1 University of Colorado Cancer Center, Aurora, CO, USA; 2 Cancer Trials Australia, Melbourne, Australia; 3 Astra Zeneca, Boston, MA, USA; 4 Astra Zeneca, Alderley Park, UK; 5 Duke University Medical Centre, Durham, NC, USA
* Correspondence to: Dr H. I. Hurwitz, Duke University Medical Centre, Box 3052, Durham, NC 27710, USA. Tel: +1-919-681-5257; Fax: +1-919-684-9712; Email: hurwi004{at}mc.duke.edu
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Abstract |
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Patients and methods:: Adult patients with tumors refractory to standard treatments received once-daily oral ZD6474 (50600 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed.
Results:: Seventy-seven patients were treated at doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg (n=8). Adverse events were generally mild, and the most common dose-limiting toxicities (DLT) were diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events appeared to be dose-dependant. In the 500 mg/day cohort, 3/8 patients experienced DLT and this dose was therefore considered to exceed the maximum tolerated dose. Pharmacokinetic analysis confirmed that ZD6474 was suitable for once-daily oral dosing.
Conclusions:: Once-daily oral dosing of ZD6474 at 300 mg/day is generally well tolerated in patients with advanced solid tumors, and this dose is being investigated in phase II trials.
Key words: anti-angiogenesis, dose escalation, pharmacokinetics, tolerability, ZD6474
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Introduction |
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VEGF signaling occurs through the endothelial cell-associated tyrosine kinase receptors VEGFR-1 (Flt-1) and VEGFR-2 (KDR). However, activation of VEGFR-2 alone appears to be sufficient to induce the angiogenic and vascular permeabilization activity of VEGF. ZD6474 is a novel, orally available inhibitor of VEGFR-2 and epidermal growth factor receptor (EGFR) tyrosine kinase activity [14, 15
]. Inhibition of VEGF signaling responses by ZD6474 has been demonstrated in preclinical studies in vivo, including reversal of VEGF-induced hypertension [16
]. Chronic once-daily administration of ZD6474 has been shown to result in significant tumor growth inhibition in a range of histologically diverse human xenograft models and to induce regression of established PC-3 prostate tumors [16
]. Because ZD6474 inhibits the growth of gefitinib-resistant tumors in human xenografts, it may be a useful treatment in tumors that do not respond to EGF inhibitors [17
]. An antimetastatic effect has also been demonstrated in a human pancreatic tumor model, showing a marked reduction in lymph node and liver metastases compared with control or gemcitabine-treated animals [18
].
The primary objective of this phase I clinical study was to assess the safety and tolerability of oral ZD6474 in patients with advanced solid tumors. Secondary objectives included assessment of single- and multiple-dose pharmacokinetics and evaluation of the antitumor activity of ZD6474.
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Patients and methods |
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Patients in the expanded cohort phase were required to have only one active tumor type, measurable using Response Evaluation Criteria in Solid Tumors (RECIST) [19], and to have tumors suitable for MRI (magnetic resonance imaging; tumors considered suitable were those affecting soft tissue, liver, fixed pelvic masses or bone). All patients provided written informed consent. The trial was conducted in accordance with the Declaration of Helsinki, and was approved by all institutional ethics committees.
Study design
Patients received a single oral dose of ZD6474 (50, 100, 200, 300, 500 or 600 mg), followed by a 7-day observation period (cycle 0; Figure 1). At the end of this period, patients received once-daily treatment at the same dose level as in cycle 0 for a total of 28 days (cycle 1). Patients received further 28-day cycles of treatment until evidence of tumor progression or dose-limiting toxicity (DLT) was observed. No intrapatient dose escalation was performed. Scheduled assessments were daily during cycle 0 and on days 115 of cycle 1, weekly during the remainder of cycles 1 and 2, and every 2 weeks for subsequent cycles.
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Initially, dose escalation proceeded by two dose levels until two or more patients experienced a grade 2 toxicity, or one or more patients experienced a grade 3 toxicity. Thereafter, dose escalation proceeded by single-dose levels.
Expanded cohorts
After recruitment was complete, an interim analysis of patients who had completed cycles 0 and 1 identified 500600 mg/day as exceeding the maximum tolerated dose (MTD; defined as the dose of drug at which there is a 33% probability of experiencing toxicity within a 28-day cycle, which cannot be controlled by maximum supportive care). Therefore, 810 patients were evaluated sequentially at 100 and 300 mg dose levels in order to further characterize the safety, tolerability, and biological activity of ZD6474. Cycle 0 was omitted from the expansion phase of the study, with patients entering cycle 1 directly.
Safety and tolerability
The primary study objective was to assess the safety and tolerability of escalating oral doses of ZD6474. Following full physical examination at enrolment, adverse events (AEs; defined as the development of a new medical condition or the deterioration of a pre-existing medical condition) were recorded at each scheduled assessment. Unless additional electrocardiograms (ECGs) were clinically indicated, 12-lead ECGs were performed at the screening visit (within 7 days of day 1), pre-treatment (cycle 1), at the end of each 28-day cycle, and at the end of the study. QTc values were obtained using Bazett's method of correction [20]. ZD6474 was withheld if the following criteria were met: QTc
490 ms or QTc
460 ms, with an increase from baseline of
60 ms. Upon resolution of QTc prolongation, ZD6474 could be restarted at 50% of the initial dose. During cycle 0, vital signs were measured before dosing and 2, 4, 6, 8 and 10 h after dosing on day 1, and then every 24 h until day 3. During cycle 1, vital signs were measured before dosing and then daily for 14 days, after which measurements were taken weekly until the end of cycle 2. Following cycle 2, vital signs were measured once every 2 weeks. A chest X-ray was performed within 14 days of day 1 and as clinically indicated.
Pharmacokinetic assessment
During cycle 0, blood samples were collected before dosing and at 1, 2, 4, 6, 8 and 10 h after dosing on day 1, and then every 24 h until day 7. During cycle 1, blood samples were collected before dosing on days 114 and day 22, and before dosing and 2, 4, 6, 8, 10 and 24 h after dosing on day 28. Samples were also collected before dosing on days 15 and 29 of any subsequent cycles. Additional pre-dose samples were collected at each ECG assessment.
Plasma concentrations of ZD6474 were determined using high performance liquid chromatography with tandem mass spectrometric detection. These data were used to calculate ZD6474 maximum concentration (Cmax), time to maximum concentration (tmax), terminal half-life (t), area under the curve to infinity (AUC), and area under the curve to 24 h (AUC024) following the first dose in cycle 0, and Cmax, tmax, AUC024 and minimum concentration at steady state (Cmin) following multiple dosing in cycle 1. The plasma concentration data from the pre-dose samples collected on days 114, 22, 28 and 29 of cycle 1 and on days 15 and 29 of cycles 2 and 3 were used to assess the escalation to steady state for the daily dosing scheme. Population pharmacokinetic [21
] and pharmacokineticpharmacodynamic [22
] modeling was conducted using the population pharmacokinetic software NONMEM.
Tumor response
Tumor response to ZD6474 therapy was evaluated according to RECIST [19]. Baseline radiological tumor assessments were performed
4 weeks before the start of treatment. Clinical assessment was performed after every treatment cycle, and radiological assessment after every even-numbered cycle.
Biomarkers
At one of the study sites, wound angiogenesis was evaluated in 10 patients using a previously reported model [23]. The wound angiogenesis results will be reported separately. Significant intra- and interpatient variability in image acquisition was seen in dynamic contrast-enhanced MRI within this study, precluding image analysis.
Statistical analyses
No formal statistical analysis was performed on the safety, biological or pharmacokinetic data from this trial, as patients were enrolled sequentially rather than randomized to a particular dosage regimen. Sample size was based on practical considerations regarding the nature of the inclusion criteria. Safety data from both phases (dose escalation and cohort expansion) and from all cycles were combined. AEs were presented by starting dose, according to both the Medical Dictionary for Regulatory Activities (MedDRA) coding system and the CTC (version 2.0) grading system.
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Results |
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Pharmacokinetic evaluation
Plasma pharmacokinetic parameters revealed that absorption and elimination of ZD6474 after a single oral dose was slow, with median tmax ranging from 4.0 to 7.5 h and a t of
120 h (Table 5). Plasma concentrationtime profiles following continuous oral dosing with 300 mg are shown in Figure 2. Trough levels indicated that a minimum of 28 days dosing is necessary to achieve steady-state plasma concentrations of ZD6474.
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Discussion |
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Pharmacokinetic assessment in this study has confirmed that ZD6474 is suitable for once-daily oral dosing. A minimum of 28 days continuous oral dosing with ZD6474 was required to achieve steady-state plasma concentrations, which is consistent with the long terminal half-life of 5 days. It is noteworthy that continuous once-daily dosing with 300 mg ZD6474 was sufficient to achieve concentrations greater than the IC50 for in vitro inhibition of VEGFR-2 tyrosine kinase activity (calculated using an in vitro IC50=19 ng/ml or 40 nM [16
], and assuming
10% free drug in human plasma). Although several patients had stable disease, no objective partial or complete tumor responses were observed in this typically refractory phase I population.
A number of angiogenesis inhibitors are currently in clinical development, including single- and multiple-targeted agents [1]. Although the therapeutic efficacy of targeting VEGF alone has been demonstrated with bevacizumab, targeting other processes essential for tumor growth and development has the potential for increasing antitumor activity with minimal overlapping toxicities. In addition to being a potent inhibitor of VEGFR signaling, ZD6474 is also a submicromolar inhibitor of EGFR tyrosine kinase activity. ZD6474 may therefore provide added therapeutic benefit in tumors with EGFR-dependent proliferation or survival: EGFR inhibition has been shown to downregulate VEGF expression and tumor-related angiogenesis in preclinical models [28
, 29
], and selective inhibition of EGFR signaling has shown clinical benefit in advanced cancer patients [30
]. Further evaluation of this activity is required, however, in order to better understand any potential benefits.
In conclusion, once-daily oral administration of ZD6474 at doses 300 mg is well tolerated in patients with advanced solid tumors. Phase II evaluation of ZD6474 in this dose range is ongoing in patients with a range of tumor types, both as monotherapy and in combination with certain other anticancer agents.
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Acknowledgements |
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Received for publication March 12, 2005. Accepted for publication March 15, 2005.
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