Annals of Oncology Advance Access originally published online on January 11, 2007
Annals of Oncology 2007 18(4):782-788; doi:10.1093/annonc/mdl469
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© 2007 European Society for Medical Oncology
phase I and pharmacokinetics |
A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer
1 University of Leicester, Leicester, UK
2 University of Duisburg-Essen Medical School, West German Cancer Center, Essen
3 Charite University Hospital CVK, Berlin
4 Schering AG, Berlin, Germany
5 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
* Correspondence to: Dr A. L. Thomas, Department of Oncology, Leicester Royal Infirmary, Leicester LE1 5WW, UK. Tel: +44-116-2587602; Fax: +44-116-2587599; E-mail: at107{at}le.ac.uk
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Abstract |
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Background: This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity.
Patients and methods: Thirty-five patients received escalating doses of PTK/ZK (range 500–2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage.
Results: Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months.
Conclusion: The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions.
Key words: colorectal cancer, FOLFOX4 chemotherapy, phase I, PTK/ZK
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Folkman hypothesized over three decades ago that angiogenesis was essential for tumor growth [1]. Much of the current interest in antiangiogenic therapy is focused on the pharmacologic inhibition of vascular endothelial growth factor (VEGF), a family consisting of four ligands (VEGF-A, -B, -C, and -D) [2]. Since VEGF activity is mediated through interaction with tyrosine kinase receptors [VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3 (Flt-4)] [3], there are a variety of pharmacologic targets potentially available to inhibit VEGF signaling pathways.
In colorectal cancer (CRC), the only licensed angiogenesis inhibitor to date is bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) [4, 5]. In the pivotal phase III study of patients with metastatic CRC, the addition of bevacizumab in combination with irinotecan-based chemotherapy improved the median duration of survival from 15.6 to 20.3 months. Bevacizumab is a monoclonal antibody specific for VEGF-A. When VEGF-A is inhibited, biologic redundancy may allow partial compensation through other VEGF ligands [6]. Moreover, since VEGF-A does not interact with VEGFR-3, inhibition of VEGF-A does not impair activation of this receptor [7, 8]. VEGFR-3 activation is closely associated with lymphangiogenesis, an important factor in tumor metastasis [9]. With the potential compensation for specific VEGF-A inhibition, a theoretically more effective alternative strategy would be the inhibition of multiple VEGF receptors, the principal downstream mediators of angiogenesis and lymphangiogenesis.
PTK787/ZK 222584 (PTK/ZK) is an orally active, small-molecule inhibitor of angiogenesis and lymphangiogenesis that blocks tyrosine kinase signaling of all known VEGF receptors [10–13]. It belongs to the chemical class of aminophthalazines and is metabolized primarily by CYP3A4 into four inactive metabolites. In preclinical studies, PTK/ZK has shown antitumor activity in several human tumor xenografts in nude mice [11]. A phase I study in patients with advanced, treatment-refractory malignancies found that PTK/ZK monotherapy was generally well tolerated with some potential activity in patients with CRC [14]. Given this finding, the known overexpression of key angiogenesis ligands and receptors in gastrointestinal carcinomas [15] we evaluated the safety and pharmacokinetics of PTK/ZK combined with a commonly used 5-fluorouracil (5-FU) and oxaliplatin-based chemotherapeutic regimen (FOLFOX4) in patients with advanced CRC.
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patients and methods |
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patient selection
Patients eligible for the study were
18 years of age with histologically confirmed inoperable locally advanced or metastatic CRC. While previous surgical resection and adjuvant chemotherapy were permitted, patients could not have received prior treatment of advanced disease. Additional entry requirements included life expectancy of 3 months, World Health Organization performance status (PS) of two or less, measurable disease, and laboratory parameters within the following ranges: absolute neutrophil count (ANC) >1.5 x 109/l, hemoglobin >9 g/dl, platelets 100 x 109/l, aspartate aminotransferase 
3.0 x upper limit of normal (ULN), serum 1.5 x ULN, serum creatinine 1.5 x ULN, 24-h creatinine clearance 50 ml/min, and total 24-h urinary protein 500 mg. Concurrent severe or uncontrolled medical disease, pregnant or breast-feeding women, and use of warfarin were all exclusion criteria. The study protocol was approved by the local ethics committees (Leicestershire Research Ethics Committee Ref no 6149, Ethik Kommission der Medizinischen Fakultät Charité Ref no 182/2000, Ethik-Kommission Medizinische Fakultät der Universität Essen, Ref no 02-2044) and all patients gave their written informed consent.
study design
This was a phase IB, open-label, dose-escalation study of once-daily continuous dosing of PTK/ZK combined with oxaliplatin/5-FU/leucovorin (FOLFOX4) conducted in three centers.
The primary study objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of escalating once-daily doses of PTK/ZK in combination with FOLFOX4 chemotherapy in patients with advanced, inoperable CRC and to characterize safety and tolerability of this combination. Secondary objectives were to determine the effect of PTK/ZK on the pharmacokinetics of FOLFOX4, the effects of FOLFOX4 on the pharmacokinetics of PTK/ZK, and to assess the antitumor activity of the combination. Although it was unlikely that there would be significant interaction between PTK/ZK and the FOLFOX4, full pharmacokinetic testing was carried out to ensure this was indeed the case.
The starting dose of FOLFOX4 was constant for cycle one of each cohort and was reduced in subsequent cycles according to toxic effects. Patients were recruited in cohorts of three to six and received sequentially increasing doses of PTK/ZK (from 500 mg to 1000 mg to 2000 mg daily) until DLT was observed. When more than two patients in a cohort of three or six patients experienced DLT, no additional patients were enrolled and dose escalation ceased. When DLT occurred at 2000 mg daily, two further dosing cohorts were allowed (1500 mg and 1250 mg daily). Treatment was continued in all cohorts until evidence of disease progression, unacceptable toxicity, or withdrawal of consent. Intraindividual dose escalation was not permitted. As this study commenced, initial data from the dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) work [13] indicated that the biological effect of PTK/ZK might plateau at doses above 1000 mg daily. This was, however provisional data and at that time the MRI technique was not validated. It was also not known whether the combination of FOLFOX4 with PTK/ZK might alter the toxicity profile previously seen with PTK/ZK. Therefore, a classical dose-escalation design was adopted.
The National Cancer Institute Common Toxicity Criteria 2.0 was used for safety evaluation. A DLT was defined as an adverse event (AE) or laboratory abnormality which was determined as related to, or exacerbated by, the addition of PTK/ZK to FOLFOX4 and occurred within 35 days of the first dose of chemotherapy. DLTs included grade 4 neutropenia lasting 5 days (ANC, including bands <0.5 x 109/l); grade 4 thrombocytopenia 5 days (platelet count <10 x 109/l); grade 3 or 4 non-hematologic events (excluding grade 3–4 elevations in alkaline phosphatase); grade 2 proteinuria; grade 2 hematuria; and serum creatinine 2.0 x ULN. The MTD was defined as the dose-producing DLT effects in less than one of six assessable patients when two or more patients experienced a DLT at the next higher dose. There was a planned expansion of the MTD cohort to evaluate further safety, tolerability, pharmacokinetics, and antitumor activity.
treatment
The starting dose of PTK/ZK (Schering AG, Berlin, Germany and Novartis, East Hanover, NJ) was 500 mg daily, a dose previously shown to be well tolerated and associated with evidence of pharmacodynamic effects on DCE-MRI [13]. Dosing of PTK/ZK began on day 3 of cycle one to allow for pharmacokinetic blood testing and was dosed continuously unless interrupted for DLT. FOLFOX4 chemotherapy was administered according to standard practice [16]. If patients experienced any of the well-documented neurological toxic effects of oxaliplatin [17], or other non-hematological toxic effects, the oxaliplatin dose was held and reintroduced according to prescribing guidelines. If Common Toxicity Criteria (CTC) grade 4 diarrhea or grade 3 neutropenia or thrombocytopenia occurred, the dose of oxaliplatin and 5-FU was reduced by 25%.
evaluation criteria and procedures
A baseline evaluation occurred within 14 days before treatment and included medical history, physical examination, PS, hematological status, blood chemistry, urinalysis, electrocardiogram (ECG), chest radiography, and tumor assessment. During an earlier PTK/ZK phase I study [14], preclinical work demonstrated duodenal hyperplasia in rats. Therefore, patients in this study underwent an upper gastrointestinal (UGI) examination by double contrast barium meal or endoscopy at baseline to exclude duodenal pathology. Safety evaluations included the monitoring and recording of all AEs as well as regular evaluation of hematology and serum chemistry, urinalysis, physical examination, vital signs, and PS. Patients were reviewed every 2 weeks and AEs were continuously monitored and recorded at these visits.
pharmacokinetics
Nine serial blood samples were taken (predose, 0.5, 1.5, 2, 4, 5, 6, 8, 24 h) for measurement of PTK/ZK with and without chemotherapy (cycle one, days 15 and 22). Serial blood samples were obtained from predose until 48 h postdose for oxaliplatin (11 samples) and 5-FU (eight samples) on day 1 (without PTK/ZK) and on day 15 (with PTK/ZK). Samples were centrifuged within 30 min, transferred to a cryogenic freezing vial, and stored at –80°C before shipment and analysis. Samples were analyzed for PTK/ZK as previously reported [14]. Free platinum, the active substance of oxaliplatin, was measured in plasma ultrafiltrate using validated inductively plasma coupled/mass spectrometry [lower limit of quantification (LLOQ) 10 ng Pt/ml], and for 5-FU using a validated gas chromatography with mass spectrometry detection, LLOQ 1 ng/ml was used. Pharmacokinetic parameters including area under the plasma concentration versus time curve (AUC) using linear trapezoidal method measured up to 24 h postdose for PTK/ZK and 48 h postdose for free platinum and 5-FU, maximum plasma concentration (Cmax), and terminal half-life (t1/2) were determined by subjecting plasma concentration versus time data to standard noncompartmental analysis, using WinNonlin 4.1 (Pharsight®, Mountain View, CA). Analyses of plasma samples were carried out by Applied Analytical Industries (PTK/ZK), Neu-Ulm, Germany (5-FU) and Xendo Laboratories, Groningen, The Netherlands (oxaliplatin).
efficacy
Tumor response was evaluated by contrast-enhanced computerized tomography scan (CT) at baseline and then every 12 weeks and was assessed using the modified Southwest Oncology Group criteria [18]. In the event of partial (PR) or complete response (CR), a follow-up scan 4 weeks later was necessary for confirmation of best response. PR was defined as >50% reduction in measurable tumor volume compared with baselines while CR was defined as complete disappearance of measurable and non-measurable disease. Progression-free survival (PFS) was defined as the time from the date of study entry to the date of the first observation of documented disease progression or death due to any cause.
statistical methods
Statistical methodology was primarily descriptive and focused on frequency of AEs, particularly those that were serious, dose limiting, associated with discontinuation of PTK/ZK or had a severity of CTC grade 3 or 4.
Inferential statistical analysis of the pharmacokinetic parameters of the chemotherapy agents was carried out to estimate the effect of PTK/ZK on FOLFOX4 as well as to evaluate the effect of the chemotherapeutic agents on PTK/ZK. A mixed effect linear model was applied to the dose-normalized, log-transformed pharmacokinetic parameters when data contained different dose levels with treatment as a fixed factor and subject as a random factor. The ratio of geometric means of the pharmacokinetic parameters and corresponding 90% confidence interval (CI) were presented. Preliminary antitumor activity was evaluated as rates of response (CR + PR with 95% CI) and Kaplan–Meier curves for PFS were generated.
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patients
A total of 35 patients were enrolled in the study. Eighteen patients were included in the dose-escalation phase and the remaining 17 patients were treated at the established PTK/ZK MTD of 1250 mg daily. Patient characteristics at baseline are summarized in Table 1. Eighteen patients (51%) were male, 24 patients (69%) were <65 years of age, and all patients were Caucasian.
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Overall, 23 patients (65.7%) remained on the study medication until the time of progressive disease (defined as either a 50% increase or an increase of 10 cm2, whichever is smaller, of measurable disease compared with baseline). The reasons for early study discontinuation were AEs in four patients, withdrawal of consent in two patients, and a combination of AEs and withdrawal of consent in a further two patients. An additional three patients had such significant tumor volume reduction that they withdrew to undergo surgical resection of metastases. One patient died within 28 days of last study drug dose without disease progression and is discussed later. Pharmacokinetic studies of PTK/ZK and oxaliplatin were complete in 34 patients. Mean treatment duration of PTK/ZK was 9.5 months (range 9–1191 days).
safety
The incidence of selected toxic effects regardless of study drug relationship is summarized in Table 2, and the majority was mild to moderate. For some toxic effects it was difficult to establish whether they were related to PTK/ZK, the FOLFOX4, or both. The most frequently occurring AEs were nausea (80%), diarrhea (71%), fatigue/lethargy (69%), and vomiting (60%). These events could potentially be attributable to both PTK/ZK and FOLFOX4. AEs that could be attributable more to PTK/ZK included dizziness (57%), hypertension (29%), and ataxia/coordination problems (20%). Dizziness and ataxia/coordination problems were mainly mild to moderate (CTC grade 1–2) and generally reversible after discontinuation of PTK/ZK.
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Of the 10 patients with hypertension (CTC grades 1–3), seven had an underlying history of hypertension. Hypertension was managed by concomitant medication or no intervention for nine cases. One case of grade 3 hypertension was managed with dose adjustment, concomitant medication, and hospitalization and resolved after 30 days.
Myelosuppression (all grades) as an AE was observed frequently and usually related to cytotoxic chemotherapy. As AEs, neutropenia occurred in 43% patients. Thrombocytopenia occurred in 20% of patients and was mostly grade 1. Anemia was documented in 17% of patients and generally did not require transfusion. Hematology laboratory analysis showed that the most common newly occurring or worsening abnormalities were grade 3 and grade 4 absolute neutrophils (ANC, 43% and 26%) and grade 3 white blood cell count (20%) abnormalities (data not shown).
The most frequently reported non-hematologic AEs that were attributable to the FOLFOX4 included paresthesia/neuropathy, constipation, dyspepsia, arthralgia, anorexia, stomatitis, rash, and chills. The majority of these were mild to moderate and none were grade 4 in severity.
DLT was typically related to the central nervous system. Of the two patients in the 2000-mg cohort, one patient reported dizziness and intermittent unsteadiness and was bedridden (all grade 4); the other patient reported dizziness and unsteadiness (all grade 3). According to the protocol, the dose was de-escalated to 1500 mg, and two of three patients in this cohort also had DLT. One patient reported worsened fatigue (grade 3) and a second patient experienced ataxia (grade 2) and expressive dysphasia, incoordination, and intermittent dizziness (all grade 3). The dose was then de-escalated to 1250 mg daily and one of six patients treated had grade 2 fatigue which was considered dose limiting by the investigators. Therefore, the MTD was established at 1250 mg daily.
Of the six patients (17%) who had AEs leading to discontinuation of PTK/ZK, the distribution of AEs are fatigue (two), ataxia (one), dehydration and syncope (one), melena (one), and pulmonary embolism (one). Overall, 40% of patients had temporary interruption of PTK/ZK, and 26% had a dose reduction, which was predominantly for dizziness (17%) and ataxia (9%). Approximately 80% of patients had their oxaliplatin or 5-FU dose reduced. No patients died during the study. Two patients died within 28 days of the last dose of study medication, one due to progression of metastatic colon cancer and one due to pulmonary embolism and shock. This latter event at the time was considered by the investigator not to be study drug related. The UGI safety testing did not demonstrate any evidence of significant duodenal pathology.
pharmacokinetics
PTK/ZK was rapidly absorbed following once-daily oral administration, with Cmax occurring 
2 h postdose, then declined biexponentially with an average terminal t1/2 of 4–5 h. Since there were only two patients in the 2000-mg cohort it is difficult to make any clear observations about the pharmacokinetics for this dose. Nevertheless, AUC and Cmax both appeared to demonstrate dose proportional increases within the 500–2000-mg/d dose range evaluated. Neither AUC nor Cmax values (Figure 1) were significantly altered by concomitant chemotherapy with FOLFOX4.
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Plasma concentrations of 5-FU were highly variable following the combined bolus dose and intravenous infusion. Comparison of 5-FU average plasma concentrations (Cavg) in the absence and presence of PTK/ZK (2704 ± 814 ng/ml versus 2010 ± 487 ng/ml; not significant) demonstrated that PTK/ZK effects on 5-FU exposure were negligible. With respect to oxaliplatin, free platinum pharmacokinetic parameters including t1/2 and clearance were not affected by concomitant treatment with PTK/ZK (Figure 2). Results were consistent with a lack of interaction between PTK/ZK and the combination of oxaliplatin, 5-FU, and leucovorin.
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efficacy
A total of 17 patients (48.6%) achieved documented best overall responses, with one patient achieving CR and the remaining 16 patients achieving PR. An additional eight patients (22.9%) had stable disease for
3 months. Five patients (14.3%) had progressive disease and in five patients (14.3%) best overall response could not be assessed (Table 3). Among responders (patients with CR/PR), the median duration of overall response was 9 months. Kaplan–Meier estimates of median PFS was 11.4 months (Figure 3).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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We found that the MTD of PTK/ZK when dosed continuously with concomitant FOLFOX4 chemotherapy (at standard dose) was 1250 mg daily. PTK/ZK was well tolerated at or below this MTD. There was no apparent evidence that the pharmacokinetic profiles of PTK/ZK, 5-FU, or oxaliplatin were significantly altered as a result of concomitant use.
Since only a single treatment group was used it is difficult in our study to rigorously identify the contribution of PTK/ZK to the aggregate of AEs in a population treated with three different drugs. The most common toxic effects reported (all grades)—nausea (80%), diarrhea (71%), fatigue/lethargy (69%), and vomiting (60%)—have been seen in studies of PTK/ZK alone, albeit mostly at lower rates (71%, 26%, 70%, and 53%, respectively) [19]. These side-effects are also commonly associated with oxaliplatin and 5-FU with rates from large phase III studies for nausea being reported as 72% or 67%, vomiting 52% or 42%, and diarrhea 51% or 52% [16, 20]. The coadministration of PTK/ZK may slightly increase the incidence of diarrhea, although the clinical impact of this is not concerning as the most common grade reported was grade 1 with no grade 4 diarrhea seen.
Causality of several less commonly reported events is somewhat more certain in light of the known relationship between oxaliplatin and peripheral neurological toxicity as well as 5-FU and stomatitis. The AE in which PTK/ZK is most likely to be implicated on the basis of earlier studies and known antiangiogenic class effects is hypertension [5, 21–23]. This was one of the most common grade 3 events reported with the majority of the affected patients having preexisting hypertension. The toxicity was readily managed with alteration of antihypertensive medication and did not necessitate drug discontinuation as a result. There was no correlation for the patients with hypertension to have neurological toxicity.
For hematological toxicity, the incidence of neutropenia as recorded by laboratory values was 89% (69% grade 3 and 4), thrombocytopenia 82% (8.6% grade 3), and anemia 92% (5.7% grade 3). The incidence of these toxic effects reported in studies with FOLFOX4 [16] and FOLFOX6 [20] are neutropenia 70% and 82%, thrombocytopenia 76% and 83%, and anemia 86% and 54%. In the PTK/ZK monotherapy studies previously reported there was one case of grade 3 and one of grade 4 neutropenia [14, 19]. The etiology for this is believed to be the presence of VEGF receptors on progenitor blood stem cells. It is likely that the PTK/ZK might contribute to the additional neutropenia seen in this study but since the rate of neutropenic sepsis is comparable with other studies [16, 20], this appears to be acceptable.
Overall, AEs were the primary reason for early study discontinuation in only four of 35 patients because the vast majority was only grade 1. Given the use of concomitant FOLFOX4 and the high incidence of symptoms at baseline in this patient population, PTK/ZK does not appear to be associated with significant worsening of the tolerability of FOLFOX4. No attempt was made to correlate the incidence of toxicity with the PK data in this trial as these toxic effects may have been caused by the combination of agents.
DLT was seen in both patients treated at 2000-mg daily and in two of the three patients at the 1500-mg daily dose. It consisted primarily of reversible grade 3 and 4 dizziness/unsteadiness and led to a reduction to 1250 mg daily, the dosage ultimately identified as the MTD. Two earlier dose-ranging studies of PTK/ZK have been reported [14, 19]. Mross and co-workers [19] studied PTK/ZK as a single therapy in patients with liver metastases from solid tumors and established 1200 mg PTK/ZK daily as the maximum dose. In the other study in a similar population, PTK/ZK was administered in a twice-daily oral regimen and the MTD identified was 750 mg twice daily [14]. Neurological toxicity was related to PTK/ZK at the MTD and was usually transient.
In this study, a secondary objective was to gather preliminary evidence of antitumor activity. The objective tumor response rate demonstrated was 49% and similar to rates found in studies with FOLFOX chemotherapy used alone (45%–54%) [16, 20, 24]. A promising finding was that the median PFS (11.4 months) observed in patients treated with PTK/ZK-FOLFOX therapy was slightly better than the 8.7–9 months reported in large, randomized studies that included FOLFOX treatment arms [16, 20, 24]. A randomized study has been completed to define whether this is a real increase (CONFIRM 1), but preliminary analysis indicates similar PFS for FOLFOX4 and FOLFOX4 with PTK/ZK [25].
In conclusion, the MTD of PTK/ZK in combination with FOLFOX4 is 1250 mg daily and this is within the PTK/ZK dose range known to demonstrate biological activity [13]. The combination is feasible and safe in the treatment of patients with advanced CRC. Our findings confirm the lack of pharmacokinetic interactions when PTK/ZK is used in combination with FOLFOX4 and provides the basis for phase III randomized studies using this combination in a larger patient population [25].
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This work is supported by Novartis Pharmaceuticals, East Hanover, NJ, and Schering AG, Berlin, Germany.
Received for publication August 24, 2006. Revision received November 15, 2006. Accepted for publication November 16, 2006.
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