Elsevier

Leukemia Research

Volume 34, Issue 2, February 2010, Pages 196-202
Leukemia Research

An open-label, Phase I study of cediranib (RECENTIN™) in patients with acute myeloid leukemia

https://doi.org/10.1016/j.leukres.2009.07.020Get rights and content

Abstract

VEGFR and c-Kit signaling pathways may contribute to the pathophysiology of acute myeloid leukemia (AML). Thirty-five patients with AML received cediranib (RECENTIN™), an oral, highly potent VEGF signaling inhibitor with c-Kit activity, at doses of ≤30 mg/day. The most common adverse events were diarrhea, hypertension and fatigue. Six patients experienced an objective response (3 each at 20 and 30 mg). Dose- and time-dependent reductions in sVEGFR-2 were observed, and there was a positive correlation between cediranib exposure and the change in plasma VEGF levels from baseline. Cediranib was generally well tolerated and showed preliminary evidence of activity as a monotherapy.

Introduction

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults [1], accounting for ∼90% of adult acute leukemias [2]. AML may arise de novo or secondary to pre-existing myelodysplasia or previous chemotherapies. The multifactorial causes of AML include chromosomal translocations resulting in loss of function of genes responsible for myeloid cell differentiation and maturation, along with activation in tyrosine kinases including c-Kit, Flt-3 and signaling via Ras and other pathways that confer proliferative and survival advantages to the clone. The prognosis is generally poor for the majority of patients with AML, particularly the elderly and those with relapsed or refractory AML, and more effective treatment options are needed [3].

There is accumulating evidence that angiogenesis may play an important part in AML progression and is correlated with poor prognosis [4]. Increased expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been detected in patients with AML compared with those in healthy donors [5], and higher plasma VEGF levels have been associated with a worse prognosis in patients with AML [6]. In addition, bone marrow biopsies obtained from patients with AML have been shown to have significantly higher microvessel density (MVD) measurements compared with healthy donors [7]. Reductions in MVD and VEGF/VEGFR expression on bone marrow endothelial cells have been observed upon successful remission induction [8]. In some cases, AML blast cells can overexpress VEGF and VEGFRs, suggesting autocrine stimulation of the leukemic cells and paracrine stimulation through VEGF-driven cytokine production [9]. It has also been suggested that VEGFR-3 has a role in leukemic cell proliferation, survival and development of resistance to chemotherapy [9], [10], [11], [12].

The c-Kit proto-oncogene encodes a receptor tyrosine kinase that has also been implicated in AML. The expression and activity of c-Kit has been shown in AML blast cells [13], [14], and several types of mutations that cause constitutive activation of c-Kit have been identified in AML patients [15], [16].

The possible contribution of VEGFR-dependent angiogenesis and c-Kit activity to the pathophysiology of AML make these attractive targets for therapeutic intervention. However, there are limited clinical data regarding the use of antiangiogenic therapies in AML. Thalidomide has anti-leukemic effects that may be partly due to its ability to inhibit angiogenesis [17]. Sunitinib is a multitargeted tyrosine kinase inhibitor with activity versus VEGFRs, c-Kit, platelet-derived growth factors (PDGFRs) and fms-like tyrosine kinase-3 (Flt-3) [18]. A Phase I study of sunitinib monotherapy in AML induced partial remissions of short duration in 3/14 evaluable patients [19]. Cediranib (RECENTIN™) is an oral, highly potent and selective inhibitor of VEGF signaling, with activity versus VEGFR-1, -2 and -3, and also has additional activity versus c-Kit [20]. Previous clinical data have demonstrated that cediranib is generally well tolerated in patients with advanced solid tumors and is suitable for once-daily oral dosing [21]. The primary objective of this Phase I, multicenter, two-part, open-label study was to investigate the safety and tolerability of cediranib in patients with AML. Secondary assessments included evaluation of pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy.

Section snippets

Patients

This study was conducted in adult patients with AML refractory to induction chemotherapy or in relapse following first or subsequent induction treatments, or elderly patients with de novo or secondary AML who were unsuitable for treatment with conventional chemotherapy regimens. Other key inclusion criteria were a WHO performance status of 0–2 (those with performance status 2 had to have been stable with no deterioration over the previous 2 weeks).

The main exclusion criteria were significant

Patients

A total of 35 patients entered the study and received treatment with cediranib (Table 1). Demographic characteristics were similar across all dose cohorts in Parts A and B, and were considered typical of a relapsed or refractory population of AML patients or of elderly patients unfit for induction chemotherapy. Following the decisions of the safety review committee in Part A there was one cohort expansion in the cediranib 20 mg group and two cohort expansions in the cediranib 30 mg group. After

Discussion

Cediranib is an oral, highly potent and selective VEGF signaling inhibitor with activity versus VEGFR-1, -2 and -3 and c-Kit [20]. The primary objective of this two-part Phase I study was to determine the safety and tolerability of multiple oral doses of cediranib in AML patients. Overall, cediranib was generally well tolerated at once-daily oral doses of ≤30 mg. The adverse event profile was consistent with that previously reported in patients with solid tumors [21] and no new adverse events

Conflict of interest

WF, RM, MH, GE and UZ have no conflicts of interests to declare. WEB has participated in advisory boards and has received consultation fees/honoraria for advisory board activity and his role on the Board of Directors regarding lung cancer and ZACTIMATM. JDR and JMJ are AstraZeneca employees. TAP was previously an AstraZeneca employee. JMJ and TAP are also AstraZeneca stock holders and JMJ has a patent pending. BC has been compensated for consultancy activities. HS has received funding from

Acknowledgements

This study, including writing assistance provided by Drs. John Matthew and Huw Williams of Mudskipper Bioscience, was supported financially by AstraZeneca.

Contributions: WF, RM, MH, GE, WEB, UZ, JDR, TAP, BC, JJM and HS contributed to the writing of this manuscript or participated in the conception and design of the study and analysis of data.

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    Present address: Centocor, Chesterbrook, PA, USA.

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