DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

A Phase II Safety and Tolerability Study of Bevacizumab When Added to Single-agent Chemotherapy to Treat Patient With Breast Cancer Metastatic to Brain

Information source: Duke University
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Breast Cancer

Intervention: Bevacizumab (Drug); Docetaxel (Drug); CPT-11 (Drug); Paclitaxel (Drug); Vinorelbine Tartrate (Drug); Gemcitabine (Drug)

Phase: Phase 2

Status: Terminated

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
Kimberly Blackwell, MD, Principal Investigator, Affiliation: Duke University


Our hypothesis is that this study design, in which bevacizumab is added to one of six single agent chemotherapies with proven activity in metastatic breast cancer, will result in regression or stabilization of this disease in a safe and tolerable manner.

Clinical Details

Official title: A Phase II Safety and Tolerability Study of Avastin When Added to Single-agent Chemotherapy to Treat Patient With Breast Cancer Metastatic to Brain

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Safety and Tolerability Will be Assessed According to Standard (CTCAE Version 3.0) Toxicity Reporting Criteria.

Determining the Safety and Tolerability of Adding Avastin to Single Agent Chemotherapy to Treat Patients With Brain Metastasis Originating From Breast Cancer

Secondary outcome:

Assess the Activity of Avastin When Added to Single Agent Chemotherapy, as Measured by Radiographic Response Rate,Progression Free Survival, and Overall Survival.

To Assess the Quality of Life During Treatment With This Therapeutic Approach

Detailed description: There is an unmet clinical need for effective therapy of breast cancer that has metastasized to the brain. In this scenario, median survival is around 12 months using currently available therapeutic interventions. The majority of chemotherapy-based clinical trials have considered the presence of central nervous system metastasis an exclusion criterion due to the risk of toxicities, the inability of chemotherapeutic agents to cross the blood brain barrier, and the limited overall survival within this patient population. The preclinical data regarding the safety and activity of bevacizumab in vascular endothelial growth factor(VEGF)-expressing tumors provide a good rationale for its study in patients with breast cancer with metastasis to the brain. Yano, et al. illustrated that tumor cell expression of VEGF messenger ribonucleic acid and protein directly correlated with angiogenesis and growth of brain metastasis in a nude mouse model. Transfecting the experimental cell lines known to produce visceral metastasis with an anti-sense VEGF-gene significantly reduced the incidence of brain metastasis. Kim, et al. illustrated that a murine model specific for brain metastases originating from breast cancer showed elevated expression of the angiogenic and permeability-inducing factor VEGF-A. The growth of the brain metastases in this model was attenuated by the addition of a VEGF-tyrosine kinase inhibitor via induction of apoptosis and decreased angiogenesis. VEGF has also been implicated in the development of brain edema, a significant source of the morbidity and mortality associated with brain metastasis. Enhanced levels of VEGF and its receptors have been reported in a murine model after induction of cortical ischemia. Finally, antagonism of VEGF was demonstrated to reduce both immediate and delayed volume of infarct. The optimal dose of bevacizumab has been extensively studied in phase I trials alone and in combination with chemotherapy. The safe and effective dose has been established as 10 mg/kg q 14 days or 15 mg/kg Q 21 days. In addition to irinotecan and paclitaxel, it has been previously used in phase II/III settings in combination with capecitabine, vinorelbine, gemcitabine, and docetaxel. Phase III studies showed an overall survival advantage when bevacizumab was added to an irinotecan/Fluorouracil (5FU)-based regimen for metastatic colorectal cancer, and when added to weekly paclitaxel for metastatic breast cancer.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Female.


Inclusion Criteria:

- Female, 18+, with evaluable metastatic breast cancer and stable brain metastases

- Must have received definitive radiotherapy

- No evidence, or history of, central nervous system hemorrhage

- Adequate organ and hematological function

Exclusion Criteria:

- Active infection, non-healing wound, or history of any bleeding diathesis or


- Uncontrolled hypertension, congestive heart failure, peripheral vascular disease

Locations and Contacts

Palm Beach Cancer Center Institute, West Palm Beach, Florida 33401-3406, United States

Presbyterian Health Care, Charlotte, North Carolina 28204, United States

Duke University Medical Center, Durham, North Carolina 27710, United States

Virginia Oncology Associates, Newport News, Virginia 23606, United States

Additional Information

Related publications:

Kirsch DG, Loeffler JS. Brain metastases in patients with breast cancer: new horizons. Clin Breast Cancer. 2005 Jun;6(2):115-24. Review.

Boogerd W, Vos VW, Hart AA, Baris G. Brain metastases in breast cancer; natural history, prognostic factors and outcome. J Neurooncol. 1993 Feb;15(2):165-74.

Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol. 2004 Sep 1;22(17):3608-17. Review.

Gaspar L, Scott C, Rotman M, Asbell S, Phillips T, Wasserman T, McKenna WG, Byhardt R. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997 Mar 1;37(4):745-51.

Engel J, Eckel R, Aydemir U, Aydemir S, Kerr J, Schlesinger-Raab A, Dirschedl P, Hölzel D. Determinants and prognoses of locoregional and distant progression in breast cancer. Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1186-95.

Patchell RA, Tibbs PA, Walsh JW, Dempsey RJ, Maruyama Y, Kryscio RJ, Markesbery WR, Macdonald JS, Young B. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990 Feb 22;322(8):494-500.

Lederman G, Wronski M, Fine M. Fractionated radiosurgery for brain metastases in 43 patients with breast carcinoma. Breast Cancer Res Treat. 2001 Jan;65(2):145-54.

Firlik KS, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for brain metastases from breast cancer. Ann Surg Oncol. 2000 Jun;7(5):333-8.

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971 Nov 18;285(21):1182-6. Review.

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003 Jun;9(6):669-76. Review.

Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM. Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res. 1995 Sep 15;55(18):3964-8.

Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, Senger DR, Connolly JL, Schnitt SJ. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995 Jan;26(1):86-91.

Na X, Wu G, Ryan CK, Schoen SR, di'Santagnese PA, Messing EM. Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas. J Urol. 2003 Aug;170(2 Pt 1):588-92.

Fontanini G, Bigini D, Vignati S, Basolo F, Mussi A, Lucchi M, Chine S, Angeletti CA, Harris AL, Bevilacqua G. Microvessel count predicts metastatic disease and survival in non-small cell lung cancer. J Pathol. 1995 Sep;177(1):57-63.

Schneider BP, Miller KD. Angiogenesis of breast cancer. J Clin Oncol. 2005 Mar 10;23(8):1782-90. Review.

Relf M, LeJeune S, Scott PA, Fox S, Smith K, Leek R, Moghaddam A, Whitehouse R, Bicknell R, Harris AL. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997 Mar 1;57(5):963-9.

Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 1999 Sep;56(3):794-814. Review.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.

Miller KD, et al. E2100: a randomized phase III trial of paclitaxel vs paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proc: ASCO 2005; (#3) (Abstract).

Yano S, Shinohara H, Herbst RS, Kuniyasu H, Bucana CD, Ellis LM, Davis DW, McConkey DJ, Fidler IJ. Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis. Cancer Res. 2000 Sep 1;60(17):4959-67.

Salmaggi A, Eoli M, Frigerio S, Silvani A, Gelati M, Corsini E, Broggi G, Boiardi A. Intracavitary VEGF, bFGF, IL-8, IL-12 levels in primary and recurrent malignant glioma. J Neurooncol. 2003 May;62(3):297-303.

Kim LS, Huang S, Lu W, Lev DC, Price JE. Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis. 2004;21(2):107-18.

Lamszus K, Ulbricht U, Matschke J, Brockmann MA, Fillbrandt R, Westphal M. Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res. 2003 Apr;9(4):1399-405.

Godard S, Getz G, Delorenzi M, Farmer P, Kobayashi H, Desbaillets I, Nozaki M, Diserens AC, Hamou MF, Dietrich PY, Regli L, Janzer RC, Bucher P, Stupp R, de Tribolet N, Domany E, Hegi ME. Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes. Cancer Res. 2003 Oct 15;63(20):6613-25.

Birner P, Piribauer M, Fischer I, Gatterbauer B, Marosi C, Ambros PF, Ambros IM, Bredel M, Oberhuber G, Rössler K, Budka H, Harris AL, Hainfellner JA. Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypes. Brain Pathol. 2003 Apr;13(2):133-43.

Stefanik DF, Fellows WK, Rizkalla LR, Rizkalla WM, Stefanik PP, Deleo AB, Welch WC. Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol. 2001 Nov;55(2):91-100.

Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, Reimann JD, Vassel A. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003 Oct;30(5 Suppl 16):117-24.

Vrendenburgh JJ, et al. Bevacizumab, a monoclonal antibody to VEGF, and irinotecan for the treatment of malignant gliomas. Proc: ASCO 2006;24(18S):1506.

van Bruggen N, Thibodeaux H, Palmer JT, Lee WP, Fu L, Cairns B, Tumas D, Gerlai R, Williams SP, van Lookeren Campagne M, Ferrara N. VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest. 1999 Dec;104(11):1613-20.

Kovács Z, Ikezaki K, Samoto K, Inamura T, Fukui M. VEGF and flt. Expression time kinetics in rat brain infarct. Stroke. 1996 Oct;27(10):1865-72; discussion 1872-3.

Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9.

Burstin HJ, et al. Phase II trial of anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer. Breast Can Res Treat 2002;76(supp 1):S115.

Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA, Karrison T, Dachman A, Stadler WM, Vokes EE. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005 Nov 1;23(31):8033-40.

Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, Allen J, Rhoades C, Kendra K, Chen HX, Eckhardt SG, Shapiro CL. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res. 2006 May 15;12(10):3124-9.

Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990 Jul;8(7):1277-80.

Jung SH, Lee T, Kim K, George SL. Admissible two-stage designs for phase II cancer clinical trials. Stat Med. 2004 Feb 28;23(4):561-9.

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat Assoc 1958;43:457-81.

Starting date: May 2007
Last updated: July 15, 2013

Page last updated: August 20, 2015

-- advertisement -- The American Red Cross
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017