Phase I trial combining gemcitabine and treosulfan in advanced cutaneous and uveal melanoma patients

Gemcitabine and treosulfan are DNA-damaging agents. Preclinical studies suggest that synergism exists when melanoma cells are exposed to both drugs concurrently. We conducted a phase I trial in advanced melanoma patients to determine the optimal dose of gemcitabine to be combined with treosulfan. Cohorts of three patients received increasing doses of gemcitabine, commencing at 0.5 g m(-2), followed by a fixed dose of 5.0 g m(-2) treosulfan on day one of a 21-day cycle. Patients alternately received a first cycle of single-agent gemcitabine or treosulfan before subsequent cycles of both drugs. Peripheral blood lymphocytes were collected in cycles 1 and 2 at various time points until 48 h post-treatment. The single-cell gel electrophoresis (Comet) assay was used to measure chemotherapy-induced DNA damage. A total of 27 patients were enrolled, no objective responses were observed, but two uveal melanoma patients had minor responses. Dose-limiting myelosuppression was reached at 3.0 g m(-2) gemcitabine. DNA single-strand breaks were detected 4 h post-gemcitabine, repaired by 24 h. DNA interstrand crosslinks were detected 4 h post-treosulfan, fully removed by 48 h. Following combination chemotherapy, treosulfan-induced DNA crosslinks persisted, still being detectable 48 h post-treatment, supporting the hypothesis that gemcitabine potentiates treosulfan-induced cytotoxicity. The recommended regimen for further study is 2.5 g m(-2) gemcitabine combined with 5.0 g m(-2) treosulfan.     

A two-cohort phase II clinical trial of gemcitabine plus treosulfan in patients with metastatic uveal melanoma

In-vitro synergy of treosulfan and gemcitabine has been observed in chemotherapy-resistant tumours. This trial investigated the efficacy of gemcitabine plus treosulfan in metastatic uveal melanoma. Patients received 1000 mg/m of gemcitabine and treosulfan at a dose of 2500 or 3000 mg/m2 in cohort 1 and 3500 or 4000 mg/m2 in cohort 2. Chemotherapy was administered on days 1 and 8 every 4 weeks. Thirty-three patients were treated, 14 in cohort 1 and 19 in cohort 2. In cohort 1 with a treosulfan dose of or=3500 mg/m2 in cohort 2, one had partial remission (5%), 10 showed disease stabilization and eight progressed. An increased survival was observed in the second cohort with higher treosulfan doses, with median survival times of 6.0 versus 9.0 months (P=0.03) in cohort 1 and 2, respectively, and a 1-year survival of 7.1% versus 47.3%, respectively. Based on the observation of prolonged disease stabilization, we recommend further investigation of the gemcitabine/treosulfan combination with a dose of 3500 mg/m2 of treosulfan in metastatic uveal melanoma.     

Phase II trial of cisplatin, gemcitabine and treosulfan in patients with metastatic uveal melanoma

Gemcitabine plus treosulfan (GeT) is under investigation in metastatic uveal melanoma. In this phase II trial, cisplatin was added to a GeT regimen to investigate the efficacy and toxicity of two alkylating agents in combination with gemcitabine. Patients received 30 or 40 mg/m of cisplatin, 1000 mg/m of gemcitabine and 3000 mg/m of treosulfan on days 1 and 8. Therapy was repeated on day 29. A maximum of six cycles was administered. Nineteen patients were included in the trial, of whom 17 were evaluable for response. No objective response was observed; seven patients (41%) had stable disease and 10 (59%) progressed. The median progression-free survival of all 19 patients was 3.0 months [95% confidence interval (CI), 1.8-3.1]; the median overall survival was 7.7 months (95% CI, 1.9-13.8). Grade 3 and 4 thrombopenia and leucopenia occurred in eight and nine of the 19 patients, respectively. The addition of cisplatin to the GeT regimen results in excessive haematological toxicity without improvement in efficacy.     

A prospective single arm phase II study of dacarbazine and treosulfan as first-line therapy in metastatic uveal melanoma

Uveal melanoma is relatively uncommon accounting for fewer than 5% of all melanoma cases. Localized tumours are curable by local therapy but a significant percentage of patients go on to have a relapse with metastatic disease. Uncertainty remains concerning the level of activity of dacarbazine in uveal melanoma as opposed to that in the cutaneous form. Recently, a possible role for treosulfan in uveal disease has been reported. A phase II study was therefore undertaken to assess the objective response rate of the combination of dacarbazine and treosulfan in previously untreated patients with metastatic uveal melanoma. All patients received dacarbazine 850 mg/m and treosulfan 8 g/m(2) every 21 days up to a maximum of six cycles. Fifteen patients enrolled in the study. As expected, the major toxicities were haematological (particularly thrombocytopaenia) but the treatment was generally well tolerated. No responses were seen; however, disease stabilization was achieved in two patients. Median progression free survival from the start of chemotherapy was 12 weeks and median overall survival was 30 weeks. This study, using the combination of dacarbazine and treosulfan, while well tolerated, did not confirm earlier reports suggesting treosulfan is active in uveal melanoma.     

Cisplatin, gemcitabine and treosulfan is effective in chemotherapy-pretreated relapsed stage IV uveal melanoma patients

Purpose  The efficacy of cisplatin, gemcitabine, and treosulfan (CGT) was evaluated in patients with chemotherapy pretreated relapsed AJCC stage IV uveal malignant melanoma. Methods  Patients received i.v./intrahepatic cisplatin, i.v. gemcitabine, and i.v. treosulfan (CGT) on day 1 and 8 as first-line (n = 1), second-line (n = 9), third-line (n = 1) or fourth-line (n = 1) therapy. Cisplatin, gemcitabine, and treosulfan (CGT)-therapy was repeated every 5 weeks until progression of disease occurred. A maximum of six CGT-cycles (mean, 2 cycles) was administered per patient. Results  No objective response was observed, six patients (50%) had stable disease and six (50%) patients progressed upon first reevaluation. Overall survival of all the 12 patients was 6 months. Patients with stable disease reached a median overall survival of 12 months, while patients with disease progression upon first reevaluation had a median overall survival of 4 months, only. Grade III/IV related hematotological side effects were experienced in six (leukopenia) and four (thrombocytopenia) patients. Conclusions  Treatment with CGT may lead to disease stabilization and prolonged survival in a substantial proportion of progressive stage IV uveal melanoma patients, even following heavy chemotherapy treatment.     

A randomized phase II trial of gemcitabine plus treosulfan versus treosulfan alone in patients with metastatic uveal melanoma.

BACKGROUND: Several trials demonstrated efficacy of the gemcitabine/treosulfan (GeT) combination in metastatic uveal melamoma. This randomized phase II trial compared the GeT combination versus treosulfan alone (T) in this rare disease. PATIENTS AND METHODS: Chemotherapy-naive patients with proven metastatic uveal melanoma were randomly assigned to receive 1000 mg/m(2) of gemcitabine plus 3500 mg/m(2) of treosulfan (GeT) or 3500 mg/m(2) of T. Chemotherapy was administered on days 1 and 8 in both arms, cycles were repeated on day 29. Primary end point was rate of responses and disease stabilizations. RESULTS: Forty-eight patients were randomized. Seven confirmed stable diseases (SDs) and one partial remission (PR) were observed in 24 patients treated with the GeT regimen, whereas no PR and only three SDs were observed in the T arm (P = 0.08). Median progression-free survival (PFS) was 3 months (95% CI 1.1-4.9) and 2 months (95% CI 1.7-2.3) in the GeT and T arm (P = 0.008, log-rank). Six and 12 months PFS was 34.8% and 17.9% and 16.7% and 0% always favoring the GeT arm. CONCLUSIONS: This first randomized trial in metastatic uveal melanoma showed a superior PFS and a trend for a higher response/stabilization rate of the GeT combination over T.     

Cisplatin, gemcitabine, and treosulfan in relapsed stage IV cutaneous malignant melanoma patients

To evaluate the efficacy of cisplatin, gemcitabine, and treosulfan (CGT) in 91 patients with pretreated relapsed AJCC stage IV cutaneous malignant melanoma. Patients in relapse after first-, second-, or third-line therapy received 40 mg m(-2) intravenous (i.v.) cisplatin, 1000 mg m(-2) i.v. gemcitabine, and 2500 mg m(-2) i.v. treosulfan on days 1 and 8. Cisplatin, gemcitabine, and treosulfan therapy was repeated every 5 weeks until progression of disease occurred. A maximum of 11 CGT cycles (mean, two cycles) was administered per patient. Four patients (4%) showed a partial response; 15 (17%) patients had stable disease; and 72 (79%) patients progressed upon first re-evaluation. Overall survival of all 91 patients was 6 months (2-year survival rate, 7%). Patients with partial remission or stable disease exhibited a median overall survival of 11 months (2-year survival rate, 36%), while patients with disease progression upon first re-evaluation had a median overall survival of 5 months (2-year survival rate, 0%). Treatment with CGT was efficient in one-fifth of the pretreated relapsed stage IV melanoma patients achieving disease stabilisation or partial remission with prolonged but limited survival.     

Topotecan and gemcitabine in platinum/paclitaxel-resistant ovarian cancer

24 patients were enrolled into a phase I-II study conducted to determine the maximum tolerated doses of topotecan-gemcitabine in sequential combination and the response rate in platinum/paclitaxel resistant ovarian cancer patients. A total of 83 courses are evaluable, with a median number of three cycles administered per patients (range 2-7). Topotecan was administered on days 1-5 by 30 min i.v. infusion immediately after gemcitabine given by 30 min i.v. on days 1 and 3; cycles were repeated every 28 days. The starting doses were topotecan 0.7 mg/m(2) and gemcitabine 200 mg/m(2). Following dose levels were 08/400; 0.9/600; 0.9/800 for topotecan and gemcitabine, respectively. The maximum tolerated dose (MTD) was reached at dose level 3, the dose-limiting toxicity being represented by febrile neutropenia and thrombocytopenia. After the MTD was reached, granulocyte-colony-stimulating factor was administered in 27% of cycles. Mild and manageable was non hematological toxicity. All patients are so far evaluable for response. Among them 2 complete responses (8.3%; 95% CI: 2.6-19), 1 partial response (4.2%; 95% CI: 3.8-12), 9 no change (37.5%; 95% CI: 18-56.8) and 12 progressions (50%; 95% CI: 30-70) have been registered. Based on these data, there is no evidence that combining topotecan and gemcitabine is better than using either of the two drugs used separately.     

A parallel dose-escalation study of weekly and twice-weekly bortezomib in combination with gemcitabine and cisplatin in the first-line treatment of patients with advanced solid tumors.

PURPOSE: To establish maximum tolerated dose (MTD) and tolerability of two schedules of bortezomib in combination with cisplatin and gemcitabine as first-line treatment of patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m(2) days 1 and 8 and cisplatin 70 mg/m(2) day 1, every 21 days. Maximum of six cycles. Plasma pharmacokinetics of cisplatin and gemcitabine were determined at MTD. RESULTS: Thirty-four patients were enrolled of whom 27 had non-small cell lung cancer (NSCLC). Diarrhea, neutropenia, and thrombocytopenia were dose-limiting toxicities leading to an MTD of bortezomib 1.0 mg/m(2) in the weekly schedule. Febrile neutropenia and thrombocytopenia with bleeding were dose-limiting toxicities in the twice-weekly schedule, leading to an MTD of bortezomib 1.0 mg/m(2) as well. Most common > or =grade 3 treatment-related toxicities were thrombocytopenia and neutropenia. No grade > or =3 treatment-related sensory neuropathy was reported. Of 34 evaluable patients, 13 achieved partial responses, 17 stable disease, and 4 progressive disease. Response and survival of NSCLC patients treated with twice weekly or weekly bortezomib were similar. However, increased dose intensity of bortezomib led to increased gastrointestinal toxicity as well as myelosuppression. Pharmacokinetic profiles of cisplatin and gemcitabine were not significantly different in patients receiving either schedule. CONCLUSIONS: Weekly bortezomib 1.0 mg/m(2) plus gemcitabine 1,000 mg/m(2) and cisplatin 70 mg/m(2) is the recommended phase 2 schedule, constituting a safe combination, with activity in NSCLC.     

Dose-finding study of fixed dose gemcitabine and escalating doses of ifosfamide given on days 1 and 8 in patients with advanced non-small cell lung cancer

This is a dose-finding study of fixed dose gemcitabine and escalating doses of ifosfamide, in chemo na?ve patients with advanced non-small cell lung cancer. The purpose of the study was to determine the optimal dosage and the maximal tolerated dose (MTD) of a specified schedule of gemcitabine and ifosfamide. Patients received gemcitabine 1250 mg/m2 and ifosfamide between 1.6 and 2.2 g/m2, intravenously, on days 1 and 8, repeated every 3 weeks for a maximum of four cycles. RESULTS: Sixteen patients entered the study. Three patients were entered at the first dose level of ifosfamide (1.6 g/m2) and none experienced any dose limiting (DLT) toxicity. In dose level 2 (1.8 g/m2), two patients had grade IV haematological toxicities, but they reached 21 days without any other dose limiting toxicity (DLT). Three further patients entered at this level but they were withdrawn due to disease progression. The sixth patient entered without any DLT. Three patients entered dose level 3 (2.0 g/m2), without any grade IV toxicity. The first patient entered into dose level 4 (2.2 g/m2), had progressive disease within 21 days and was withdrawn and another three were entered and had no DLT during the first 21 days. Four (33%) of the patients had stable disease and 67% had progressive disease. CONCLUSION: The MTD of the ifosfamide gemcitabine combination was not reached in the present study, as no DLT was observed. This combination at the dose levels of this protocol has little or no activity in patients with advanced NSCLC.     

A phase 1 study of fixed dose rate gemcitabine and irinotecan in patients with advanced pancreatic and biliary cancer

BACKGROUND: The combination of a fixed dose rate (FDR) infusion of gemcitabine and irinotecan may have a synergistic effect in the treatment of patients with advanced and metastatic pancreatic and biliary cancer. The current study was conducted to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of the combination. METHODS: There were 32 patients with metastatic pancreatic and advanced unresectable/metastatic biliary adenocarcinoma who were entered into this open-label, phase 1 dose escalation trial. Gemcitabine was administered at an FDR of 10 mg/m(2)/minute intravenously (iv). Irinotecan was administered iv over 60 minutes after gemcitabine. Both gemcitabine and irinotecan were given on Days 1 and 8 of a 21-day cycle. RESULTS: The MTD of the combination was gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The DLTs were neutropenia and neutropenic fever. Other DLTs included diarrhea, dehydration, and fatigue. Two patients developed deep venous thrombosis during the treatment. The efficacy of the combination was encouraging, even at the lower dose levels. Of 30 assessable patients, there was 1 complete response, 6 partial responses, and 16 patients with stable disease, with a response rate of 23%, a disease control rate of 76%, a median progression-free survival of 4.7 months, and a median overall survival of 7.0 months. The average number of treatment cycles received was 11. CONCLUSIONS: The recommended doses of the combination for future study are gemcitabine at an FDR of 1200 mg/m(2) and irinotecan at a dose of 100 mg/m(2). The efficacy of the combination is encouraging. Further assessment of the combination with or without biologic agents is suggested.     

A phase I study of erlotinib in combination with gemcitabine and radiation in locally advanced, non-operable pancreatic adenocarcinoma.

PURPOSE: To determine the maximum tolerated dose (MTD) of erlotinib when administered concurrently with twice weekly gemcitabine and radiation therapy (RT) for locally advanced pancreatic cancer, assess the safety and toxicity profile of this combination and secondarily evaluate response, time to tumor progression and overall survival. METHODS: Patients with untreated locally advanced pancreas cancer were treated with daily erlotinib in combination with gemcitabine 40 mg/m(2)/30 min twice weekly and RT delivered at 180 cGy/day in 28 fractions over 5.5 weeks for a total of 5040 cGy. Erlotinib was dose escalated in successive cohorts (100 mg, 125 mg). When the MTD was determined, the cohort was expanded to better define toxicity and preliminarily efficacy. All patients were surgically staged. After chemoradiation, patients received maintenance weekly gemcitabine 1000 mg/m(2) on days 1 and 8 of a 21 day cycle and daily erlotinib for four cycles. RESULTS: Three patients were treated at dose level 1 (erlotinib 100 mg) without limiting toxicity. Two of six patients at dose level 2 (erlotinib 125 mg) had dose-limiting toxicities, neutropenia and thrombocytopenia, causing dose delay and elevated liver enzymes. The MTD for erlotinib in combination with twice weekly gemcitabine-based chemoradiation was 100 mg/day. Eleven additional patients were treated at dose level 1. All twenty patients were assessable for toxicity. Seventeen patients were assessable for response. The partial response rate was 35% and 53% had stable disease. The median survival for all patients was 18.7 months. CONCLUSION: In combination with fixed dose gemcitabine at 40 mg/m(2) twice weekly and radiation at 180 cGy/day, the MTD of erlotinib was found to be 100 mg/day. This is a relatively well tolerated, biologically active combination in a poor prognostic cancer.     

A dose-escalation and pharmacokinetic study of gemcitabine and oxaliplatin in patients with advanced solid tumors.

BACKGROUND: Gemcitabine and oxaliplatin have broad antineoplastic activity and favorable toxicity. We conducted a phase I study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the combination in patients with advanced solid tumors. PATIENTS AND METHODS: Sixty-eight patients with advanced stage solid tumors were enrolled. Treatment was first-line for 35% of patients, second-line for 27%, and third-line for 38%. Gemcitabine was administered at escalating doses of 1000-2000 mg/m(2) as a 30-min intravenous (i.v.) infusion on days 1 and 8 and oxaliplatin at 60-130 mg/m(2) as a 4-h i.v. infusion on day 8 every 21 days without growth factor support. RESULTS: The MTD was defined at gemcitabine 1800 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8. Twelve dose levels were evaluated and DLTs occurring during the first cycle consisted of grade 4 neutropenia, grade 3 asthenia or mucositis and grade 1-3 neutropenia or thrombocytopenia resulting in treatment delays. A total of 266 cycles were administered with only one episode of febrile neutropenia and no toxic deaths. Seven (3%) and 26 (10%) cycles were complicated by grade 4 and 3 neutropenia, respectively, three (1%) and 13 (5%) by grade 4 and 3 thrombocytopenia, and eight (3%) by grade 3 anemia. The most common non-hematological toxicity was grade 2/3 asthenia observed in 23% of cycles. Responses were observed in patients with a variety of epithelial neoplasms. The pharmacokinetic study revealed no significant interaction between the two drugs. CONCLUSIONS: The combination of gemcitabine and oxaliplatin has excellent tolerability and promising activity in patients with advanced solid tumors. As the MTD exceeds the recommended single-agent dose for gemcitabine, and a dose-response effect has not been established, we recommend using both drugs at full doses, e.g. gemcitabine 1200-1400 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8 for further phase II studies.     

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 clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors

BACKGROUND: Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated. METHODS: Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned. RESULTS: There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration. CONCLUSION: Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.     

Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. METHODS: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m2, respectively; level 2, 800 and 40 mg/m2; level 3, 1,000 and 40 mg/m2; and level 4, 1,250 and 40 mg/m2. At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine-->docetaxel or docetaxel-->gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine-->docetaxel) to determine the MTD in minimally pretreated patients. RESULTS: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P< 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1,250 mg/m2 and docetaxel 40 mg/m2. There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). CONCLUSIONS: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.     

Phase I study of gemcitabine and carboplatin in advanced non-small cell lung carcinoma

BACKGROUND: This phase I study was designed to determine the maximum tolerated dose of carboplatin with a fixed dose of gemcitabine without growth factor or hematopoietic precursor support. METHODS: Nineteen patients with previously untreated non-small cell lung cancer (NSCLC) were treated at three dose levels. Initially, the gemcitabine dose was 1000 mg/m(2) given on days 1 and 8. Of the first five patients treated with carboplatin AUC 4, three experienced dose limiting toxicity (DLT). The study was, therefore, amended to decrease the dose of gemcitabine to 800 mg/m(2) given on days 1 and 8 in a 21-day cycle. RESULTS: Dose limiting toxicity (neutropenia and thrombocytopenia) were seen at dose level 2A (carboplatin AUC=5). Thus, no further dose escalation was performed. Grade 3 and 4 toxicities were seen as follows: leukopenia in five of 18 (28%); neutropenia, four of 18 (22%); and thrombocytopenia, four of 18 (22%) evaluable patients. Grade 3 or 4 anemia occurred in one of 18 (6%) patients and no neutropenic fever or treatment related mortality was observed. Partial responses were seen in six patients and one patient with evaluable disease had an objective response. The overall response rate was 37% (seven of 19). Six other patients had stable disease. A total of 89 courses were administered with a median of five courses per patient (range: two to six courses). The median time to progression for all patients was 3.7 months. The median overall survival was 7.4 months with four patients still alive (median follow up 13.5 months). The survival at 6 months and 1 year is 64 and 23%, respectively. CONCLUSION: The maximum tolerated dose (MTD) in this group of patients was defined as carboplatin AUC 4 when administered with gemcitabine 800 mg/m(2) on days 1 and 8 of a 21-day schedule.     

Phase I study of rubitecan and gemcitabine in patients with advanced malignancies.

BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.     

Phase I trial of topotecan in combination with gemcitabine in refractory solid tumor patients

PURPOSE: To determine maximum tolerated dose (MTD) and evidence of antitumor activity of topotecan in combination with gemcitabine in refractory cancer patients. METHODS: This was a Phase I, prospective, dose-escalation trial that employed a novel-dosing schema to investigate clinical safety. Patients were treated in six cohorts with topotecan (T)+gemcitabine (G). The doses of T and G were administered by 30-minute IV infusion, T on days one through five (0.3 mg/m2 to 1 mg/m2) and G on days one and 15 of a 28-day cycle (1000 mg/m2 to 1500 mg/m2). Toxicity was monitored. RESULTS: Twenty-three cancer patients were enrolled (colorectal, n=5; lung, n=4; gastric, n=4; esophageal, n=2; other, n=8). Two of three patients developed grade 3 nonhematologic toxicity attributed to study regimen, thereby fulfilling dose limiting toxicity requirements at cohort 6 (T, 1 mg/m2, G, 1500 mg/m2). Maximum tolerated dose (MTD) was established at cohort 5 (T, 1 mg/m2, G, 1250 mg/m2). Ten patients were treated at cohort 5. Nonhematologic adverse effects (AEs) >grade 3 attributed to the study regimen were not observed. Hematologic toxicity was frequent. Twenty-five percent of patients in cohort 2 and 50% of patients in cohorts 4, 5, and 6 had a reduction of ANC to <500 mm3. All neutropenic episodes were less than one week in duration. Five of the patients in the last three cohorts required delay and/or dose-reduction of G. Nineteen of 23 enrolled patients were evaluable for response. Two patients achieved a minimal response. CONCLUSIONS: The MTD was observed at a T dose of 1 mg/m2 administered on days 1 through 15, and a G dose of 1250 mg/m2 administered on days 1 and 15 via 30 minute intravenous (IV) infusion.     

Dose-intense PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) in advanced pancreatic adenocarcinoma: a dose-finding study

The aim of this study was to assess the maximum tolerated dose (MTD) of an intensified PEFG regimen administered every 14 days to patients with Stage III or metastatic pancreatic adenocarcinoma. Twenty-nine patients received fixed doses of both epirubicin (30 mg/m2) and 5-fluorouracil (200 mg/m2/day on Days 1-14) and of escalating doses of cisplatin and gemcitabine. The MTD was cisplatin 30 mg/m2 and gemcitabine 800 mg/m2. With respect to classical PEFG, intensified regimen potentially improved the dose-intensity of both cisplatin and epirubicin by 50 percent and of gemcitabine by 33 percent, reduced Grade 3-4 haematological toxicity and the number of outpatient accesses.