吉西他滨固定剂量率输注联合奥沙利铂一线治疗晚期胰腺癌的Meta分析

背景与目的:有研究提示吉西他滨(Gemcitabine,GEM)固定剂量率(Fixed-dose rate,FDR)输注治疗晚期胰腺癌似有较好的疗效,Meta分析也显示含铂类联合化疗优于GEM单药化疗,本文试图通过Meta分析,探讨GEM FDR输注联合奥沙利铂(GEMOX)一线治疗晚期胰腺癌的地位和价值.方法:通过MEDLINE、EMBASE、ASCO等数据库及论文集检索国内外的相关文献.选择治疗组为GEMOX方案化疗,对照组为标准GEM单药化疗的晚期胰腺癌随机对照试验.由2位评价者分别按上述检索策略收集资料,按纳入标准入选,主要对总生存率及主要不良反应进行Meta分析.结果:从182篇文献中筛选出符合纳入标准的2个随机对照试验,共涉及869例患者.与GEM单药组比较,GEMOX组半年生存率提高9%(95%CI 0.03～0.16,P=0.005),1年生存率提高5%(95%CI-0.01～0.11,P=0.08),客观有效率提高6%(95%CI 0.02～0.10,P=0.006);WHO Ⅲ/Ⅳ度贫血发生率下降5%(95%CI-0.08～-0.01,P=0.01),恶心/呕吐提高13%(95%CI 0.08～0.18,P＜0.001),神经毒性增加14%(95%CI 0.04～0.24,P=0.009),粒细胞减少症、血小板减少症两组相似,差异无统计学意义.结论:现有的证据提示,GEM固定剂量率输注联合奥沙利铂组成的GEMOX方案一线治疗晚期胰腺癌可能有较好的应用前景,值得进行进一步的临床试验.     

Phase I study of weekly (day 1 and 8) docetaxel in combination with capecitabine in patients with advanced solid malignancies

Purpose Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in a number of tumor types, but at the expense of significant toxicity. To improve the therapeutic index, we evaluated a weekly regimen of docetaxel in combination with capecitabine, and determined the maximum tolerated dose, toxicities and pharmacokinetics of this combination.Patients and methods Patients with advanced solid malignancies were treated with docetaxel on days 1 and 8, and capecitabine, twice daily on days 1–14, of an every-21-day cycle. Pharmacokinetics of docetaxel were assessed on days 1 and 8 of the first cycle of chemotherapy.Results Enrolled in the study were 25 patients. The most frequent toxicities were asthenia, hand-foot syndrome and mucositis. Inability to deliver at least 75% of the planned doses of both drugs during the first two cycles of chemotherapy was noted at dose levels 2, 3 and 4. Dose level 1 (docetaxel 30 mg/m² and capecitabine 825 mg/m² twice daily) is the recommended dose for phase II studies. Five patients experienced a partial response, and eight patients had stabilization of disease. Coadministration of capecitabine did not alter the pharmacokinetics of docetaxel.Conclusion The regimen consisting of docetaxel 30 mg/m² (days 1, 8) and capecitabine 825 mg/m² twice daily (days 1–14) was well tolerated. Capecitabine did not alter pharmacokinetics of docetaxel. Further testing of this regimen in tumor-specific trials, especially gastric, lung and breast cancer, is warranted.Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, May 2003, Chicago, IL.     

吉西他滨联合卡培他滨治疗紫杉类化疗失败的晚期乳腺癌的临床观察

目的探讨吉西他滨联合卡培他滨治疗紫杉类治疗失败的晚期乳腺癌的临床疗效及不良反应。方法对2008年3月至2010年2月住院治疗的69例紫衫类及葸环类治疗失败的晚期乳腺癌患者给予吉西他滨（1000mg／m2）和卡培他滨（1500mg／m2）治疗，3周为1个疗程，至少经过2个疗程的治疗。结果完全缓解3例（4．3％），部分缓解27例（39．1％），稳定22例（31．9％），进展17例（24．6％），总有效率为43．5％，临床获益率为75．4％，中位无进展生存时间为8．2个月，中位生存时间为13．4个月。骨转移患者总有效率为100％，明显高于多发转移、肺部转移和肝脏转移等患者，差异有统计学意义（P〈0．05）。绝经前患者临床获益率明显高于绝经后患者，两组比较差异有统计学意义（P〈0．05）。不良反应以手足综合征和血小板减少为主，均为可逆性，无治疗相关死亡发生。结论吉西他滨联合卡培他滨治疗紫杉类化疗失败的晚期乳腺癌临床效果显著，对于骨转移患者和绝经前患者的治疗效果更佳。     

吉西他滨联合卡培他滨治疗晚期三阴性乳腺癌的临床观察

目的观察吉西他滨联合卡培他滨治疗ER、PR、HER-2均阴性（三阴性）晚期转移性乳腺癌的疗效与安全性。方法 2004年7月至2009年6月共14例经免疫组化证实ER、PR、HER-2均阴性的晚期转移性乳腺癌复治患者参与研究。患者接受吉西他滨联合卡培他滨方案治疗：吉西他滨800mg/m2,静脉滴注30min,d1、d8、d15;卡培他滨2500mg/m2口服,d1～14。28d重复。结果全组14例共完成58个周期的治疗,中位数4个周期,范围2～6个周期,均可评价疗效。完全缓解0例,部分缓解4例（28.6%）,病情稳定6例（42.9%）,病情进展4例（28.6%）,客观有效率为28.6%;中位疾病进展时间（mTTP）6个月（95%CI：2～10个月）,中位生存期（OS）16个月（95%CI：6～32个月）,1年生存率为64.4%,3年生存率为14.3%。毒副反应主要为Ⅰ～Ⅲ度骨髓抑制、胃肠道反应、手足综合征、末梢神经毒性、流感样症状、轻度肝功能损伤等。结论吉西他滨联合卡培他滨治疗晚期三阴性乳腺癌患者,初步观察有一定的疗效,其毒副作用患者可以耐受。     

A phase II study of capecitabine plus gemcitabine in patients with locally advanced or metastatic pancreatic cancer

PURPOSE: This open-label, multicenter phase II study was conducted to investigate the efficacy and safety of capecitabine plus gemcitabine combination chemotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: We enrolled 63 patients who received capecitabine 830 mg/m(2) orally twice daily on days 1-21 plus gemcitabine 1000 mg/m(2) as a 30-min infusion on days 1, 8 and 15 every 4 weeks for up to six cycles. RESULTS: A total of 14 patients had partial responses giving an overall response rate of 22% (95% confidence interval [CI] 13-34%) in the intent-to-treat population. The median time to progression and overall survival were 3.9 months (95% CI 3.5-5.7) and 7.5 months (95% CI 5.0-10.0), respectively, and 1-year survival rate was 27.1% in the intent-to-treat population. Capecitabine plus gemcitabine was well tolerated. Grade 3 hematological adverse events were neutropenia (21%) and thrombocytopenia (2%); the only grade 4 hematological events were anemia (2%) and neutropenia (6%). Non-hematological adverse events were mainly gastrointestinal events and hand-foot syndrome, which affected 16% of patients. Grade 3/4 non-hematological events were infrequent. CONCLUSION: The combination of capecitabine plus gemcitabine appears to be active and well tolerated as first-line treatment in patients with advanced/metastatic pancreatic cancer.     

A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors

INTRODUCTION: Chemotherapy regimens including gemcitabine in combination with microtubule inhibitors such as docetaxel and paclitaxel have wide clinical application. Patupilone is a novel tubulin-polymerizing agent with activity against paclitaxel-resistant cell lines. We conducted a phase I trial to assess the maximum tolerated dose, dose limiting toxicity (DLT) and antitumor activity of gemcitabine and patupilone. METHODS: Patients with refractory solid tumors enrolled in cohorts of three. Cohorts received fixed doses of gemcitabine (1,000 or 750 mg/m(2)) along with escalating doses of patupilone (1.5-3 mg/m(2)) on days 1 and 8 of a 21-day cycle. RESULTS: Twenty-seven patients received a total of 99 courses of treatment on study. Hematologic toxicity in the first cohort required a modification of the protocol to decrease the gemcitabine dose. Subsequent patients received gemcitabine 750 mg/m(2) and escalating doses of patupilone from 1.5 to 3 mg/m(2). DLTs were grade 3 asthenia and grade 3 dehydration. There was also one treatment-related death due to neutropenic infection. Other clinically significant toxicities were persistent asthenia and persistent nausea. Four patients, one each with pancreatic cancer, esophageal carcinoma, cholangiocarcinoma and gallbladder carcinoma, experienced a partial response. CONCLUSIONS: The dose-limiting toxicities of gemcitabine and patupilone were asthenia and dehydration. Dose reductions also occurred due to persistent fatigue that was not dose-limiting. However, patients with advanced malignancies were able to tolerate gemcitabine and patupilone at doses that resulted in clinical benefit. The recommended phase II dose for this schedule is gemcitabine 750 mg/m(2) and patupilone 1.5 mg/m(2) on days 1 and 8 of a 21-day cycle.     

三维适形放疗同步卡培他滨联合吉西他滨治疗３２例局部晚期胰腺癌的临床观察

目的　探讨同步放化疗（ＣＣＲＴ）治疗局部晚期胰腺癌的疗效和毒性反应。方法　２００３年１月至２００６年２月共收治局部晚期胰腺癌患者３２例,采用三维适形放疗（３ＤＣＲＴ）,总量４５～５４Ｇｙ;同步化疗方案为：卡培他滨１５００ｍｇ／ｍ^２,分２次口服,第１～１４天;吉西他滨１０００ｍｇ／ｍ２,静脉滴注第１、８、１５天。２１天为１周期,与放疗同时开始,ＣＣＲＴ结束后１个月巩固化疗２～４周期。结果　所有患者均完成ＣＣＲＴ治疗,其中２１例完成４个周期巩固化疗,７例３个周期,４例２个周期。有效率为５６.２％,中位生存期为１８.８个月,１、２年生存率分别为４６.８％和２２５％;疼痛缓解率６５.６％（２１／３２）,生活质量明显改善,无治疗相关性死亡。结论　三维适形放疗同步卡培他滨联合吉西他滨治疗局部晚期胰腺癌疗效显著,能提高局部控制率,延长生存期,缓解疼痛,提高生活质量,且毒副反应能够耐受。     

A phase II trial of gemcitabine plus capecitabine for patients with advanced pancreatic adenocarcinoma

Purpose While gemcitabine (GEM) is widely accepted for the treatment of advanced pancreatic cancer, capecitabine (CAP) has shown single agent activity and promising efficacy in combination with GEM. This phase II study was conducted to evaluate the efficacy and toxicity of GEM combined with dose escalated 14-day CAP as first-line chemotherapy for advanced pancreatic cancer. In addition, we also analyzed the correlation between CA19-9 response and clinical outcomes. Methods Patients had advanced pancreatic adenocarcinoma, no prior systemic chemotherapy other than that given concurrently with radiation therapy, at lease one measurable disease, and adequate organ functions. The patients were treated with GEM 1,000 mg/m² IV on days 1, 8 and CAP 1,000 mg/m² twice a day PO on days 1–14, in 21-day cycles. Results The objective RR among 45 patients was 40.0% (95% CI; 25.1–54.9), including 1CR (2.2%). The median TTP and OS were 5.4 months (95% CI; 1.8–9.0) and 10.4 months (95% CI; 6.2–14.5), respectively. Patients with ≥25% decline of serum CA19-9 had significantly better outcomes in terms of TTP and OS than those who did not (P < 0.03). The most frequent, grade 3–4, non-hematologic toxicity was hand–foot syndrome (6.7%). Conclusions The combination of GEM with dose escalated 14-day CAP is well tolerated and offers encouraging activity in the treatment of advanced pancreatic cancer. In addition, CA19-9 response correlates well with clinical outcomes in this population.     

Phase I trial of weekly trabectedin (ET-743) and gemcitabine in patients with advanced solid tumors

Purpose  To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors. Methods  Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m²) followed by trabectedin (starting dose, 0.3 mg/m²). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses. Results  Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m² and gemcitabine 1,000 mg/m², which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration. Conclusions  Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.     

A phase II study of fixed-dose rate gemcitabine plus low-dose cisplatin followed by consolidative chemoradiation for locally advanced pancreatic cancer

PURPOSE: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. METHODS AND MATERIALS: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m(2) at 10 mg/m(2)/min) plus cisplatin 20 mg/m(2) on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m(2) orally twice daily on the day of radiation) as a radiosensitizer. RESULTS: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. CONCLUSIONS: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.     

Myelopathy after radiation therapy and chemotherapy with capecitabine and gemcitabine

This article describes a woman with metastatic upper gastrointestinal cancer who developed thoracic myelopathy unexpectedly after standard dosage and fractionation radiotherapy. She also was receiving capecitabine and gemcitabine concomitantly. There are few reported cases of chemotherapy potentiation of spinal cord radiation toxicity. These agents are known radiosensitizers, making it likely that they contributed to this adverse outcome. As these agents are increasingly incorporated into clinical trials of combined therapy, caution will be necessary in both trial design and clinical management.     

Phase I and pharmacokinetic study of vatalanib plus capecitabine in patients with advanced cancer

Angiogenesis inhibition is now a proven therapeutic strategy in treatment of several solid tumors. Vatalanib is a potent inhibitor of all known vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. In view of the effectiveness of angiogenesis inhibitor therapy when combined with chemotherapy and the established role of capecitabine in treatment of colorectal and breast cancer, we undertook a phase I clinical trial of the combination of capecitabine and vatalanib with the goal of developing a combination oral regimen. The study objectives were to determine the maximally tolerated dose of vatalanib that could be safely administered daily with capecitabine given orally for 14 out of 21 days to patients with advanced cancer; to characterize the safety, tolerability, and pharmacokinetic profile of vatalanib given in combination with capecitabine; and to describe any pharmacokinetic interactions between the drugs. The study had an initial dose escalation phase followed by a dose expansion phase. During the dose escalation phase, cohorts of at least three patients each were treated with capecitabine and escalating doses of vatalanib until the maximally tolerated dose of vatalanib was determined. Vatalanib given continuously at a dose of 1,250 mg/day could be safely combined with capecitabine at a dose of 2,000 mg/m²/day given for 14 of 21 days. Dose-limiting toxicities of the combination included fatigue, hypertension, dizziness, and proteinuria. Vatalanib did not alter the pharmacokinetics of 5-FU, the active metabolite of capecitabine. Vatalanib and capecitabine can be safely combined without unexpected toxicities or significant pharmacokinetic interactions.     

Cetuximab,gemcitabine and capecitabine in patients with inoperable biliary tract cancer: A phase 2 study

PurposeBiliary tract cancer is rare and has dismal prognosis. Chemotherapy has its role in inoperable disease but the role of targeted agents like cetuximab remains to be defined. On the basis of high epidermal growth factor receptor expression of biliary tract cancers this study aims to investigate the efficacy of cetuximab, gemcitabine and capecitabine in an exploratory phase 2 trial.Patients and methodsInoperable biliary tract cancer patients were treated with the combination of gemcitabine (1000 mg/m² on day 1 and 8), capecitabine (1300 mg/m²/d on day 1–14) and weekly cetuximab (400 mg/m² loading and 250 mg/m² maintenance dose) in 21-d cycles until progression or the appearance of intolerable side-effects.ResultsOut of 34 patients (mean age 59.7 years) accrued in this study 16 had intrahepatic, eight extrahepatic cholangiocarcinoma and 10 gall bladder cancer. The best overall response rate was 17.6% (two complete responses and four partial responses) and the clinical benefit rate was 76.5%. After a median of 15.4 months follow-up the median progression free survival was 34.3 weeks and the median overall survival was 62.8 weeks. The performance status and chemotherapy efficacy were independent and significant markers of survival. Only moderate side-effects were registered in this study. KRAS mutation was evaluable in 24 tumours, all of these were of wild type.ConclusionThe efficacy of cetuximab, gemcitabine and capecitabine combination is encouraging and a well tolerated treatment of inoperable biliary tract cancers.     

吉西他滨联合氟尿嘧啶类药物治疗耐药性晚期结直肠癌的临床观察

目的　观察吉西他滨（ＧＥＭ）联合氟尿嘧啶类药物治疗耐药性晚期结直肠癌（ｍＣＲＣ）的有效性和安全性。方法　３２例二线及二线以上方案化疗失败的ｍＣＲＣ患者,使用ＧＥＭ（１０００ｍｇ／ｍ^２,ｄ_１、ｄ_８）联合氟尿嘧啶（５-ＦＵ５００ｍｇ／ｍ^２,ｄ_１～ｄ_５）１３例,联合卡培他滨（１２５０ｍｇ／ｍ^２,ｄ_１～ｄ_１４）１９例,直至疾病进展或出现不可耐受的不良反应,每２个周期按照ＲＥＣＩＳＴ标准（１.０版）进行疗效评价,按ＮＣＩ-ＣＴＣ（３.０版）评价毒性并随访生存情况。结果　３２例均可评价疗效和毒性,其中获ＰＲ４例,ＳＤ１４例,ＰＤ１４例,疾病控制率（ＤＣＲ）为５６.３％,中位肿瘤进展时间（ｍＴＴＰ）为３.８个月,中位总生存时间（ｍＯＳ）为８.１个月。主要毒副反应为骨髓抑制、皮疹及发热,多为１～２级,支持对症处理可以恢复。结论　ＧＥＭ联合氟尿嘧啶类药物治疗国人耐药性ｍＣＲＣ具有一定疗效,不良反应可以耐受,值得进一步研究。     

吉西他滨联合卡培他滨治疗难治性乳腺癌的临床观察

目的观察吉西他滨联合卡培他滨（GX方案）治疗术后复发的乳腺癌患者的疗效和不良反应。方法50例患者分别接受GX方案化疗3～6个周期,按世界卫生组织（WHO）标准评价疗效及不良反应。结果50例患者均可评价,其中完全缓解（CR）4例（8．0％）,部分缓解（PR）22例（44．0％）,稳定（SD）18例（36．0％）,进展（PD）6例（12．0％）。中位肿瘤进展时间（mTTP）为8．3个月（95％CI：6．55—10．89）,中位总生存时间（mOS）为18．0个月（95％CI：14．34～21．98）。主要不良反应为骨髓抑制和皮疹。结论GX方案治疗晚期乳腺癌安全有效,不良反应较轻,值得临床推广应用。     

A phase I study of gemcitabine plus palliative radiation therapy for advanced lung cancer

Purpose  To determine the maximum-tolerated dose (MTD) and antitumor activity of twice-weekly gemcitabine when combined with palliative-dose thoracic radiation therapy (RT) in patients with recurrent or progressive lung cancer. Methods  Patients were enrolled in a dose-escalating study of gemcitabine with a starting dose level of 40 mg/m² given as 30-minute infusions twice weekly concurrent with RT. The RT dose was 30 Gy in 10 fractions, 5 fractions per week. Results  A total of 18 patients were enrolled on three dose levels: 40, 50, and 65 mg/m². Four patients came off study early due to rapid progression of disease and therefore were not evaluated. The MTD of gemcitabine was found to be 50 mg/m². Dose-limiting toxicities were grade-4 esophagitis in one patient and grade-4 neutropenia in another patient. Overall response included 1 partial response (PR). Local response included six PR, four minor response (MR), three stable disease (SD), and one progressive disease (PD). Conclusion  The MTD of gemcitabine with concominant palliative thoracic radiation therapy is 50 mg/m² twice weekly. The DLTs observed were grade-4 esophagitis and grade-4 myelotoxicity at 65 mg/m².     

Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial

Background. Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. Methods. Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m², respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m², respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III–IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III–IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. Results. Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m² for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III–IV hematological or nonhematological toxicity. Conclusion. The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m² on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials. Received: January 29, 2001 / Accepted: September 13, 2001     

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 I dose-escalating study of biweekly fixed-dose rate gemcitabine plus pemetrexed in patients with advanced solid tumors

Purpose  

To determine the maximum tolerated dose (MTD) and the recommended phase II dose and to identify the dose-limiting toxicities (DLTs) of gemcitabine, administered by fixed-dose rate (FDR) infusion, combined with the antifolate agent pemetrexed in patients with advanced solid tumors.     

A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors

PURPOSE: This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75-125 mg po BID) with gemcitabine (750-1,000 mg/m(2) on days 1, 8, 15) and fixed cisplatin (75 mg/m(2) day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered "heavily pre-treated" and the protocol was amended to limit prior therapy and re-escalate lonafarnib in "less heavily pre-treated patients" on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed. RESULTS: Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer. CONCLUSION: Lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) day 1 on a 28-day schedule was established as the MTD. Lonafarnib did not demonstrate FTPase inhibition at these doses. Despite the observed efficacy, substantial toxicity and questionable contribution of anti-tumor activity of lonafarnib to gemcitabine and cisplatin limits further exploration of this combination.