in 30 (60%) and 8 (16%) patients. The median survival was 13 months (9–17), with 32 patients still alive after a median follow-up of 8 months. Conclusions:This study suggests that 1) OHP plus protracted 5-FU infusion is an active combination in MCRC patients resistant to pre-treatment bolus 5-FU; 2) it has a good tolerability profile and 3) the optimum dose level is OHP 130 mg/m² and 5-FU 250 mg/m².     

Cisplatin, gemcitabine and vinorelbine in locally advanced or metastatic non-small-cell lung cancer: A phase I study

Purpose: The objective of this study was to determine the maximally tolerable doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when combined with a fixed dose of cisplatin (CDDP).Patients and methods: Chemotherapy-naïve patients with stage IIIB–IV non-small-cell lung cancer (NSCLC) received a fixed dose of CDDP (50 mg/m²) and escalating doses of VNR (starting from 20 mg/m²) and GEM (starting from 800 mg/m²) on days 1 and 8, every three weeks. The single escalation of GEM alone, by 200 mg/m² at each step, was initially planned up to a dose of 1,200 mg/m², to be followed by increments of the VNR dose of 5 mg/m² at each step.Results: Thirty-one patients were enrolled at five different dose levels. The escalation was stopped at level 4 (GEM 1,200 mg/m² and VNR 25 mg/m²) since two of six patients of this cohort showed dose-limiting neutropenia at treatment cycle 1. Two different dose levels, GEM 1,200 mg/m² + VNR 20 mg/m², and GEM 1,000 mg/m² + VNR 25 mg/m², were fairly well tolerated. No treatment-related deaths occurred. Neutropenia was the main toxic effect, occurring in 76% of the total of 116 cycles delivered, and in 24% of them was of grades 3 or 4. A total of eight patients (26%) experienced grade 4 neutropenia lasting more than seven days; in five of them it occurred in the first course. Neutropenic fever was observed in four cases. Grade 4 thrombocytopenia occurred in only two patients. Non-hematologic toxicity was a minor problem in all patients but was never dose-limiting. No complete responses were obtained, but sixteen out of 31 (52%) patients achieved partial responses. The median duration of response was 20 (range 6–56+) weeks, while at a nine-month median follow-up, the median survival time has not yet been reached. To date, 18 patients are still alive. The one-year projected survival for all patients was 51%.Conclusions: Our results show that CDDP, VNR and GEM can be safely given together without substantial reductions in their individual dose intensities. In our opinion, the dose level of GEM 1,000 mg/m² + VNR 25 mg/m² given in combination with CDDP 50 mg/m² on days 1 and 8 of a three-week cycle can be recommended for phase II trials, since it provides a better balance in dose intensity of GEM and VNR. A phase II randomised study is underway to establish the activity of this new regimen (at the above-cited dose level) in chemo-naïve NSCLC patients.     

Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours

Purpose: To determine the maximum tolerated dose (MTD) of intravenous (iv) diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Experimental design: Twenty-four patients received a total of 75 cycles of iv diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m². Haematological and non-haematological toxicities were evaluated. Plasma concentrations of diflomotecan were measured after the first drug administration. Results: Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m² dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m² was considered the MTD and the dose of 4 mg/m² the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m² dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m² and one patient at each dose level of 2, 5, and 6 mg/m²). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (V _c) increased linearly with body surface area (BSA) as: V _c (L) = 41.5 × (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. Conclusions: The MTD and RD after a 20-min iv infusion of diflomotecan every 3 weeks are 4 and 5 mg/m², respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m² of diflomotecan was 0.86 × 10⁹ /L neutrophil cell counts and 11 days, respectively. Part of this work was presented as a poster in the 12th Population Approach Group in Europe (PAGE) meeting [12–13, June, 2003, Verona (Italy)]and in the Annual meeting of American Society of Clinical Oncology (ASCO) in 2004.     

Phase II study of a fixed dose-rate infusion of gemcitabine associated with docetaxel in advanced non-small-cell lung carcinoma

Purpose To evaluate the efficacy and toxicity profile of the combination of docetaxel and prolonged gemcitabine infusion in front-line chemonaive patients with advanced non-small-cell lung cancer (NSCLC).Patients and methods A total of 50 chemonaive patients diagnosed with advanced NSCLC according to the AJCC/TNM classification system were included in the present study. Treatment consisted of 1000 mg/m² gemcitabine given as a 100-min continuous infusion (10 mg/m² per min) on days 1 and 8 of each course and 75 mg/m² docetaxel as a 60-min infusion on day 8, repeating each course every 21 days.Results The ECOG performance status of the patients were as follows: 0 (10%), 1 (60%), and 2 (30%). All patients had two-dimensionally measurable disease. Their median age was 63 years (range 41–75 years). Of the 50 patients, 28 (56%) had squamous cell carcinoma, 14 adenocarcinoma (28%), and 8 (16%) large-cell carcinoma, and 40% and 60% of patients presented with stage IIIB and IV disease, respectively. Of those with stage IV disease, 33% had more than one metastatic site. A total of 220 courses were administered with a median of five courses per patient. Of 46 patients assessed for response, 12 (26%) had a partial remission (95% CI 13–39%). In 19 patients (41%) the disease remained stable, while disease progression was observed in 15 (33%). The median time to disease progression was 4 months, and median survival time was 7 months. At 1 year, 25% of patients remained alive, and the main grade 3/4 toxicity (according to the WHO scale) consisted of neutropenia (n=6, 12%), asthenia (n=4, 8%), peripheral edema (n=3, 6%), dyspnea (n=3, 6%), and diarrhea (n=2, 4%).Conclusions Prolonged gemcitabine infusion combined with docetaxel is well tolerated and its efficacy is similar to that of other chemotherapeutic schemes used for NSCLC treatment. However, the prolonged infusion of gemcitabine did not appear to result in any improvement in outcome or toxicity versus the standard dose rate.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphon-acetyl)-L-aspartate (PALA) is inactive in advanced pancreatic carcinoma

Purpose: To evaluate the effect of biochemical modulation by PALA and methotrexate on the therapeutic activity of 5-fluorouracil (5-FU) in patients with advanced pancreatic adenocarcinoma.Patients and methods: The treatment protocol consisted of phosphonacetyl-L-aspartate (PALA) 250 mg/m² i.v. 15-minute infusion followed by methotrexate 200 mg/m² i.v. 30-minute infusion on day 1 and 5-FU 600 mg/m² i.v. push on day 2. Folinic acid was given at 15 mg/m² p.o. every six hours for eight doses, starting 24 hours after methotrexate infusion. Cycles were repeated every two weeks.Results: Thirty patients with advanced chemotherapy-naive pancreatic cancer were included; 26 had measurable disease. Median age 56 years (27–72); median PS 1 (0–2). One PR (3.9%) was achieved; nine patients had stable disease. Median time to progression was 91 days. Median survival was 177 days and one year survival was 13.3% (4 of 30 patients). Treatment was well tolerated; diarrhea WHO grade 2 or 3 occurred in six patients; stomatitis WHO grade 2 and 3 in nine patients.Conclusions: Modulation of 5-FU by PALA and MTX given in this dose and schedule appears to be ineffective in patients with advanced pancreatic adenocarcinoma.     

Phase I study of a weekly schedule of oxaliplatin, high-dose leucovorin, and infusional fluorouracil in pretreated patients with advanced colorectal cancer

Purpose:To identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin (L-OHP) given on a weekly schedule including fixed doses of leucovorin (LV) and infusional 5-fluorouracil (5-FU), to define the toxicity profile of this regimen and to find preliminary evidence of its activity in pretreated patients with metastatic colorectal cancer (MCRC). Patients and methods: Twenty-one patients with progressive disease, treated with fluoropyrimidines and with histologically measurable MCRC entered into this phase I study. Fixed doses of LV (500 mg/m²) followed by a 48-hour 5-FU 2600 mg/m² infusion (5-FU_48h) were administered with escalating doses of L-OHP, starting from 60 mg/m² and with stepwise increments of 5 mg/m². No intra-patient dose escalation was allowed. Treatment was given once a week for four consecutive weeks, followed by a one-week rest period. Results:Three dose levels were tested. The MTD was L-OHP 70 mg/m² since two of the three patients showed dose-limiting diarrhea and the third developed neutropenia during the first cycle of chemotherapy. Most patients complained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Treatment delays were necessary for a total of 42 cases, but only in 11 of 42 after the pre-arranged 10% dose reduction of 5-FU (2300 mg/m²). Sixteen patients were evaluable for response: seven (33%; 95% confidence interval (CI): 14.6%–57.0%) were considered to show a major response (one complete), six showed a stable disease, and in addition progressive disease was observed in three patients. Conclusions:Our results show that L-OHP, LV and 5-FU can be administered safely and repetitively using a weekly schedule. Diarrhea and neutropenia are the DLT of this regimen. Its activity and its manageable toxicity profile deserve further evaluation in chemotherapy-naïve MCRC patients. The doses recommended for phase II trials are: L-OHP 65 mg/m², LV 500 mg/m² and 5-FU_48h 2300 mg/m² infusion given on a weekly-times-four schedule followed by a one-week rest period.     

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.     

A phase I trial of gemcitabine administered as a 96-h continuous intravenous infusion in patients with advanced carcinoma and lymphoma

Background and objective Preclinical data suggest gemcitabine may have schedule-dependent activity fovoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h. Patients and methods Gemcitabine was initially given at 1 mg/m²/d for 48, then, 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m²/d. Dose levels of 7, 8, 9 mg/m²/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule. we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk. Results Thirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1–10 cycles). The RPTD, was 8 mg/m²/d every 3 wk, and 6 mg/m²/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (>- grade 2) included fever (n=14), dyspnea (n=7). mucositis (n=6), hypotension (n=6), nausea/vomiting (n=6), and fatigue (n=5). Neutropeni and/or thrombocytopenia were uncommon. Conclusion A dministration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m²/d (32 mg/m²/course) when given every 3 wk, or 6 mg/m²/d (24 mg/m²/course) when given every 2 wk.     

Phase III trial comparing intensive induction chemoradiotherapy (60 Gy,infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study

BackgroundThe role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC) is uncertain.Patients and methodsOne hundred and nineteen patients with LAPC, World Health Organization performance status of zero to two were randomly assigned to either the induction CHRT group (60 Gy, 2 Gy/fraction; concomitant 5-fluorouracil infusion, 300 mg/m²/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m²/day, days 1–5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000 mg/m² weekly for 7 weeks). Maintenance gemcitabine (1000 mg/m² weekly, 3/4 weeks) was given in both arms until disease progression or toxicity.ResultsOverall survival was shorter in the CHRT than in GEM arm [median survival 8.6 (99% confidence interval 7.1–11.4) and 13 months (8.7–18.1), P = 0.03]. One-year survival was, respectively, 32% and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3–4 toxic effects were recorded in the CHRT arm, both during induction (36 versus 22%) and maintenance (32 versus 18%).ConclusionThis intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone.     

Gemcitabine plus celecoxib (GECO) in advanced pancreatic cancer: a phase II trial

Introduction: Single agent gemcitabine (GEM) is the standard treatment of pancreatic adenocarcinoma. Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. Recent studies in human pancreatic tumor cell lines suggest an involvement of COX-2 in tumor-dependent angiogenesis and provide the rational for inhibition of the COX pathway as an effective therapeutic approach. The aim of this study is to evaluate the toxicity and activity of gemcitabine plus celecoxib. Patients and methods: Forty-two consecutive patients with histologically or cytologically confirmed pancreatic adenocarcinoma entered the trial. Twenty-six patients (pts) were metastatic, 16 pts had locally advanced disease. The schedule consisted of GEM 1,000 mg/m² (as a 30 min iv infusion) on days 1, 8 every 3 weeks and celecoxib 400 mg bid. Results: Four pts (9%) achieved a partial response and 26 (62%) had stable disease, gaining a total disease control in 30 pts (71% [95% CI, 58–84%]). Overall clinical benefit response was experienced by 23 pts (54.7% [95%CI, 38.6–70.1%]). Neither grade 4 neutropenia nor grade 3–4 thrombocytopenia was observed. Grade 3 neutropenia was detected in 19% of pts. Grade 3 non-hematological toxicity was as follows: hepatic toxicity 7%, nausea 2.3%. Three pts (7%) and 5 pts (12%) had respectively a minimum creatinine increase and edema. Median survival was 9.1 months (95% CI, 7.5–10.6 months). Conclusion: GEM in combination with celecoxib showed low toxicity, good clinical benefit rate and good disease control. Further clinical investigation is warranted.     

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 study of 5-fluorouracil and leucovorin by a 14-day circadian infusion in metastatic adenocarcinoma patients

Initial experimental and clinical studies have indicated that 5-fluorouracil (5-FU) toxicity can be reduced by delivering 5-FU at around 4 a.m. More recent data have suggested that the toxicity might be reduced even more with delivery at around 9–10 p.m. The current study determined the maximum tolerated dose (MTD) for 5-FU and leucovorin (LV) delivered as a continuous circadian infusion over 14 days every 28 days, with the peak of the infusion occurring at around 3–4 a.m. The peak drug delivery was shifted to 9–10 p.m. in all patients developing toxicity of grade II (Eastern Cooperative Oncology Group) to determine if this timing further reduced toxicity and enabled increased dose intensity. A total of 14 patients with metastatic adenocarcinoma received an admixture of 5-FU and LV via a programmable portable infusion pump, with 62.5% of the 24-h dose being given over 7 h around the infusion peak. The starting dose level of 5-FU (200 mg/m² daily) and LV (5 mg/m² daily) was that established as the highest tolerable dose rate in a previously reported phase I study using a 14-day flat infusion of 5-FU and LV. The LV dose was first escalated to 20 mg/m² daily, followed by escalations of the 5-FU dose. A total of 51 courses were evaluable for toxicity. The dose-limiting toxicity was oral mucositis and hand-foot syndrome. More dose intensity could be delivered using a circadian infusion peaking at around 3–4 a.m. than was possible with a flat infusion of these drugs. Toxicity was redouced even further with peak drug delivery at around 9–10 p. m. The recommended dose for phase II studies using this schedule is 250 mg/m² 5-FU daily and 20 mg/m² LV daily with the peak of the infusion occurring at 9–10 p.m. This is a 300% and 25% higher dose for LV and 5-FU, respectively, than was found to be safe for a flat infusion.This work was supported in part by a grant from Lederle Laboratories Division, Cyanamid Canada Inc. This paper was presented in part in abstract form (abstract 528) at the 6th European Conference on Clinical Oncology and Cancer Nursing, October 27–31, 1991, Florence, Italy     

Phase I trial with weekly EO9, a novel bioreductive alkylating indoloquinone, by the EORTC Early Clinical Study Group (ECSG)

Purpose: EO9 is a new synthetic bioreductive alkylating indoloquinone, with preferential activity against solid tumors and higher antitumor activity under anaereobic conditions compared with aerobic conditions. In preclinical models EO9 demonstrated no major organ toxicity. The aim of the present phase I study was to determine the toxicities and the maximal tolerated dose (MTD) of EO9 administered as a 5-min i.v. infusion weekly to patients with solid cancers. Methods: Twenty-eight patients entered the study. The dose was escalated from 2.7 mg/m² according to a Fibonacci-like schedule. Results and conclusion: The dose-limiting toxicity was proteinuria. No other major toxicities were detected and in particular there was no significant increase in serum creatinine. This was in contrast to findings in a previous phase I trial using EO9 in a 3-weekly schedule, where a number of patients experienced severely decreased kidney function. The MTD in the present study was 15.0 mg/m² weekly and the recommended dose for phase II studies was 12.0 mg/m² weekly. Compared with 3-weekly EO9, the dose intensity could be increased from 22 mg/m² to 36 mg/m² with the weekly administration. Phase II studies have been performed by the EORTC Early Clinical Study Group in advanced breast, gastric, colorectal, pancreatic, and non-small-cell lung cancer. Received: 5 July 1999 / Accepted: 20 July 1999