Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study.

BACKGROUND: Patients with biliary tract cancer have a poor prognosis, and, until recently, no standard palliative chemotherapy has been defined. We aimed to investigate the efficacy and safety of cetuximab in combination with gemcitabine and oxaliplatin (GEMOX) for first-line treatment of biliary tract cancer. METHODS: From Oct 1, 2006, to July 26, 2008, patients with unresectable locally advanced or metastatic biliary tract cancer were sequentially enrolled and treated at one centre in Austria. All patients received intravenous infusions of 500 mg/m(2) cetuximab on day 1, 1000 mg/m(2) gemcitabine on day 1, and 100 mg/m(2) oxaliplatin on day 2, every 2 weeks for 12 cycles. The primary outcome was overall response rate. Analysis was by intention to treat. Adverse reactions were assessed according to National Cancer Institute Common Toxicity Criteria. The study is completed and registered with ClinicalTrials.gov, number NCT01216345. FINDINGS: 30 patients with median age of 68 years (IQR 62-73) were enrolled and included in the analysis. Objective response occurred in 19 patients (63%; 95% CI 56·2-69·8), of whom three (10%; 3·2-16·8) achieved complete response, and 16 (53%; 46·2-59·8) achieved partial response. Nine patients underwent potentially curative secondary resection after major response to therapy. Grade 3 adverse events were recorded in 13 patients: skin rash (n=4), peripheral neuropathy (n=4), thrombocytopenia (n=3), nausea (n=1), diarrhoea (n=1), and neutropenia (n=1); no grade 4 adverse events were recorded. INTERPRETATION: Cetuximab plus GEMOX was well tolerated and had encouraging antitumour activity, leading to secondary resection in a third of patients. These findings warrant further study of cetuximab plus GEMOX in a large randomised trial.

Pharmacokinetics of darbepoetin alfa after intravenous or subcutaneous administration in patients with non-myeloid malignancies undergoing chemotherapy.

BACKGROUND AND OBJECTIVE: The pharmacokinetics of darbepoetin alfa after intravenous (IV) administration in the oncology setting have not been previously reported. The objective of this study was to evaluate the pharmacokinetics of IV or subcutaneous (SC) darbepoetin alfa in patients with non-myeloid malignancies undergoing multicycle chemotherapy. METHODS: Fifty-six patients (haemoglobin

Pharmacokinetics and metabolism of irinotecan combined with capecitabine in patients with advanced colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid is used successfully for first-line treatment of metastatic colorectal cancer. Capecitabine (CCB) represents a very convenient alternative to 5-fluorouracil, either as single agent or in a combination of regimens acting synergistically and with the potential to further improve efficacy. Both CPT-11 and CCB need to be activated by human carboxyl esterases, therefore a probable pharmacokinetic drug interaction was checked. PATIENTS AND METHODS: Ten patients suffering from advanced colorectal cancer were enrolled in this trial. CPT-11 was administered as a 30-min i.v.-infusion (70 mg/m2) weekly. CCB was given p.o. twice daily for two weeks (2,000 mg/m2 daily) starting the day after the first CPT-11 infusion. Plasma samples were analysed during/after the first (MONO) and third (CAPIRI) CPT-11 infusion. RESULTS: CCB did not alter CPT-11 plasma disposition, and no significant changes in c(max), AUC(last), Vdss and Cl(tot) during CAPIRI treatment could be observed. However, co-administration of CCB appeared to decrease SN-38 (the cytotoxic CPT-11 metabolite) plasma concentrations during the first three hours after initiation of CPT-11 infusion, with strongly time-dependent plasma percentage differences between control and CAPIRI treatment (p < 0.005, R = 0.981). Co-administration of CCB also had a similar impact on the initial plasma disposition of SN-38gluc, but not on that of the APC metabolite. CONCLUSION: Overall, our findings indicate that, while the administration of CCB resulted in reversible lower formation rates of SN-38 and SN-38gluc, it did not have a significant impact on CPT-11 pharmacokinetics.

Clinical pharmacokinetics of capecitabine and its metabolites in combination with the monoclonal antibody bevacizumab.

AIM: Capecitabine, designed as a pro-drug to the cytotoxic agent 5-fluorouracil, is widely used in the management of colorectal cancer. This study was designed to investigate whether co-administration of the monoclonal antibody bevacizumab (BVZ) shows potential to modulate the plasma disposition of capecitabine (CCB) and its metabolites. PATIENTS AND METHODS: Nine patients treated with CCB and BVZ for advanced colorectal cancer entered this pharmacokinetic study. In the first cycle CCB was given alone at doses of 1,250 mg/m2 bi-daily for two weeks with one week rest. In the second cycle BVZ co-administration started simultaneously with oral intake of CCB by short infusion of 7.5 mg/kg. RESULTS: Mean plasma concentration time curves of CCB and its metabolites were insignificantly lower in the BVZ combination regimen compared to CCB monotherapy. After repeated cycles of BVZ no significant pharmacokinetic interaction was observed. CONCLUSION: From the pharmacokinetic point of view and in agreement with numerous clinical study data, co-administration of BVZ with CCB appears to be safe and efficient.

A rapid and simple HPLC assay for quantification of capecitabine for drug monitoring purposes.

AIM: Capecitabine, a 5-fluorouracil prodrug, has been integrated into the management of multiple cancer types. In order to obtain information about plasma levels of capecitabine in patients who had drug intake at home during chemotherapy, a simple HPLC method for capecitabine monitoring has been developed and validated. PATIENTS AND METHODS: Capecitabine levels were quantified by a simple reversed-phase HPLC system with an external standard method. Plasma samples were obtained from 12 colorectal cancer patients who underwent chemotherapy with capecitabine alone (1000 mg/m(2)) or combined with oxaliplatin (130 mg/m(2)). RESULTS: Although there was evidence that capecitabine had not been taken according to the chemotherapeutic schedule in two cases, the study demonstrated that its combination with oxaliplatin showed no significant drug-drug interactions. CONCLUSION: Due to its robustness, specificity and sensitivity, the method is also well-suited for capecitabine analysis in other pharmacokinetic studies.

Pharmacokinetics of irinotecan in combination with biweekly cetuximab in patients with advanced colorectal cancer.

BACKGROUND: The effect of biweekly cetuximab (CTX) on the pharmacokinetics of CPT-11 and its metabolites was evaluated in this prospective, paired, crossover study. PATIENTS AND METHODS: Patients with epidermal growth factor receptor-positive advanced colorectal cancer received infusions of CPT-11 (180 mg/m(2); FOLFIRI schedule) every second week. CTX (500 mg/m(2) for 120 min) was infused on day 2, followed by biweekly infusions (500 mg/m(2) for 120 min). Plasma samples were analysed on day 1 of cycle 1 (CPT-11 monotherapy) and on day 1 of cycle 3 or 4 (CPT-11 plus CTX). The endpoint of this study was to evaluate differences in plasma concentrations of CPT-11 and metabolites between cycle 1 and cycle 3 (or 4). RESULTS: Generally, there was little difference in CPT-11 pharmacokinetics when combined with CTX in the 11 enrolled patients. However, a significantly lower area under the concentration-time curve from 0-48 hours was observed for the SN-38 glucuronide metabolite with combination therapy versus monotherapy (by 27%, p<0.05). CONCLUSION: CTX has no clinically relevant impact on the pharmacokinetics of CPT-11 or its activation into SN-38; however, there may be a delay in detoxification of SN-38 by beta-D-glucuronidation.

Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer.

PURPOSE: Patients with colorectal cancer (CRC) and liver metastases have a poor prognosis, but can benefit from perioperative chemotherapy and disease resection. Bevacizumab improves outcomes in patients with metastatic CRC; however, its impact on surgical complications and hepatic regeneration after liver resection remains to be determined. PATIENTS AND METHODS: Fifty-six patients with metastatic CRC with liver metastases potentially curable by resection were eligible for this single-center, nonrandomized phase II trial. Eligibility criteria defined patients at high risk of early recurrence. Patients received biweekly bevacizumab plus capecitabine and oxaliplatin for six cycles. The sixth cycle of therapy did not include bevacizumab, resulting in 5 weeks between the last administration of bevacizumab and surgery. RESULTS: Objective response to neoadjuvant chemotherapy was achieved in 41 patients (73%). Fifty-two patients underwent liver resection including 11 with synchronous primary tumor resection. No increased intraoperative bleeding events or wound-healing complications were observed and only three patients (6%) required perioperative blood transfusions. Further surgery was necessary in a single patient. Postoperative liver function and regeneration were normal in all but one patient. No postoperative mortality occurred and morbidity was encountered in 11 patients (20%). The mean length of postoperative hospitalization was 9 days (+/- 4.0). CONCLUSION: These data suggest that bevacizumab can be safely administered until 5 weeks before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or severity of bleeding. To our knowledge, they are also the first to show that neoadjuvant bevacizumab does not affect liver regeneration after resection.

Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: the European Organisation for Research and Treatment of Cancer Chronotherapy Group.

PURPOSE: In two previous randomized trials, the adjustment of chemotherapy delivery to circadian rhythms improved tolerability and anticancer activity compared with constant-rate infusion during 5 days in patients with metastatic colorectal cancer. PATIENTS AND METHODS: For this multicenter randomized trial, it was hypothesized that a chronomodulated infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronoFLO4) would improve survival by 10% compared with conventional 2-day delivery of the same drugs (FOLFOX2). Patients were treated every 2 weeks with intrapatient dose escalation. RESULTS: Baseline characteristics were similar in both arms for the 564 patients (36 institutions, 10 countries). Median survival was 19.6 months (95% confidence limit [CL] = 18.2, 21.2) with chronoFLO4 and 18.7 months with FOLFOX2 (95% CL = 17.7, 21.0; P = .55). The main dose-limiting toxicities were diarrhea for chronoFLO4 and neutropenia for FOLFOX2. The analysis of survival predictors showed that sex was the single most important factor (P = .001). In women, the risk of an earlier death with chronoFLO4 was increased by 38% compared with FOLFOX2, with median survival times of 16.3 and 19.1 months (P = .03), respectively. In men, the risk of death was decreased by 25% with chronoFLO4 compared with FOLFOX2, with median survival times of 21.4 and 18.3 months (P = .02), respectively. CONCLUSION: Both regimens achieved similar median survival times more than 18 months with an acceptable toxicity. The chronomodulated schedule produced a survival advantage over FOLFOX in men. The strong sex dependency of optimal scheduling of fluorouracil, leucovorin, and oxaliplatin calls for translational investigations of determinants related to the patient's molecular clock.

Pharmacokinetics of gemcitabine combined with trastuzumab in patients with advanced breast cancer.

BACKGROUND: Combining the monoclonal antibody trastuzumab (TMAB) with chemotherapy is a new strategy in treatment of advanced breast cancer in HER+++ overexpressing patients. PATIENTS AND METHODS: The disposition of gemcitabine has been investigated in 8 breast cancer patients (prospective cross-over design). Gemcitabine was administered as a 30-min i.v. infusion (1,000 mg/m(2) in 250 ml) on day 1 weekly for 3 weeks. On day 2 TMAB was infused with a loading dose of 4 mg/kg (90-min infusion) followed by a weekly maintenance dose of 2 mg/kg (30-min infusion). Pharmacokinetic analysis was performed after the first (= MONO) and after the third gemcitabine infusion (= TMAB). RESULTS: Cmax was 22.2 microg/ml (t(max) = 24 min) in the MONO and 24.6 microg/ml (t(max) = 23 min) in the TMAB schedule. Gemcitabine distributed rapidly from plasma within a few minutes and was eliminated with a t1/2el of about 80 min in both arms of the study. The metabolite difluorodeoxyuridine (dFdU) appeared in plasma with t1/2appin = 12.8 min (MONO) or t1/2appin = 10.2 min (TMAB) reaching a mean peak concentration of 35.9 microg/ml (MONO) or 30.4 microg/ml (TMAB), respectively. CONCLUSION: The results gave evidence that TMAB does not affect the disposition of gemcitabine.