A phase I study of vandetanib and metronomic chemotherapy in advanced breast cancer.
Mayer EL1, Isakoff SJ2, Hannagan K1, Savoie J1, Beckman J3, Klement G4, Gelman R1, Winer EP1, Burstein HJ1.
1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2 Massachusetts General Hospital, Harvard Medical School, Boston, MA; 3 Brigham and Womenâ€™s Hospital, Harvard Medical School, Boston, MA; 4 Childrenâ€™s Hospital, Harvard Medical School, Boston, MA.
Background: Vandetanib (V) is an oral tyrosine kinase inhibitor of the vascular endothelial growth factor (VEGF) receptors 2 and 3 and the epidermal growth factor receptor. Metronomic chemotherapy, continuous low-dose oral cyclophosphamide and methotrexate (CM), has activity in combination with anti-angiogenic treatments. We sought to define the safety and tolerability of all-oral combination therapy with V and CM in advanced breast cancer.
Patients and Methods: Eligible patients (pts) had stage IV breast cancer; measurable disease was not required and stable brain metastases were acceptable. Up to 4 prior chemotherapy regimens were allowable, as was prior bevacizumab. Pts with systemic anticoagulation or QTc abnormalities were excluded. Three sequential dose escalation cohorts of approximately 8 pts were enrolled. All pts received CM (C 50 mg PO qd, M 2.5 mg PO d1-2 q week), and V in 3 dose-escalation cohorts: 100 mg qd (Cohort 1), 200 mg qd (Cohort 2), and 300 mg qd (Cohort 3). Pts received V + CM until progression or unacceptable toxicity; dose adjustments were made for treatment related toxicity. The primary endpoint was safety and toxicity of the regimen; secondary endpoints included response rate, non-invasive vascular analysis of hypertension, and platelet proteomics.
Results: 24 pts (median age 49 years) entered the study. 83% had visceral disease, 92% had received prior chemotherapy for metastatic disease (median number of regimens, 2), and 38% had received prior bevacizumab. Median cycles of therapy completed was 2 (range 1-8); median number of weeks on study was 8 (range 2-33). Toxicities in Cohorts 1 and 2 were generally manageable, and most commonly consisted of diarrhea, nausea, fatigue, abnormal hepatic function, and hyperglycemia. Despite fewer cycles of drug exposure, increased toxicity was observed in Cohort 3, including 3 episodes of dose limiting toxicity (mucositis/rash, 1; abnormal hepatic function, 2). One-third of pts required V dose reduction, and 21% of pts came off study for toxicities including cerebrovascular event (1), pulmonary embolus (1), rash (1), abnormal hepatic function (1), and myocarditis (1). Moderate hypertension was observed in 42% of pts, with a single grade 3 event. Of the 20 response-evaluable pts, 2 (10%, 95% CI 1.2 â€“ 31.7 %) demonstrated partial response, one lasting over 30 weeks, and 3 had stable disease > 24 wks (15%, 95% CI 3.2 â€“ 37.9%). Results from correlative vascular hypertension analyses and platelet proteomics will be presented.
Conclusions: The all-oral regimen of V + CM was tolerable at a maximum dose of V 200 mg qd. Dose-limiting toxicity was seen in the V 300 mg cohort. Modest clinical activity in this heavily pretreated population was observed, and supports further investigation of this anti-angiogenic regimen in advanced breast cancer.