A dose finding study of carboplatin and gemcitabine in advanced non-small cell lung cancer

The excellent activity of the cisplatin-gemcitabine combination and favorable toxicological profile of carboplatin are the basis of carboplatin-gemcitabine combination therapy for non-small cell lung cancer. We carried out a dose-finding study with the aim of establishing the maximum tolerated dose (MTD) of carboplatin on day 1 in combination with gemcitabine at the dose of 1000 mg/m2 on days 1 and 8 in a 21-day cycle. The starting dose level for carboplatin was the area under the concentration time curve (AUC) 4 mg/ml/min. 18 patients were treated and a dose limiting toxicity was observed in 2 cases at the level of AUC 6 mg/ml/min. AUC 5 mg/ml/min was considered as the MTD for carboplatin in our regimen. Notably, 7 objective responses were observed.     

A phase I study and pharmacologic evaluation of irinotecan and carboplatin for patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy

BACKGROUND: The objectives of the current study were to determine the maximum tolerated dose (MTD) of irinotecan and carboplatin in combination, to evaluate the efficacy and toxicity of the combination in patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy, and to examine the pharmacokinetics and pharmacodynamics of both drugs by using the Chatelut formula. METHODS: Patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy were treated with a combination of irinotecan and carboplatin. Carboplatin was administered as a 60-minute intravenous infusion on Day 1 and was followed by irinotecan, which was administered as a 90-minute intravenous infusion on Days 1, 8, and 15. Six dose levels of irinotecan (in mg/m(2))/carboplatin (mg . mL/min) were planned: 50 mg/m(2)/4 mg . mL/minute, 60 mg/m(2)/4 mg . mL/minute, 50 mg/m(2)/5 mg . mL/minute, 60 mg/m(2)/5 mg . mL/minute, 50 mg/m(2)/6 mg . mL/minute, and 60 mg/m(2)/6 mg . mL/minute. The carboplatin dosage was calculated by using the Chatelut formula. Treatment was repeated at 28-day intervals. RESULTS: In total, 19 patients in cohorts of 3 to 5 patients received irinotecan and carboplatin at 5 dose levels. The dose-limiting toxicities were Grade 4 neutropenia and Grade 4 thrombocytopenia. The MTD of the irinotecan/carboplatin combination was 60 mg/m(2)/5 . mg mL/minute. Partial responses were observed at higher dose levels. Pharmacologic studies demonstrated that administration of the dosage estimated with the Chatelut formula instead of the Chatelut formula with adjustment for serum creatinine resulted in a slightly excessive dose of carboplatin. CONCLUSIONS: The recommended dose for the Phase II study was irinotecan 60 mg/m(2) on Days 1, 8, and 15 with carboplatin 5 mg/mL . minute on Day 1 repeated every 4 weeks.     

A Dose Finding Study of Carboplatin and Gemcitabine in Advanced Non-Small Cell Lung Cancer

Abstract

The excellent activity of the cisplatin-gemcitabine combination and favorable toxicological profile of carboplatin are the basis of carboplatin-gemcitabine combination therapy for non-small cell lung cancer. We carried out a dose-finding study with the aim of establishing the maximum tolerated dose (MTD) of carboplatin on day 1 in combination with gemcitabine at the dose of 1000 mg/m2 on days 1 and 8 in a 21-day cycle. The starting dose level for carboplatin was the area under the concentration time curve (AUC) 4 mg/ml/min. 18 patients were treated and a dose limiting toxicity was observed in 2 cases at the level of AUC 6 mg/ml/min. AUC 5 mg/ml/min was considered as the MTD for carboplatin in our regimen. Notably, 7 objective responses were observed.     

Phase I dose-finding and pharmacokinetic study of paclitaxel and carboplatin with oral valspodar in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m(2) and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg.min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-na?ve patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg.min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated with 186 courses of paclitaxel, carboplatin, and valspodar. Neutropenia, thrombocytopenia, and hepatic transaminase elevations were DLTs. In previously treated patients, no DLTs occurred at the first dose level (paclitaxel 54 mg/m(2) and carboplatin AUC 6 mg.min/mL). However, one of 12, two of six, two of four, four of 11, and two of five patients experienced DLTs at doses of paclitaxel (mg/m(2))/carboplatin AUC (mg.min/mL) of 67.5/6, 81/6, 94.5/6, 67. 5/7.5, and 67.5/9, respectively. In chemotherapy-na?ve patients, one of 17 developed DLT at paclitaxel 81 mg/m(2) and carboplatin AUC 6 mg/mL.min. There was prolongation of the terminal phase of paclitaxel elimination as evidenced by an increased time that plasma paclitaxel concentration was >/= 0.05 micromol/L, ranging from 16.6 +/- 6.7 hours to 41.5 +/- 9.8 hours for paclitaxel doses of 54.5 mg/m(2) to 94.5 mg/m(2), respectively. CONCLUSION: The recommended phase II dose in chemotherapy-na?ve patients is paclitaxel 81 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. In previously treated patients, the recommended phase II dose is paclitaxel 67.5 mg/m(2), carboplatin AUC 6 mg.min/mL, and valspodar 5 mg/kg every 6 hours. The acceptable toxicity profile supports the rationale for performing disease-directed evaluations of paclitaxel, carboplatin and valspodar on the schedule evaluated in this study.     

Phase I study of second-line chemotherapy with docetaxel and carboplatin in advanced non-small-cell lung cancer

PURPOSE: Docetaxel and carboplatin have a broad spectrum of antitumor activity. We conducted a phase I study of docetaxel and carboplatin as second-line chemotherapy in previously treated non-small-cell lung cancer (NSCLC). This study aimed to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this second-line combination chemotherapy. METHODS: Patients with advanced NSCLC were treated with escalating docetaxel doses in combination with a fixed-target area under the concentration-time curve (AUC) of 5 mg min/ml of carboplatin on day 1 of a 3-4-week cycle. The carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The docetaxel dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2 increments. RESULTS: A total of 16 patients previously treated with anticancer drugs were enrolled through three dose levels (40, 50 and 60 mg/m2 of docetaxel). All patients were assessable for toxicity and response. The MTD was docetaxel 60 mg/m2 with a carboplatin target AUC of 5 mg min/ml, and the dose-limiting toxicities in two of four patients were neutropenia and thrombocytopenia. Overall, neutropenia and thrombocytopenia of grade 3/4 occurred in eight patients (50%) and three patients (19%), respectively. Four patients (25%) and two patients (13%) experienced both grade 1 diarrhea and dermatitis, respectively. Allergic reactions, fluid retention, pneumonitis, neurotoxicity and mucositis were not observed. Of 16 patients, 5 showed an objective response (response rate 31%; 95% CI 14-56%). CONCLUSIONS: The combination of docetaxel and carboplatin is a feasible and well-tolerated second-line chemotherapy regimen in the treatment of NSCLC. Docetaxel 50 mg/m2 under the carboplatin target AUC of 5 mg x min/ml using the Chatelut formula was the recommended dose for phase II study.     

Pegylated liposomal doxorubicin and carboplatin in advanced gynecologic tumors: a prospective phase I/II study of the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR).

BACKGROUND: Single-agent platinum and single-agent pegylated liposomal doxorubicin (PLD) are both effective in the treatment of gynecologic malignancies. Based on evidence that combination platinum-containing regimens offer superior efficacy versus single-agent regimens, we conducted this study to determine the maximum tolerated dose (MTD) of PLD in combination with carboplatin. PATIENTS AND METHODS: In this phase I/II dose-finding study, six courses of PLD (20, 30, 40 or 50 mg/m2) and carboplatin (AUC 6) were administered every 28 days to women with advanced gynecologic malignancies. Three to six patients were treated at each dose level; an additional 12 patients were treated at the MTD. RESULTS: PLD 40 mg/m2 was identified as the MTD when administered with carboplatin. Five of 18 patients experienced a dose-limiting toxicity at the MTD; two patients had grade 3/4 neutropenia, and one each had grade 3 emesis and grade 3 thrombocytopenia and thrombosis. No patient developed cardiotoxicity. In 11 patients evaluable for response, there were two complete responses, two partial responses and four patients with stable disease. CONCLUSIONS: The MTD for PLD when administered in combination with carboplatin is 40 mg/m2. This regimen is well tolerated and offers promising activity in women with advanced gynecologic malignancies.     

A phase Ib and pharmacokinetic trial of patupilone combined with carboplatin in patients with advanced cancer.

PURPOSE: Patupilone is a microtubule-targeting chemotherapeutic agent with clinical activity in a broad range of taxane-sensitive/resistant tumor types. The present phase Ib study examined the safety/tolerability and pharmacokinetics of patupilone in combination with carboplatin in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced cancer received patupilone via a 5- to 10-min i.v. infusion at doses of 3.6 to 6.0 mg/m(2) q3w, immediately followed by carboplatin area under the curve (AUC) 5 or 6 mg/mL/min. RESULTS: Of the 37 patients enrolled, the majority previously received taxanes (81%) and/or platinum-containing drugs (97.3%). The maximum tolerated dose (MTD) of patupilone with carboplatin AUC 6 was 4.8 mg/m(2); additional patients were enrolled to consolidate experience at this dose. Of the 22 patients who received the MTD, the most common nonhematologic adverse events were fatigue in six (27.3%) and diarrhea, nausea, vomiting, abdominal pain, and neuropathy in one each (4.5%; all grade 3); hematologic toxicities included two patients (9.1%) with grade 3 neutropenia. The pharmacokinetics of patupilone were similar to those in a previous study of patupilone monotherapy. Of the 26 patients with recurrent platinum-sensitive ovarian cancer, tumor response was assessable by response evaluation criteria in solid tumors in 17; 1 patient (6%) achieved a complete response, and 10 (59%) achieved a partial response. CONCLUSIONS: The combination of patupilone 4.8 mg/m(2)/carboplatin AUC 6 was well tolerated and showed antitumor activity similar to established regimens in patients with recurrent platinum-sensitive ovarian cancer. The optimal dose for this regimen is currently being further refined in phase II trials.     

Phase I and pharmacokinetic study of carboplatin and paclitaxel with a biweekly schedule in patients with advanced non-small-cell lung cancer

PURPOSE: A phase I study was conducted to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of carboplatin in combination with paclitaxel using a biweekly schedule in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The pharmacokinetics of paclitaxel were determined preliminarily in some patients. The criteria for eligibility for study entry included histologically and/or cytologically confirmed NSCLC (stage IIIb or IV), no prior treatment, and measurable disease. Paclitaxel was given in combination with a fixed dose of carboplatin at an area under the concentration-time curve (AUC) of 3 mg/ml x min, every 2 weeks. The starting dose of paclitaxel was 100 mg/m(2), and the dose was increased in increments of 20 mg/m(2). Three to six patients were allocated to each dose level. RESULTS: A total of 19 patients (11 male and 8 female) with a median age of 61 years (range 43-74 years) and a median ECOG performance status of 0 (range 0-1) were enrolled. The MTD of paclitaxel proved to be 160 mg/m(2), and the DLT was neutropenia, which improved well following treatment with G-CSF. Gastrointestinal toxicity was well tolerated. Of 17 patients who received four cycles or more, 7 (41%; 95% confidence interval 18.4-67.1%) responded to this combination therapy. The pharmacokinetics of paclitaxel did not differ from published data. CONCLUSIONS: The recommended dose for phase II study is paclitaxel 140 mg/m(2) with a carboplatin AUC of 3 mg/ml.min. This biweekly regimen is highly effective and acceptable, and the present data indicate that the regimen may be suitable for use on an outpatient basis.     

Phase I and pharmacokinetic study of the multitargeted antifolate pemetrexed in combination with oxaliplatin in patients with advanced solid tumors.

BACKGROUND: This phase I and pharmacokinetic study of pemetrexed in combination with oxaliplatin was performed to determine the maximum tolerated dose (MTD), and to evaluate safety and pharmacokinetics in patients with metastatic solid tumors. PATIENTS AND METHODS: Pemetrexed was administered as a 10- min i.v. infusion followed 30 min later by oxaliplatin as a 2- h infusion, once every 21 days. Up to two previous chemotherapy regimens were allowed. Vitamin B(12) supplementation and folic acid were not included in this study. RESULTS: Thirty-six patients were treated in six escalating dose levels. Dose-limiting toxicities at dose level 6 (pemetrexed 500 mg/m(2) plus oxaliplatin 130 mg/m(2)) were febrile neutropenia, grade 3-4 diarrhea and grade 3 paresthesia. The MTD was not reached. The most common toxicity was neutropenia, with grade 3-4 occurring in 61% of patients. The pharmacokinetics of this pemetrexed-oxaliplatin combination are consistent with those following single-agent administration. Five responses (all partial) were observed over a broad range of solid tumors. CONCLUSIONS: This pemetrexed-oxaliplatin combination (without vitamin supplementation) every 21 days can be administered using full therapeutic doses of each agent with acceptable tolerability and no overlapping toxicity. The recommended regimen for phase II studies is pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2).     

Phase I study of biweekly paclitaxel and carboplatin administration in patients with advanced non-small cell lung cancer

A phase I study of a biweekly outpatient regimen composed of carboplatin (CBDCA) and paclitaxel (TXL) was conducted for advanced non-small cell lung cancer. TXL was given in combination with a fixed dose of CBDCA (AUC 3) every 2 weeks. The starting dose of TXL was 100 mg/m2, and the dose was escalated in increments of 20 mg/m2. Three to six patients were allocated to each level. Toxicities were evaluated in the first 4 courses to determine the maximum tolerated dose (MTD). TXL 160 mg/m2 dosages proved to be MTD, and the dose limiting toxicity (DLT) was hematotoxicity (neutropenia). The patients, however, recovered from neutropenia using G-CSF immediately, when G-CSF was used. Gastrointestinal toxicity was well-tolerated. A response was found in 9 out of 20 patients who received 4 courses or more (45%). These results suggest that the recommended dose would be CBDCA (AUC 3) + TXL 140 mg/m2. The biweekly regimen has a high level clinical activity and excellent tolerability, and is suitable for outpatients. We started a phase II study because of these results.     

Phase I trial of gemcitabine and carboplatin in metastatic non-small-cell lung cancer: a Groupe Français de Pneumo-Cancérologie Study

BACKGROUND: The purpose of this study was to determine the maximum-tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the 21 days carboplatin plus gemcitabine regimen in previously untreated patients with stage IV non small-cell lung cancer (NSCLC). METHODS: At least three patients were entered at each dose level. The starting dose was carboplatin AUC 4 mg/ml per min (Area Under the Curve; Calvert formula) on day 1 and gemcitabine 750 mg/m(2) on days 1 and 8. Carboplatin was increased to AUC 5 (level 3, 4) then to AUC 6 (level 5-7). Gemcitabine was increased to 875 (level 2, 3), 1000 (level 4, 5), 1250 (level 6) and finally 1500 mg/m(2) (level 7). Twenty-nine patients were entered into this phase I study. RESULTS: At dose level 6, a DLT (grade 4 thrombocytopenia) was observed in one out of six patients. At dose level 7, no DLT was observed during the first course, so the MTD was not reached. During the second course, two out of four patients presented grade 4 thrombocytopenia. None of the five patients receiving two courses at level 6 presented a DLT, so this level was retained for further phase II studies. Of the 25 patients assessable for response, five achieved partial responses with a response rate of 20% (95% CI, 7 to 41%). The median survival time was 7 months and the 1-year survival rate was 24% (95% CI, 9 to 45%). CONCLUSION: The combination of carboplatin given on day 1 and gemcitabine given on days 1 and 8 every 3 weeks seems to be an acceptable regimen. The DLT consists exclusively of severe thrombocytopenia. Despite the MTD was not reached with carboplatin AUC 6 mg/ml per min and gemcitabine 1500 mg/m(2), the recommended dose for further phase II studies is carboplatin AUC 6 mg/ml per min and gemcitabine 1250 mg/m(2).     

Phase I trial of fixed dose-rate gemcitabine in combination with carboplatin in chemonaive advanced non-small-cell lung cancer: a Cancer Therapeutics Research Group study

PURPOSE: To determine the maximally tolerated dose (MTD) of gemcitabine administered at a fixed dose-rate of 10 mg/m(2) per min in combination with fixed dose carboplatin, to evaluate the toxicity of this regimen and to determine the pharmacokinetics of plasma gemcitabine. METHODS: Patients with advanced stage non-small-cell lung cancer (NSCLC) received carboplatin (AUC 5) on day 1 followed by gemcitabine at a fixed dose rate of 10 mg/m(2) per min in escalating durations of infusion on days 1 and 8 every 21 days. Pharmacokinetic sampling was obtained on day 1, cycle 1 of treatment. RESULTS: A total of 15 patients received carboplatin and gemcitabine in cohorts of three to six patients at three dose levels. The doses of gemcitabine studied were 600, 750, and 900 mg/m(2). The MTD was reached at 900 mg/m(2). Dose-limiting toxicities were thrombocytopenia and liver failure, and with repeated dosing neutropenia was commonly observed. The recommended phase II dose of gemcitabine was 750 mg/m(2). Partial responses were observed at 600 and 750 mg/m(2) of gemcitabine. Plasma gemcitabine did not reach steady state except in one patient with the durations of infusion studied. Plasma concentrations, however, were above 10 micro mol/l between 20 and 90 min in all patients. CONCLUSIONS: Gemcitabine administered as a 75-min infusion at a fixed dose rate of 10 mg/m(2)/min on days 1 and 8 in combination with carboplatin on day 1 every 21 days is tolerable and active in NSCLC. Pharmacokinetic studies demonstrated that the target plasma gemcitabine concentration above 10 micro mol/l was achieved. Further studies are warranted to compare this regimen against standard regimens of carboplatin and gemcitabine.     

Phase I trial of combretastatin a-4 phosphate with carboplatin.

PURPOSE: Preclinical evidence of synergy led to a phase I trial employing combretastatin A-4 phosphate (CA4P), a novel tubulin-binding antivascular drug, in combination with carboplatin. EXPERIMENTAL DESIGN: Based on preclinical scheduling studies, patients were treated on day 1 of a 21-day cycle. Carboplatin was given as a 30-minute i.v. infusion and CA4P was given 60 minutes later as a 10-minute infusion. RESULTS: Sixteen patients with solid tumors received 40 cycles of therapy at CA4P doses of 27 and 36 mg/m(2) together with carboplatin at area under the concentration-time curve (AUC) values of 4 and 5 mg min/mL. The dose-limiting toxicity of thrombocytopenia halted the dose escalation phase of the study. Four patients were treated at an amended dose level of CA4P of 36 mg/m(2) and carboplatin AUC of 4 mg min/mL although grade 3 neutropenia and thrombocytopenia were still observed. Three lines of evidence are adduced to suggest that a pharmacokinetic interaction between the drugs results in greater thrombocytopenia than anticipated: the carboplatin exposure (as AUC) was greater than predicted; the platelet nadirs were lower than predicted; and the deviation of the carboplatin exposure from predicted was proportional to the AUC of CA4, the active metabolite of CA4P. Patient benefit included six patients with stable disease lasting at least four cycles. CONCLUSION: This study of CA4P and carboplatin given in combination showed dose-limiting thrombocytopenia. Pharmacokinetic/pharmacodynamic modeling permitted the inference that altered carboplatin pharmacokinetics caused the increment in platelet toxicity.     

The combination of carboplatin and weekly paclitaxel: a safe and active regimen in advanced non small-cell lung cancer patients. A phase I-II study

The combination of carboplatin and paclitaxel given every three weeks is a tolerated and reasonably active regimen in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the maximum tolerated dose (MTD) of a fixed dose of carboplatin with an area under the curve (AUC) of 6 and escalating doses of weekly paclitaxel with an initial dose of 50 mg/m2 with 10 mg/m2 increments at each level in untreated NSCLC patients (phase I study). The study continued with a phase II study. Thirty patients entered the phase I study. The MTD was: carboplatin AUC = 6 on days 1 and 28 plus paclitaxel 100 mg/m2 (1 hour) on days 1, 8,15, 28. The dose-limiting toxicity (DLT) was severe neutropenia and cardiological toxicity. Subsequently, 42 patients entered the phase II study with the same treatment schedule. The 2-drug combination was globally well tolerated. The overall response rate (RR) was 42% [CI 95%: 26.3-57.7], stable disease (SD) 29% and progression (PD) 29%. The median duration of response was 8.0 mos (range: 1.0-19.0).The median time to progression was 8.0 mos (range: 7.0-19.0) and the median survival was 14.0 months (range: 9.0-19.0). The association of carboplatin AUC = 6 and weekly paclitaxel 100 mg/m2 proved to be manageable, active and extremely safe even in elderly patients (one third of all patients in our cohort). The survival results were interesting: the median survival time was 14 months (9-19 months) and the 1- and 2-year survival was 59% and 16%, respectively.     

培美曲塞与卡铂静脉化疗联合榄香烯乳胸腔灌注治疗恶性胸膜间皮瘤的临床观察

目的　评价培美曲塞与卡铂化疗同时联合榄香烯乳胸腔灌注治疗恶性胸膜间皮瘤（ＭＰＭ）合并胸腔积液的疗效与安全性。方法　回顾性分析１５例ＭＰＭ合并胸腔积液患者的临床资料,具体用药：培美曲塞５００ｍｇ／ｍ２,ｄ１;卡铂（ＡＵＣ＝５）ｄ２,每２１天重复;同时引流尽胸腔积液,榄香烯乳２００ｍｇ／ｍ２胸腔注入,ｄ１或ｄ８。结果　１５例患者中,１３例（８６.７％）胸腔积液得到控制,１０例（６６.７％）胸腔积液癌细胞检查由阳性转为阴性;获ＣＲ４例,ＰＲ６例,ＳＤ３例,ＰＤ２例;总有效率为６６.７％,疾病控制率为８６.７％,中位无进展时间为５.０个月,中位总生存时间为１１.１个月,１年生存率为３６.０％。主要毒副反应为骨髓抑制、发热、胸痛、皮疹,多为１～２级,支持对症处理后均可恢复。结论　培美曲塞联合卡铂化疗同时榄香烯乳胸腔灌注治疗ＭＰＭ合并胸腔积液有较好的疗效,毒副反应轻,值得临床推广应用。     

Phase I/II and pharmacologic study of irinotecan and carboplatin for patients with lung cancer

PURPOSE: To determine the maximum tolerated dose (MTD) of irinotecan combined with carboplatin, to evaluate its efficacy and toxicity for patients with lung cancer, and to examine its pharmacokinetics and pharmacodynamics. METHODS: The dose of irinotecan was escalated from 40 mg/m2 per week in increments of 10 mg/m2. Carboplatin was fixed at 300 mg/m2. Multivariate regression models with an interaction term were used to evaluate synergistic pharmacodynamic interactions. RESULTS: The MTD and recommended dose of irinotecan were 60 and 50 mg/m2, respectively. Dose-limiting toxicities were grade 4 neutropenia and grade 3 or 4 diarrhea. In phase II studies, response rates were 81.3% (95% confidence interval 61.8-100%) in 16 patients with small-cell lung cancer and 22.2% (2.7-41.8%) in 18 patients with non-small-cell lung cancer. Two patients (6%) experienced grade 4 neutropenia, thrombocytopenia, and grade 3 diarrhea. The area under the plasma concentration versus time curve (AUC) of carboplatin ranged from 2.87 to 9.31 mg x min/ml, with a median of 4.66 mg x min/ml. In pharmacodynamic analyses, the log-transformed surviving fraction in platelet count (SFp) showed a significant association with the AUC of carboplatin (P=0.010), while that in neutrophil count (SFn) was not significantly correlated with any pharmacokinetic parameter. The interaction term was not significant in either case. CONCLUSIONS: These results indicate that AUC-based dosing of carboplatin is still rational in combination chemotherapy. A more sensitive method for predicting life-threatening toxicities is needed, however, because traditional pharmacokinetic parameters were not adequate tools for identifying patients at high risk of severe neutropenia and diarrhea. This combination regimen has only modest activity, and further studies are necessary to evaluate a different dose schedule.     

Phase I study of vinorelbine and carboplatin combination in patients with taxane and anthracycline pretreated advanced breast cancer

AIM: To define the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the carboplatin-vinorelbine combination in pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Patients with histologically confirmed metastatic breast cancer relapsing or progressing after prior taxane and anthracycline containing chemotherapy were enrolled. Cohorts of 3-6 patients were treated at successive dose levels (DLs) with escalated doses of carboplatin [range, area under the curve (AUC) 4-6] on day 1 and vinorelbine (range, 20-35 mg/m(2)) on days 1 + 8 recycled every 28 days. RESULTS: Twenty-seven patients with a median age of 58 years and performance status (WHO) of 0-2 were treated at 6 DLs. All patients were assessable for toxicity and 20 for response. DLT was reached at carboplatin 6 AUC and vinorelbine 35 mg/m(2), and therefore, this was considered as the MTD. Prophylactic G-CSF administration could not allow further dose escalation. The recommended dose for further phase II testing was defined at carboplatin 6 AUC on day 1 and vinorelbine 30 mg/m(2) on days 1 and 8. Among 98 administered treatment cycles 41 (42%) and 7 (7%) were complicated with grades 3 and 4 neutropenia and thrombocytopenia, respectively. Nonhematologic toxicities included grade 2 peripheral neuropathy in 3 cycles and grades 2 and 3 fatigue in 32 (32%). CONCLUSION: The present study determined the feasibility of the combination of carboplatin at AUC 6 (day 1) and vinorelbine at 30 mg/m(2) (days 1 and 8 ) without G-CSF support in patients with taxane and anthracycline pretreated advanced breast cancer. Phase II studies at these doses should follow in order to determine the activity of the regimen.     

Phase 1 and pharmacokinetic study of concurrent carboplatin and irinotecan in subjects aged 1 to 21 years with refractory solid tumors

BACKGROUND:

Preclinical testing suggests the combination of carboplatin and irinotecan has at least additive antitumor activity. The primary objectives of the current study were to determine the maximum tolerated doses (MTDs) and recommended phase 2 doses of carboplatin administered with irinotecan to pediatric patients with refractory solid tumors.

METHODS:

This was a multicenter, open‐label, single‐arm dose escalation study in which subjects with refractory solid tumors received 21‐day treatment cycles of intravenous carboplatin on Day 1 followed by intravenous irinotecan administered daily for 10 days within 2 consecutive weeks. The plasma pharmacokinetics of ultrafiltrable platinum, irinotecan, and 2 irinotecan metabolites were determined during Cycle 1. The interpatient plan for dose escalation at study initiation was to increase irinotecan first followed by increases in carboplatin.

RESULTS:

Twenty‐eight patients with a median age of 8.5 years (range, 1‐21 years) were enrolled with a variety of solid tumors. Two of 6 subjects at the first dose level (carboplatin target area under the curve [AUC], 4.0 mg/mL*min; irinotecan, 18 mg/m²/dose) experienced dose‐limiting gastrointestinal toxicities requiring a dose de‐escalation scheme (carboplatin AUC, 4.0 mg/mL*min; irinotecan, 15 mg/m²/dose). Three of 6 subjects at the second dose level experienced dose‐limiting gastrointestinal complications and bone marrow suppression. A further dose de‐escalation to carboplatin AUC of 4.0 mg/mL*min and irinotecan of 12 mg/m²/dose resulted in dose‐limiting bone marrow suppression in 1 of 13 patients treated at that dose, and therefore was determined to be the MTD. One complete response (in a patient with medulloblastoma) and 3 partial responses (in patients with neuroblastoma, medulloblastoma, and lymphoendothelial carcinoma, respectively) were observed.

CONCLUSIONS:

The recommended phase 2 dose in heavily pretreated pediatric patients is carboplatin (AUC, 4 mg/mL*min on Day 1) and irinotecan (12 mg/m²/ day × 10 days) given every 21 days. Cancer 2009. © 2008 American Cancer Society.     

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.     

Docetaxel in combination with carboplatin for the treatment of advanced non-small cell lung carcinoma: a multicentre phase I study

Docetaxel and carboplatin have shown in vitro and in vivo activity against non-small cell lung cancer (NSCLC). A phase I study was conducted in order to determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of their combination. Chemotherapy-na?ve patients with stage IIIB and IV NSCLC, age<75 years old, performance status (WHO) 0-2, with adequate bone marrow, renal, liver and cardiac function, were treated with docetaxel and carboplatin. Docetaxel was given at escalated doses starting from 70 mg/m(2) with increments of 10 mg/m(2) followed by carboplatin also administered at escalated doses starting from AUC 5 to 7 AUC (mg/ml. min); the regimen was administered every 3 weeks. No colony-stimulating factor or intrapatient escalation was allowed. The toxicity of the regimen was assessed during the first chemotherapy cycle. 35 enrolled patients received a total of 114 chemotherapy cycles (median 3 cycles/patient; range: 1-8). All patients were assessable for toxicity. Neutropenia was the main dose-limiting toxicity of the regimen; overall, grade 3/4 neutropenia occurred in 16 (14%) cycles; six (5%) neutropenic episodes were complicated with fever but there was no septic death. Grade 3/4 thrombocytopenia was uncommon (two cycles; 2%). Grade 3/4 diarrhoea occurred in 5 (14%) patients whilst neurotoxicity, fatigue and mucositis were extremely uncommon. Two MTDs were defined: the MTD(1) was docetaxel 80 mg/m(2) and carboplatin AUC 7 mg/ml x min whilst MTD(2) was docetaxel 100 mg/m(2) and carboplatin AUC 6 mg/ml x min. The combination of docetaxel and carboplatin is a feasible and well-tolerated outpatient regimen for the treatment of patients with locally advanced and metastatic NSCLC. This regimen merits further investigation in phase II trials.