Photo of Erica L. Mayer,  M.D. M.P.H.

Erica L. Mayer, M.D. M.P.H.

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-2335
Fax: (617) 632-1930

Erica L. Mayer, M.D. M.P.H.

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Assistant Professor, Medicine, Harvard Medical School
  • Director, Clinical Research (Faulkner Hospital), Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

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 Women’s Hospital, Harvard Medical School, Boston, MA; 4 Children’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 – 31.7 %) demonstrated partial response, one lasting over 30 weeks, and 3 had stable disease > 24 wks (15%, 95% CI 3.2 – 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.

 

Publications

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  • Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, Rugo HS, Liu MC, Stearns V, Come SE, Timms KM, Hartman AR, Borger DR, Finkelstein DM, Garber JE, Ryan PD, Winer EP, Goss PE, Ellisen LW. TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer. J Clin Oncol 2015. PubMed
  • Mayer EL, Dominici LS. Breast cancer axillary staging: much ado about micrometastatic disease. J Clin Oncol 2015; 33:1095-7. PubMed
  • Magbanua MJ, Carey LA, DeLuca A, Hwang J, Scott JH, Rimawi MF, Mayer EL, Marcom PK, Liu MC, Esteva FJ, Park JW, Rugo HS, . Circulating tumor cell analysis in metastatic triple-negative breast cancers. Clin Cancer Res 2015; 21:1098-105. PubMed
  • Gropper AB, Calvillo KZ, Dominici L, Troyan S, Rhei E, Economy KE, Tung NM, Schapira L, Meisel JL, Partridge AH, Mayer EL. Sentinel Lymph Node Biopsy in Pregnant Women with Breast Cancer. Ann Surg Oncol 2014. PubMed
  • Meisel JL, Economy KE, Calvillo KZ, Schapira L, Tung NM, Gelber S, Kereakoglow S, Partridge AH, Mayer EL. Contemporary multidisciplinary treatment of pregnancy-associated breast cancer. Springerplus 2013; 2:297. PubMed
  • Lin NU, Freedman RA, Ramakrishna N, Younger J, Storniolo AM, Bellon JR, Come SE, Gelman RS, Harris GJ, Henderson MA, Macdonald SM, Mahadevan A, Eisenberg E, Ligibel JA, Mayer EL, Moy B, Eichler AF, Winer EP. A phase I study of lapatinib with whole brain radiotherapy in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer brain metastases. Breast Cancer Res Treat 2013; 142:405-14. PubMed
  • Vaz-Luis I, Zeghibe CA, Frank ES, Sohl J, Washington KE, Silverman SG, Fonte JM, Mayer EL, Overmoyer BA, Richardson AL, Krop IE, Winer EP, Lin NU. Prospective clinical experience with research biopsies in breast cancer patients. Breast Cancer Res Treat 2013; 142:203-9. PubMed
  • Ruddy KJ, Desantis SD, Gelman RS, Wu AH, Punglia RS, Mayer EL, Tolaney SM, Winer EP, Partridge AH, Burstein HJ. Personalized medicine in breast cancer: tamoxifen, endoxifen, and CYP2D6 in clinical practice. Breast Cancer Res Treat 2013; 141:421-7. PubMed
  • Mayer EL, Scheulen ME, Beckman J, Richly H, Duarte A, Cotreau MM, Strahs AL, Agarwal S, Steelman L, Winer EP, Dickler MN. A Phase I dose-escalation study of the VEGFR inhibitor tivozanib hydrochloride with weekly paclitaxel in metastatic breast cancer. Breast Cancer Res Treat 2013; 140:331-9. PubMed
  • Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of Doxorubicin and cyclophosphamide or Paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: cancer and leukemia group B 40101. J Clin Oncol 2012; 30:4071-6. PubMed
  • Mayer EL, Lin NU. Long term follow-up of national surgical adjuvant breast and bowel project trial B-31: how well can we predict cardiac toxicity with trastuzumab? J Clin Oncol 2012; 30:3769-72. PubMed
  • Mayer EL, Isakoff SJ, Klement G, Downing SR, Chen WY, Hannagan K, Gelman R, Winer EP, Burstein HJ. Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics. Breast Cancer Res Treat 2012; 136:169-78. PubMed
  • Carey LA, Rugo HS, Marcom PK, Mayer EL, Esteva FJ, Ma CX, Liu MC, Storniolo AM, Rimawi MF, Forero-Torres A, Wolff AC, Hobday TJ, Ivanova A, Chiu WK, Ferraro M, Burrows E, Bernard PS, Hoadley KA, Perou CM, Winer EP. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol 2012; 30:2615-23. PubMed
  • Choueiri TK, Mayer EL, Je Y, Rosenberg JE, Nguyen PL, Azzi GR, Bellmunt J, Burstein HJ, Schutz FA. Congestive Heart Failure Risk in Patients With Breast Cancer Treated With Bevacizumab. J Clin Oncol 2011. PubMed
  • Mayer EL, Krop IE. Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clin Cancer Res 2010; 16:3526-32. PubMed
  • Mayer EL, Burstein HJ. Weighing a dose-dense option for adjuvant chemotherapy and trastuzumab in early-stage breast cancer. J Clin Oncol 2008; 26:1198-200. PubMed
  • Mayer EL, Burstein HJ. Chemotherapy for metastatic breast cancer. Hematol Oncol Clin North Am 2007; 21:257-72. PubMed
  • Mayer EL, Lin NU, Burstein HJ. Novel approaches to advanced breast cancer: bevacizumab and lapatinib. J Natl Compr Canc Netw 2007; 5:314-23. PubMed
  • Mayer EL, Carey LA, Burstein HJ. Clinical trial update: implications and management of residual disease after neoadjuvant therapy for breast cancer. Breast Cancer Res 2008; 9:110. PubMed
  • Curigliano G, Mayer EL, Burstein HJ, Winer EP, Goldhirsch A. Cardiac toxicity from systemic cancer therapy: a comprehensive review. Prog Cardiovasc Dis 2010; 53:94-104. PubMed
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