A phase I clinical and pharmacokinetic study of tipifarnib in combination with docetaxel in patients with advanced solid malignancies*

ABSTRACT

Purpose: This phase I study assessed the maximum tolerated doses (MTDs), safety, pharmacokinetics, and efficacy of combined tipifarnib and docetaxel treatment in patients with advanced solid malignancies.

Experimental design: The study protocol was sensitive to myelosuppression, as both drugs have been associated with this adverse event. Due to myelosuppression incidence, and in order to determine the MTD of docetaxel, multiple treatment regimens were employed. Tipifarnib was administered orally at 200 or 300?mg, twice daily (BID) for 21 days, 14 days, or 7 days for multiple 21?day cycles; intravenous (IV) docetaxel was administered on day 1 of each cycle at 60, 75, or 85?mg/m².

Results: A total of 36 patients entered into the study. For each drug, MTDs were identified (tipifarnib: 300?mg BID for 14 days with 60?mg/m² docetaxel; tipifarnib: 200?mg BID for 14 days with 75?mg/m² docetaxel). The major dose-limiting toxicity was myelosuppression, particularly febrile neutropenia (44%). Mutual pharmacokinetic interactions (the effect of docetaxel on tipifarnib pharmacokinetics and the effect of tipifarnib on docetaxel pharmacokinetics) were not evident, as maximum plasma concentration (C_max) and the area under the serum concentration–time curve (AUC) values of both tipifarnib and docetaxel were similar (?p ≥ 0.43) whether the two drugs were concomitantly administered or not. Seven of 31 evaluable patients (23%) had an objective response, 11 (35%) had stable disease (six ≥ 24 weeks), and the overall clinical benefit rate (objective response and/or stable disease ≥ 24 weeks) was 42%.

Conclusions: Although the high incidence of febrile neutropenia necessitated a multiple scheduling adaptation of tipifarnib compared to the original protocol, the apparent lack of mutual pharmacokinetic interactions, the ability to coadminister tipifarnib and docetaxel near single-agent MTDs, and suggestive evidence of efficacy make this drug combination attractive for further examination.     

A phase I and pharmacokinetic study of the nonpolyglutamatable thymidylate synthase inhibitor ZD9331 plus docetaxel in patients with advanced solid malignancies

PURPOSE: To assess the feasibility of administering ZD9331, a thymidylate synthase (TS) inhibitor that does not undergo polyglutamation and has broad antitumor activity, in combination with docetaxel in patients with advanced solid malignancies. The study also sought to determine the principal toxicities of the regimen and recommend appropriate doses for phase II studies, characterize the pharmacokinetics of the agents, evaluate the possibility of major drug-drug interactions, and seek preliminary evidence of anti-cancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of docetaxel as a 60-minute intravenous (IV) infusion followed 30 minutes later by ZD9331 as a 30-minute IV infusion every 3 weeks. At least three patients were treated at each dose level, and the maximum tolerated dose level was defined as the highest dose level that was not associated with an unacceptably high incidence of severe toxicity. The pharmacokinetics of both ZD9331 and docetaxel were also characterized. RESULTS: Nineteen patients were treated with 71 cycles of ZD9331 and docetaxel (ZD9331/docetaxel) at dose levels that encompassed dosing iterations of ZD9331 ranging from 65 to 260 mg/m(2) and docetaxel doses in the range of 50 to 75 mg/m(2). Neutropenia was the principal toxicity of the ZD9331/docetaxel regimen. Since five of six patients treated at the ZD9331/docetaxel dose-level of 260/60 mg/m(2) had grade 4 neutropenia that was brief and uncomplicated in the first course, a rigorous exploration of higher dose levels was not undertaken. Nonhematologic toxicities, consisting of malaise, diarrhea, rash, nausea, and vomiting, were also observed, but these effects were rarely severe. No major antitumor responses were observed. The pharmacokinetics of both ZD9331 and docetaxel were similar to those reported in previous studies of each agent administered alone, suggesting the lack of major drug-drug interactions. CONCLUSION: The combination regimen, consisting of ZD9331 and docetaxel, is feasible and well tolerated at single-agent doses that are clinically-relevant. This ZD9331/docetaxel regimen does not appear to be associated with either major pharmacokinetic or toxicologic drug-drug interactions. A ZD9331/docetaxel dose level of 260/60 mg/m(2) is recommended as an initial dose level in disease-directed studies of the regimen, with further dose escalation of docetaxel to 75 mg/m(2) if the initial treatment is well tolerated. Further studies with this regimen are warranted in tumor types that have demonstrated sensitivity to both agents.     

多西他塞合用顺铂的Ⅰ期临床药动学研究

目的:研究多西他塞(泰索帝)在与顺铂联合用药情况下的药动学特征,确定和推荐Ⅱ期临床试验的给药方案.方法:选择晚期转移ⅢB或Ⅳ期非小细胞肺癌(NSCLC)患者15例,分成4组,分别按25,30,35,40mg·m-2剂量,每周1次方案给药,在每28d中的d1,8,15静注给药,4个剂量组均按75mg·m-2固定剂量给予顺铂.在第1周期的d1和d15给药前即刻,静注30min给药结束印刻,给药结束后10,30,45,60,90min及3,5,8,12,24h分别采血,用LC MS/MS测定血药浓度.用WinNonlin软件按恒速静脉输注给药的三室模型进行分析并计算相关药动学参数.经对数转换的药动学参数包括剂量归一化的AUCN,CmaxN和Cl,用SAS Proc混合程序进行检验.结果:在给药d1,当剂量从25增加到40mg·m-2时,平均AUC值从(1 393±288)增加到(1 968±757)μg·h·L-1;d15平均AUC值从(1 423±149)增加到(1 751±564)μg·h·L-1.在给药d1和d15,CmaxN,AUCN及Cl值均无显著性差异.结论:多西他塞静脉给药后Cmax和AUC值与剂量成比例增加,而Cl值与剂量水平无关,其药动学不受合用顺铂的影响.     

A phase I and pharmacokinetic study of liposomal vinorelbine in patients with advanced solid tumor

Purpose This phase I study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of an untargeted liposomal formulation of vinorelbine (NanoVNB?) and to characterize its plasma pharmacokinetics in patients with advanced solid tumors which were refractory to conventional treatment or without an effective treatment. Patients & methods The study incorporated an accelerated titration design. Twenty-two patients with various solid tumors were enrolled. NanoVNB^? was administered intravenously at doses of 2.2–23 mg/m² once every 14 days. Pharmacokinetic endpoints were evaluated in the first cycle. The safety profiles and anti-tumor effects of NanoVNB? were also determined. Results Skin rash was the DLT and the most common non-hematological toxicity. The MTD was 18.5 mg/m². Drug-related grade 3–4 hematological toxicities were infrequent. Compared with intravenous free vinorelbine, NanoVNB? showed a high C_max and low plasma clearance. Of the 11 patients completing at least 1 post-treatment tumor assessment, 5 had stable disease. No responders were noted. Conclusion NanoVNB? was well tolerated and exhibited more favorable pharmacokinetic profiles than free vinorelbine. Based on dose-limiting skin toxicity, further evaluation of NanoVNB? starting from 18.5 mg/m² as a single agent or in combination with other chemotherapeutic agents for vinorelbine-active malignancies is warranted.     

The impact of drug administration sequence and pharmacokinetic interaction in a phase I study of the combination of docetaxel and gemcitabine in patients with advanced solid tumors

Our objective was to determine the maximum tolerated dose (MTD) of two administration sequences of docetaxel and gemcitabine in cancer patients, and to describe the pharmacokinetics of both drugs. Patients were treated in a 4-weekly schedule at two dose levels: gemcitabine 800 mg/m2 on days 1, 8 and 15, and docetaxel 85 or 100 mg/m2 on day 15 (levels I and II). The protocol was amended to a 3-weekly schedule, testing gemcitabine 800 or 1000 mg/m2 on days 1 and 8, with docetaxel 85 mg/m2 on day 8 given initially (dose levels IIIa and IV). At the recommended dose, an extra cohort of patients initially received gemcitabine (dose level IIIb). Eleven patients were treated with the 4-week schedule; 29% of cycles were delayed predominantly because of hematological toxicity. Four patients developed dose-limiting toxicities (DLTs), predominantly hematological. In the 3-week schedule, 14 patients were treated. At level IV, three of four patients developed DLTs, defining the MTD. With the reverse sequence, three patients received a total of 10 cycles. Overall, nine partial remissions were observed. We conclude the recommended dose for phase II studies is gemcitabine 800 mg/m2 on days 1 and 8, combined with docetaxel 85 mg/m2 on day 8, on a 3-weekly schedule. Gemcitabine distribution is significantly altered upon docetaxel administration.     

Phase I study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies

Summary   Purpose: This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. Patients and Methods: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m² intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m²/day which was escalated by 250 mg/m²/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. Results: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m², two DLT of prolonged neutropenia of grade ≥3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m²/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. Conclusions: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts. Previous presentations: C. F. Verschraegen, F. C. Lee, I. Rabinowitz, A. Mangalik, C. Jennings, A. Maestas, Z. Shen. Phase I and translational study of capecitabine, cisplatin, and irinotecan in patients with solid tumors. Proc ASCO, A2114, 2004 H. Sayar, C. Verschraegen, H. Smith, I. Rabinowitz, F. C. Lee, Z. Shen. Phase I study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies. Proc ASCO, AB-31962, 2008 Support: Supported by the Oxnard Foundation; Period of Support: 07/01/2003–06/30/2005     

UFT in combination with oxaliplatin: clinical phase I study in patients with advanced or metastatic solid tumors

This phase I trial evaluated the combination of oxaliplatin plus UFT in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and the dose limiting-toxicity for future phase II trials. Eligible patients (N = 27) were treated in sequential cohorts of three to six patients. The starting doses for oxaliplatin and UFT were 70 mg/m2 and 250 mg/m2/day respectively, and five dose levels were designed up to 85 mg/m2 and 400 mg/m2/day. Oxaliplatin was administered i.v. on day 1 and 15, and oral UFT was given daily in three divided doses on days 1-21 followed by 1 week rest of a 28-day cycle. At the recommended dose, six additional patients were entered. In total, 79 courses were administered with a median of 3 (range 1-6). MTD was not reached; oxaliplatin 85 mg/m2 on day 1 and 15 plus UFT 400 mg/m2/day for 21 days was considered the optimum combination for phase II trials. Gastrointestinal toxicity and asthenia were the most common adverse events. Eight out of 13 patients (61.5%) with metastatic colorectal cancer achieved stable disease. UFT plus oxaliplatin is a feasible and safe combination. A phase II trial in first-line advanced colorectal cancer is ongoing.     

A phase I clinical and pharmacokinetic study of CS-682 administered orally in advanced malignant solid tumors

Summary CS-682 (1-(2-C-cyano-2-deoxy-β-D-arabino-pentofuranosyl)-N⁴-palmitoylcytosine) is a novel orally administered 2’-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m²/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3–4) were seen more frequently with 10 patients experiencing grade 3–4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m²/day. The maximum tolerated dose was determined to be 160 mg/m²/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 ± 0.9 h after drug administration and the terminal elimination half-life was 1.7 ± 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 ± 0.31 h, peak plasma concentrations were achieved 3.1 ± 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 ± 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m²/day for 4 weeks repeated after a 2-week rest period. Supported by Sankyo Co., Ltd, and Cyclacel Ltd.     

Phase I study of vorinostat (suberoylanilide hydroxamic acid, NSC 701852) in combination with docetaxel in patients with advanced and relapsed solid malignancies

Introduction Vorinostat is an inhibitor of histone deacetylase 6, which acetylates tubulin and stabilizes microtubules. Since taxanes also stabilize microtubules, we hypothesized that the administration of vorinostat followed by docetaxel should result in synergistic cytotoxicity. We conducted a phase I trial to determine the dose level of vorinostat plus docetaxel that would result in dose-limiting toxicity (DLT) in ≤30% of patients. Methods Eligible patients had castration-resistant prostate cancer (CRPC) or relapsed urothelial or non-small-cell lung cancer (NSCLC) after ≥1 prior chemotherapy regimen not containing docetaxel, performance status of 0–2, and adequate organ function. Vorinostat was given orally for 14 days beginning on day 1 of a 21-day cycle, with docetaxel given intravenously over 1 h on day 4. The time-to-event continuous reassessment method (TITE-CRM) guided dose escalation. Dose levels (DL) -1, 0, 1 and 2 corresponded to vorinostat 100, 100, 200 and 200 mg plus docetaxel 50, 60, 60, and 75 mg/m², respectively. Pharmacokinetic studies were performed on days 1 and 4 of cycle 1. Results Twelve patients were enrolled: median age 65 years (range 49–74); 9 male, 3 female; 4 CRPC, 5 urothelial, 3 NSCLC. The median number of cycles administered was 2. Two patients were treated at DL -1, 4 at DL 0, 5 at DL 1 and 1 at DL 2. Five DLTs occurred in 5 patients: neutropenic fever/sepsis (2), anaphylactic reaction (1), myocardial infarction (1) and gastrointestinal bleed (1). Other toxicities included grade 3/4 neutropenia (4), peripheral neuropathy (1), and gastrointestinal bleed (n = 1). The estimated probability of DLT for DL -1 was 0.32 (90% posterior probability interval [PI], 0.11 to 0.53) for DL 0, 0.38 (90% PI, 0.16 to 0.58) and for DL 1, 0.43 (90% PI, 0.23 to 0.64). The trial was stopped due to excessive toxicity. No responses were noted. Conclusions The combination of vorinostat and docetaxel was poorly tolerated with excessive DLTs that required early study termination. No responses were identified. Vorinostat and docetaxel pharmacokinetics were comparable to previous reports in the literature, without obvious drug-drug interactions.     

A phase I trial and pharmacokinetic evaluation of CI-980 in patients with advanced solid tumors

CI-980 is a synthetic mitotic inhibitor that binds to the colchicine binding site of tubulin. It demonstrates broad activity against human and marine tumor models and shows no cross resistance with tumor models whose mechanism of resistance is mediated by P-glycoprotein (MDR-1). A phase I study was completed in 25 patients with solid tumors using a 24-hour infusion schedule, with courses repeated every 3 weeks. Eight dose levels were tested between 1.2 and 15.6 mg/m². The maximum tolerated dose was 14.4 mg/m². Neutropenia was dose-related but not dose-limiting; thrombocytopenia was infrequent. CNS toxicities were dose-limiting and consisted of dizziness, headache, loss of coordination, loss of consciousness, nervousness, and other symptoms. These events occurred near the end of the infusion and were reversible, usually within 24 hours. One patient who was to be treated at dose level 8 (intended dose was 19.2 mg/m²; actual dose was 15.6 mg/m²) became encephalopathic prior to completion of the infusion. Other adverse events included gastrointestinal toxicities (nausea, vomiting, anorexia, constipation, stomatitis, dyspepsia, bleeding, cheilitis), IV site erythema, fever, and fatigue. A partial response was observed in one patient with colon cancer and reductions in CA-125 levels were observed in 2 patients with ovarian cancer. Pharmacokinetics were linear and dose-proportional. Results indicate high systemic clearance and wide tissue distribution. Mean pharmacokinetic parameter values: T² = 5.52 hours, plasma clearance 1163 mL/min/m², and Vd_ss 376 L/m².[N.T.S., L.B., A.I.E., S.T., J.R., P.H.W[C.D.L., W.R.G     

Temozolomide in patients with advanced cancer: phase I and pharmacokinetic study

STUDY OBJECTIVE: To determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and potential antitumor activity of temozolomide administered as a single dose every 28 days. DESIGN: Open label, phase I, dose-escalation trial. SETTING: University-affiliated cancer center. PATIENTS: Eleven patients aged 33-73 years with a documented solid tumor or lymphoma who failed therapy of proven efficacy for their disease or had a disease for which no conventional therapy was available. INTERVENTION: Temozolomide 500 mg/m2 was administered as a single oral dose every 28 days. Doses were escalated to 750 or 1000 mg/m2. No intrapatient dose escalation was allowed. At least two patients were enrolled at each dose level. Patients who did not have progressive disease and did not experience a dose-limiting toxicity, or experienced a dose-limiting toxicity but were eligible for dose reduction, were eligible to continue on the study. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic analysis was performed for temozolomide and its active metabolite, 5-(3-methyltriazeno)-imidazole-4-carboxamide (MTIC). Neutropenia and thrombocytopenia were dose limiting at 1000 mg/m2. Temozolomide was absorbed rapidly (mean time to maximum concentration 1.4 hrs) and eliminated, with average half-life and apparent oral systemic clearance values of 1.8 hours and 97 ml/minute/m2, respectively. Mean systemic exposure to MTIC was 3.7% of temozolomide. No objective responses were observed. The maximum tolerated dose of temozolomide was 750 mg/m2. CONCLUSION: Temozolomide 750 mg/m2 administered orally every 28 days was well tolerated. Alternate temozolomide dosing schedules such as continuous daily administration may enhance antitumor activity through sustained depletion of the DNA repair protein O6-alkylguanine DNA alkyltransferase.