A clinical phase I trial of gemcitabine and treosulfan in uveal melanoma and other solid tumours

This trial was performed to define the maximum tolerated dose (MTD) of treosulfan administered in combination with a fixed dose of gemcitabine in uveal melanoma patients. Preclinical studies suggested synergistic activity against uveal melanoma. Gemcitabine (1 g/m2) and treosulfan (2.5-4 g/m2) were administered on days 1 and 8, and cycles were repeated on day 29 for a maximum of six cycles. For treosulfan, dose escalation cohorts of 2-4 patients were enrolled. An additional 25 patients were entered at treosulfan dose levels II (3 g/m2) and III (3.5 g/m2). Thirty three patients with uveal melanoma and six patients with other histologies were accrued. Side-effects were predominantly haematological. The MTD was 3.5 g/m2 of treosulfan together with 1 g/m2 of gemcitabine. In the uveal melanoma patients, one partial response (PR) and 15 stablisations of disease (SD) were recorded and whether this translates into a survival gain should be explored further.     

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.     

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.     

The use of treosulfan and gemcitabine in the treatment of platinum-resistant ovarian cancer

The combination of treosulfan and gemcitabine (TG) has been shown to have activity in ovarian cancer. These two agents are thought to be synergistic, with gemcitabine causing the persistence of treosulfan-induced DNA crosslinks. This study aimed to investigate the response rates, survival and toxicity in patients with platinum-resistant ovarian cancer treated with TG. A retrospective case note review of the patients treated with TG was performed in one cancer centre between May 1st, 2000 and November 1st, 2005. Estimates of cumulative survival were obtained using the Kaplan-Meier method. Forty-nine patients were identified; median age at diagnosis was 55 years (range, 31-72) and the median follow-up was 45.1 months (range, 12.2-118.3). TG was used as second-, third-, fourth- and fifth-line chemotherapy in 15, 19, 13 and 2 patients, respectively. Fifteen patients (30.6%) had stable disease; 25 (51%), a partial response; 1 (2%), a complete response and 8 (16.3%) had progressive disease. Median survival following diagnosis was 45.1 months and the median relapse-free survival was 12 months. The median survival time from the start of TG was 13.7 months with a relapse-free survival of 6.3 months. The median number of cycles given was 7. The most common toxicity recorded was myelosuppression. There were no treatment-related deaths. TG chemotherapy produced favourable response rates in a heavily pre-treated group of patients with platinum-resistant epithelial ovarian cancer. This doublet warrants further investigation in a phase III trial setting.     

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.     

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.     

吉西他滨固定剂量率静滴联合奥沙利铂治疗晚期胆道癌的临床研究

[目的]评价吉西他滨固定剂量率静滴联合奥沙利铂（GEMOX方案）治疗晚期胆道癌的疗效和毒副作用。[方法]47例晚期胆道癌患者均接受吉西他滨1 000mg/m2,10mg/（m2.min）静滴,d1、8;奥沙利铂130mg/m2,静脉滴注2h,d1;每3周重复。至少化疗3个周期。[结果]47例患者均可评价疗效,无完全缓解病例,部分缓解9例（19.2%）,稳定22例（46.8%）,进展16例（34.0%）,总有效率（CR＋PR）为19.2%（9/47）。中位无进展生存期（PFS）4.7个月,中位总生存期（OS）9.3个月。主要毒副反应为中性粒细胞减少、血小板减少,恶心、呕吐,肝肾和外周神经毒性等。[结论]吉西他滨固定剂量率静滴联合奥沙利铂治疗晚期胆道癌有效,但其血液学毒性需引起重视。     

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.     

Flexible chemotherapy regimen with gemcitabine and vinorelbine for metastatic nonsmall cell lung carcinoma: a phase II multicenter trial

BACKGROUND: This Phase II study evaluated a flexible 3- or 4-week dosing schedule of gemcitabine and vinorelbine to determine its effect on response rate and survival of patients with metastatic nonsmall cell lung carcinoma (NSCLC). METHODS: Thirty-four response-evaluable patients, 24 with performance status (PS) 0-1 and 10 with a PS of 2, 30 with Stage IV, and 4 with Stage IIIB NSCLC were treated with gemcitabine 1000 mg/m(2) intravenously and vinorelbine 25 mg/m(2) intravenously (first 15 patients) or 30 mg/m(2) intravenously (next 19 patients) on Days 1, 8, and 15 of a 4-week cycle, if on Day 15 neutrophils were > or = 1500/uL and platelets > or = 100,000/uL. If chemotherapy could not be administered on Day 15, then Day 22 became Day 1 of the next cycle. RESULTS: When vinorelbine 25 mg/m(2) was given with gemcitabine 1000 mg/m(2), 11 patients received 4-week cycles, 3 patients 3-week cycles, and 1 patient both 3- and 4-week cycles. With vinorelbine 30 mg/m(2) and gemcitabine 1000 mg/m(2), 7 patients received 4-week cycles, 2 patients 3-week cycles, and 10 patients both 3- and 4-week cycles. The partial response rate for 34 patients was 53% (18 patients). Median survival (MS) was 11.1 months, and 1-year survival 50% (17 patients). Patients with PS 0+1 had a MS of 17.5 months compared with patients with PS 2, who had MS of 3.3 months. Patients < 70 years of age had a MS of 18 months, and those >/= 70 years had a MS of 5.5 months. CONCLUSION: This flexible schedule with gemcitabine and vinorelbine enabled optimal dose delivery and suggested excellent efficacy but less toxicity than treatment with platinum regimens.     

Second-line chemotherapy of metastatic malignant melanoma with intravenous treosulfan: a phase II multicentre trial

The purpose of this multicentre phase II trial was to evaluate time to progression, survival time, rate of objective tumour response and toxicity of second-line intravenous treosulfan chemotherapy in stage IV melanoma patients. Thirty-one patients with measurable stage IV malignant melanoma and prior chemotherapy with a dacarbazine-containing regimen were included. Of this group, 26 patients were evaluable. All patients received treosulfan (8 g/m intravenously on day 1; cycle repeated every 28 days up to six courses). Patients were evaluated for tumour response, survival time and toxicity. No objective responses (complete or partial) were observed. Five patients (19%) showed no change and 21 had progressive disease after treosulfan treatment. Four patients experienced a minor or mixed response. The median time to progression was 1.8 months (95% confidence interval [CI] 1.6-2.1 months) and the median overall survival was 6.5 months (95% CI 3.1-10 months). The 1 year survival rate was 33.9% (95% CI 15.4-52.3%). Leukocytopenia and thrombocytopenia (Common Toxicity Criteria grades 3 and 4) occurred in 15% and 18% of cases, respectively. The non-haematological toxicity of this outpatient regimen was mild. In conclusion, intravenous treosulfan treatment does not induce objective response rates when used as a second-line treatment of metastatic malignant melanoma.     

Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies.

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.     

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.     

Pilot study of gemcitabine (10 mg/m<Superscript>2</Superscript> per min) and cisplatin

PURPOSE: Gemcitabine and cisplatin are routinely used in combination. In this combination, gemcitabine at conventional doses of 1000-1500 mg/m(2) is delivered weekly as a 30-minute bolus. Laboratory data suggest that the synthesis of gemcitabine triphosphate is saturable, and that gemcitabine infused at a rate of 10 mg/m(2) per min optimizes accumulation of the triphosphate. Early clinical experience suggests that gemcitabine delivered by a more prolonged infusion is more myelosuppressive. In this pilot study, we wished to assess if full-dose gemcitabine when given with cisplatin could be delivered by this more prolonged infusion. METHODS: In this study, all patients received cisplatin 75 mg/m(2). All gemcitabine doses were delivered at 10 mg/m(2) per min. For the initial cohort (level 1) the gemcitabine dose was 800 mg/m(2) per min. Subsequent escalations were 1000 mg/m(2) per min (level 2), and 1250 mg/m(2) per min (levels 3 and 4). For the first three cohorts, patients received gemcitabine on days 1, 8, and 15 and cisplatin on day 15 on a 28-day cycle. Patients on level 4 received gemcitabine on days 1 and 8 and cisplatin on day 8 on a 21-day cycle. Dose omissions or delays (holds) were mandated for NCI CTC grade 3 or 4 granulocytopenia or grade 2-4 thrombocytopenia. RESULTS: Entered onto this dose-finding study were 23 patients (12 male, 11 female) with advanced solid tumors. Seven patients were treatment-naive. Six patients were treated on level 1, five each on levels 2 and 3 and seven on level 4. Patients received one to seven cycles of treatment. Myelosuppression-related dose holds occurred at all levels. First-cycle dose holds occurred in three of six, four of five, three of five and two of seven patients on successive levels. First-cycle grade 3 or 4 granulocytopenia/thrombocytopenia occurred in three patients on level 1, one patient on level 2, two patients on level 3 and three patients on level 4. There were no partial or complete responses. Four patients were removed for toxicity (three myelosuppression, one nephrotoxicity), one at physician discretion, and 15 with disease progression. Three patients stopped therapy with stable disease after 5-6 months. On level 3, three of five patients remained on therapy for 4 months or more, compared to only one patient on each of the other three levels. CONCLUSIONS Weekly gemcitabine 1250 mg/m(2), utilizing a 10 mg/m(2) per min infusion rate, can be delivered with cisplatin 75 mg/m(2) with tolerable toxicity. When used in combination with cisplatin, however, the benefit of this fixed dose rate infusion gemcitabine compared to standard bolus gemcitabine remains to be determined.     

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 dose and schedule finding study of gemcitabine and etoposide in patients with progressive non-small cell lung cancer after platinum containing chemotherapy.

BACKGROUND: Combination chemotherapy improves survival in patients with disseminated non-small cell lung cancer (NSCLC). Gemcitabine is active against NSCLC and etoposide has an additive effect in vitro. We describe a dose finding study for the combination of these drugs. PATIENTS AND METHODS: NSCLC patients progressive after chemotherapy received gemcitabine (1000 mg/m2 days 1, 8, 15) and one of five etoposide schedules in doses ranging from 60 to 100 mg/m2 per day administered on days 1-3 (schedules 1-2) or 8-10 (schedules 3-5). RESULTS: 23 patients (median age 59 years) were entered. Number of patients and cycles evaluable for toxicity was 22 and 75. Non-hematological toxicity was mild. In cycle 1 leukocytopenia grade III/IV was observed in 33 and 56% of the patients treated with etoposide 60 and 80 mg/m2 days 1-3 and in 50% treated with etoposide 60 and 80 mg/m2 days 8-10. During cycle 1 thrombocytopenia grade III/IV was observed in 0, 33, 0 and 33% of these patients, respectively. Both patients treated at etoposide 100 mg/m2 days 8-10 experienced febrile leukocytopenia. During cycle 1 single doses of gemcitabine were administered as planned more frequently in patients receiving etoposide 80 mg/m2 per day on days 8-10 compared to etoposide days 1-3 (83 versus 70%). Postponement of combination gemcitabine and etoposide was not necessary. The overall response rate was 21% (95% confidence interval 3-39%) with a median duration of 7.5 + months in this dose finding study. CONCLUSIONS: Combined gemcitabine etoposide is feasible in patients with progressive NSCLC. The optimal combination was gemcitabine 1000 mg/m2 per day on days 1, 8 and 15 and etoposide 80 mg/m2 per day on days 8-10 of each 28-day cycle. The response rate of 21% warrants further investigation in patients with advanced NSCLC.     

低剂量持续静脉滴注吉西他滨一线治疗晚期非小细胞肺癌的临床研究

背景与目的:目前已将吉西他滨联合顺铂作为晚期非小细胞肺癌的一线化疗方案,吉西他滨的常规使用剂量和方法是1000mg/m2半小时静脉滴注,第1、8天,每3周为一个疗程。本研究旨在评价低剂量吉西他滨持续6h静脉滴注联合顺铂一线治疗晚期非小细胞肺癌的有效性和安全性。方法:48例经病理和/或细胞学检查确诊、未经化疗的晚期非小细胞肺癌患者,采用吉西他滨250mg/m2持续静脉滴注6h,第1、8天,顺铂75mg/m2,每3周为一疗程,连续使用2疗程以上。结果:48例患者中46例可评价疗效,所有患者可评价不良反应。完全缓解率2.2%,部分缓解率30.3%,总有效率为32.5%,中位治疗至进展时间为5.1个月,中位生存时间为10.2个月,1年生存率36.6%。白细胞减少发生率为60.4%,血小板减少发生率为39.5%,Ⅲ～Ⅳ度的白细胞和血小板减少发生率分别为20.8%和12.5%。结论:低剂量吉西他滨持续6h静脉滴注联合顺铂一线治疗晚期非小细胞肺癌疗效确切、不良反应轻。     

A Phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors

Purpose

Pazopanib plus gemcitabine combination therapy was explored in patients with advanced solid tumors.

Methods

In a modified 3 + 3 enrollment scheme, oral once-daily pazopanib was administered with intravenous gemcitabine (Days 1 and 8, 21-day cycles). Three protocol-specified dose levels were tested: pazopanib 400 mg plus gemcitabine 1,000 mg/m², pazopanib 800 mg plus gemcitabine 1,000 mg/m², and pazopanib 800 mg plus gemcitabine 1,250 mg/m². Maximum-tolerated dose was based on dose-limiting toxicities during treatment Cycle 1. In the expansion phase, six additional patients were enrolled at the highest tolerable dose level.

Results

Twenty-two patients were enrolled. At the highest dose level tested (pazopanib 800 plus gemcitabine 1,250), patients received >80 % of their planned dose and the regimen was deemed safe and tolerable. The most common treatment-related adverse events included fatigue, neutropenia, nausea, and decreased appetite. Neutropenia and thrombocytopenia were the most common events leading to dose modifications. Pharmacokinetic interaction between pazopanib and gemcitabine was not observed. One objective partial response at the highest dose was observed in a patient with metastatic melanoma. Prolonged disease stabilization (>12 cycles) was reported in three patients (metastatic melanoma, cholangiocarcinoma, and colorectal carcinoma).

Conclusion

Combination pazopanib plus gemcitabine therapy is tolerable, with an adverse event profile reflective of that associated with the individual agents. There was no apparent pharmacokinetic interaction with pazopanib plus gemcitabine co-administration, although patient numbers were limited. Further investigation of combined pazopanib plus gemcitabine is warranted.     

Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California Cancer Consortium Trial

Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.     

Combination chemotherapy for choroidal melanoma: ex vivo sensitivity to treosulfan with gemcitabine or cytosine arabinoside

Treatment of choroidal melanoma by chemotherapy is usually unsuccessful, with response rates of less than 1% reported for dacarbazine (DTIC)-containing regimens which show 20% or more response rates in skin melanoma. Recently, we reported the activity of several cytotoxic agents against primary choroidal melanoma in an ATP-based tumour chemosensitivity assay (ATP-TCA). In this study, we have used the same method to examine the sensitivity of choroidal melanoma to combinations suggested by our earlier study. Tumour material from 36 enucleated eyes was tested against a battery of single agents and combinations which showed some activity in the previous study. The combination of treosulfan with gemcitabine or cytosine arabinoside showed consistent activity in 70% and 86% of cases, respectively. Paclitaxel was also active, particularly in combination with treosulfan (47%) or mitoxantrone (33%). Addition of paclitaxel to the combination of treosulfan + cytosine analogue added little increased sensitivity. For treosulfan + cytosine arabinoside, further sequence and timing experiments showed that simultaneous administration gave the greatest suppression, with minor loss of inhibition if the cytosine analogue was given 24 h after the treosulfan. Administration of cytosine analogue 24 h before treosulfan produced considerably less inhibition at any concentration. While we have so far been unable to study metastatic tumour from choroidal melanoma patients, the combination of treosulfan with gemcitabine or cytosine arabinoside shows activity ex vivo against primary tumour tissue. Clinical trials are in progress.     

Phase II trial of cisplatin and gemcitabine in patients with advanced gastric cancer.

BACKGROUND: This phase II study was performed to determine the efficacy and toxicity of cisplatin and gemcitabine in patients with advanced gastric cancer. PATIENTS AND METHODS: Forty chemo-na?ve patients with measurable locoregionally advanced or metastatic gastric cancer were included; the median patient age was 53 years (range 35-71). Cisplatin was administered at a dose of 50 mg/m2, given in 1 h intravenously (i.v.) on days 1 and 8, followed after 24 h by gemcitabine at a dose of 800 mg/m2 given in 30 min i.v. on days 2, 9 and 16, every 28 days. RESULTS: A median number of four therapy cycles were given (range 2-8). Myelosuppresion was the most important toxicity. Grade 3-4 thrombopenia was observed in 19 patients (48%) and grade 3-4 leukopenia was observed in 23 (58%). Myelotoxicity was cumulative and caused omission of gemcitabine on day 16 in 55% of cycles. Non-haematological toxicity consisted mainly of grade 1-2 nausea and vomiting. Objective responses were observed in 30% of patients including two complete remissions and 10 partial remissions. Median survival was 11 months (range 3-27+). CONCLUSIONS: This cisplatin-gemcitabine regimen had moderate efficacy in patients with advanced gastric cancer, with manageable toxicity. Further studies with this combination may be warranted.