A Phase II Study of Neoadjuvant Trastuzumab+Docetaxel+NPLD+/-Bevacizumab in Her2-pos. Early Breast Cancer

NCT01367028 | Completed Phase 2 DMC

• 2 other identifiers: ABCSG 322010-023324-25
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 11

Brief Summary

Multicenter randomised phase II study of neoadjuvant therapy in HER2 positive early breast cancer. Primary aim is to evaluate the cardiac toxicity of the combined treatment (trastuzumab, docetaxel, bevacizumab, NPLD) in comparison to the standard therapy.

Conditions

Breast Cancer

Keywords

HER2-positive early breast cancer

Outcome Measures

Primary Outcomes (1)

• Cardiac toxicity

  to evaluate the cardiac toxicity of the combination trastuzumab+docetaxel+bevacizumab and trastuzumab+docetaxel+NPLD +/- bevacizumab in comparison to the standard therapy, trastuzumab+docetaxel using a composite endpoint appearing between day 1 of cycle 1 and day 28 after the day of final surgery.

  between day 1 of cycle 1 and day 28 after the day of final surgery

Secondary Outcomes (4)

• Pathological complete response (ypCR)

  up to 22 weeks

• Total pathological complete response (ytpCR)

  up to 22 weeks

• Overall clinical response rate (cORR)

  up to 22 weeks

• Safety evaluation according to patients numbers of AEs, SAEs, lab test abnormalities, cardiac assessment, clinical evaluation

  up to 22 weeks

Study Arms (4)

A: Trastuzumab+Docetaxel

OTHER

Drug: Trastuzumab, Docetaxel

B: Trastuzumab+Docetaxel+Bevacizumab

EXPERIMENTAL

Drug: Trastuzumab, Docetaxel, Bevacizumab

C: Trastuzumab+Docetaxel+NPLD

EXPERIMENTAL

Drug: Trastuzumab+Docetaxel+NPLD

D: Trastuzumab+Docetaxel+NPLD+Bevacizumab

EXPERIMENTAL

Drug: Trastuzumab+Docetaxel+NPLD+Bevacizumab

Interventions

Trastuzumab, Docetaxel DRUG

6 cycles - Day1 (Day22 = Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 100 mg/m2 by 60 min i.v. infusion

Also known as: Therapy Arm A

A: Trastuzumab+Docetaxel

Trastuzumab, Docetaxel, Bevacizumab DRUG

6 cycles - Day1 (Day22 = Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 100 mg/m2 by 60 min i.v. infusion Bevacizumab 15 mg/kg

Also known as: Therapy Arm B

B: Trastuzumab+Docetaxel+Bevacizumab

Trastuzumab+Docetaxel+NPLD DRUG

6 cycles - Day1 (Day22=Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 75 mg/m2 by 60 min IV infusion NPLD 50 mg/m2 by 60 min i.v. infusion

Also known as: Therapy Arm C

C: Trastuzumab+Docetaxel+NPLD

Trastuzumab+Docetaxel+NPLD+Bevacizumab DRUG

6 cycles - Day1 (Day22= Day1): Trastuzumab: 8 mg/kg loading dose (1st cycle) i.v.; 6 mg/kg maintenance dose in subsequent cycles i.v. Docetaxel: 75 mg/m2 by 60 min i.v. infusion NPLD: 50 mg/m2 by 60 min i.v. infusion; Bevacizumab 15 mg/kg

Also known as: Therapy Arm D

D: Trastuzumab+Docetaxel+NPLD+Bevacizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female or male, age ≥ 18 years
• Pathologically confirmed invasive primary breast adenocarcinoma (except inflammatory breast cancer, T4d) scheduled for taxane containing neoadjuvant systemic treatment with/without palpable lymph nodes.
• Documented HER2 protein overexpression as determined by immunohistochemistry (IHC) 3+ or by demonstrated HER2/c-erbB2 gene amplification of the primary tumor by a local laboratory.
• LVEF ≥ 55% measured by echocardiography or MUGA within 4 weeks before randomization
• ECOG Performance Status ≤ 1
• Able and willing to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
• Written Informed Consent

You may not qualify if:

• Current Treatment
• Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.
• Chronic daily treatment with corticosteroids excl. inhaled steroids.
• Chronic daily treatment with aspirin and aspirin analogs or clopidogrel
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization or anticipation of need for major surgery during the course of study treatment
• Current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
• Laboratory
• Inadequate bone marrow function
• Inadequate liver function
• Inadequate renal function
• Patients not receiving anticoagulant medication who have activated partial thromboplastin time (aPTT) within 7 days prior to Day1 of the cycle 1.
• Concomitant Conditions
• Other malignancy within the last 5 years before randomization except for curatively treated carcinoma in situ of the cervix or non-melanomatous skin cancer
• Evidence of distant metastasis judged clinically and at least by chest-X-ray, liver-sonography and bone scan. If there is any clinical suspicion of brain metastasis, a CT-scan or MRI of the brain must be conducted within 4 weeks prior to randomization.
• Serious concurrent disease which could affect compliance with the protocol or interpretation of results, including, but not limited to:

Sponsors & Collaborators

• Austrian Breast & Colorectal Cancer Study Group: lead
• Hoffmann-La Roche: collaborator
• Cephalon: collaborator

Study Sites (11)

Paracelsus Medical University Salzburg-Oncology, Coop. Group

Salzburg, Salzburg, 5020, Austria

Location

Medical University of Graz-Oncology; Coop. Group

Graz, Styria, 8036, Austria

Location

State Hospital Leoben

Leoben, Styria, 8700, Austria

Location

Gynaegological Medical University Innsbruck

Innsbruck, Tyrol, 6020, Austria

Location

District Hospital Kufstein

Kufstein, Tyrol, 6330, Austria

Location

Hospital BHS Linz, Coop. Study Group

Linz, Upper Austria, 4010, Austria

Location

AKH Linz

Linz, Upper Austria, 4020, Austria

Location

Med. Univ. Vienna; General Hospital Vienna

Vienna, Vienna, 1090, Austria

Location

Medical University Vienna, General Hospital

Vienna, Vienna, 1090, Austria

Location

State Hospital Vienna-Hietzing

Vienna, Vienna, 1130, Austria

Location

State Hospital Feldkirch, Coop. Group

Feldkirch, Vorarlberg, 6807, Austria

Location

Related Publications (114)

• Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. doi: 10.1093/annonc/mdh393.

  PMID: 15367414 BACKGROUND

• Clark GM, Sledge GW Jr, Osborne CK, McGuire WL. Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol. 1987 Jan;5(1):55-61. doi: 10.1200/JCO.1987.5.1.55.

  PMID: 3806159 BACKGROUND

• 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. doi: 10.1053/j.seminoncol.2003.08.013.

  PMID: 14613032 BACKGROUND

• Coleman MP, Gatta G, Verdecchia A, Esteve J, Sant M, Storm H, Allemani C, Ciccolallo L, Santaquilani M, Berrino F; EUROCARE Working Group. EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann Oncol. 2003;14 Suppl 5:v128-49. doi: 10.1093/annonc/mdg756. No abstract available.

  PMID: 14684503 BACKGROUND

• Cortes J, Di Cosimo S, Climent MA, Cortes-Funes H, Lluch A, Gascon P, Mayordomo JI, Gil M, Benavides M, Cirera L, Ojeda B, Rodriguez CA, Trigo JM, Vazquez J, Regueiro P, Dorado JF, Baselga J; Spanish Breast Cancer Cooperative Group SOLTI. Nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and trastuzumab in HER-2-overexpressing breast cancer: a multicenter phase I/II study. Clin Cancer Res. 2009 Jan 1;15(1):307-14. doi: 10.1158/1078-0432.CCR-08-1113.

  PMID: 19118059 BACKGROUND

• Crown J, O'Leary M, Ooi WS. Docetaxel and paclitaxel in the treatment of breast cancer: a review of clinical experience. Oncologist. 2004;9 Suppl 2:24-32. doi: 10.1634/theoncologist.9-suppl_2-24.

  PMID: 15161988 BACKGROUND

• Eskens FA. Angiogenesis inhibitors in clinical development; where are we now and where are we going? Br J Cancer. 2004 Jan 12;90(1):1-7. doi: 10.1038/sj.bjc.6601401.

  PMID: 14710197 BACKGROUND

• Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. doi: 10.1210/edrv.18.1.0287. No abstract available.

  PMID: 9034784 BACKGROUND

• Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851-8. doi: 10.1016/0006-291x(89)92678-8.

  PMID: 2735925 BACKGROUND

• Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9 Suppl 1:2-10. doi: 10.1634/theoncologist.9-suppl_1-2.

  PMID: 15178810 BACKGROUND

• Folkman J. What is the role of thymidine phosphorylase in tumor angiogenesis. J Natl Cancer Inst. 1996 Aug 21;88(16):1091-2. doi: 10.1093/jnci/88.16.1091. No abstract available.

  PMID: 8757181 BACKGROUND

• Fountzilas G, Razis E, Tsavdaridis D, Karina M, Labropoulos S, Christodoulou C, Mavroudis D, Gogas H, Georgoulias V, Skarlos D. Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the hellenic cooperative oncology group. Clin Breast Cancer. 2003 Jun;4(2):120-5. doi: 10.3816/cbc.2003.n.017.

  PMID: 12864940 BACKGROUND

• Gelmon KA, Mackey J, Verma S, Gertler SZ, Bangemann N, Klimo P, Schneeweiss A, Bremer K, Soulieres D, Tonkin K, Bell R, Heinrich B, Grenier D, Dias R. Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories. Clin Breast Cancer. 2004 Apr;5(1):52-8; discussion 59-62. doi: 10.3816/cbc.2004.n.010.

  PMID: 15140285 BACKGROUND

• Gerber HP, Ferrara N. Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in combination with cytotoxic therapy in preclinical studies. Cancer Res. 2005 Feb 1;65(3):671-80.

  PMID: 15705858 BACKGROUND

• Giordano SH, Duan Z, Kuo YF, Hortobagyi GN, Freeman J, Goodwin JS. Impact of a scientific presentation on community treatment patterns for primary breast cancer. J Natl Cancer Inst. 2006 Mar 15;98(6):382-8. doi: 10.1093/jnci/djj090.

  PMID: 16537830 BACKGROUND

• Greene FL, Page DL Fleming ID et al. eds. AJCC Cancer Staging Handbook. 6th Edition. 2002; Springer

  BACKGROUND

• Griffiths L, Dachs GU, Bicknell R, Harris AL, Stratford IJ. The influence of oxygen tension and pH on the expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast tumor cells grown in vitro and in vivo. Cancer Res. 1997 Feb 15;57(4):570-2.

  PMID: 9044826 BACKGROUND

• Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E; TLC D-99 Study Group. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002 Jan 1;94(1):25-36. doi: 10.1002/cncr.10201.

  PMID: 11815957 BACKGROUND

• Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005 Feb 10;23(5):1011-27. doi: 10.1200/JCO.2005.06.081. Epub 2004 Dec 7.

  PMID: 15585754 BACKGROUND

• Bonneterre ME, Bonneterre J. Reply to the article

  BACKGROUND

• Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):188S-203S. doi: 10.1378/chest.126.3_suppl.188S.

  PMID: 15383472 BACKGROUND

• Hotchkiss KA, Ashton AW, Mahmood R, Russell RG, Sparano JA, Schwartz EL. Inhibition of endothelial cell function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired repositioning of the microtubule organizing center. Mol Cancer Ther. 2002 Nov;1(13):1191-200.

  PMID: 12479700 BACKGROUND

• Itakura J, Ishiwata T, Shen B, Kornmann M, Korc M. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer. 2000 Jan 1;85(1):27-34. doi: 10.1002/(sici)1097-0215(20000101)85:13.0.co;2-8.

  PMID: 10585578 BACKGROUND

• Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature. 2002 Mar 21;416(6878):279-80. doi: 10.1038/416279b.

  PMID: 11907566 BACKGROUND

• Jain D. Cardiotoxicity of doxorubicin and other anthracycline derivatives. J Nucl Cardiol. 2000 Jan-Feb;7(1):53-62. doi: 10.1067/mnc.2000.103324. No abstract available.

  PMID: 10698235 BACKGROUND

• Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001 Sep;7(9):987-9. doi: 10.1038/nm0901-987. No abstract available.

  PMID: 11533692 BACKGROUND

• Jiang BH, Agani F, Passaniti A, Semenza GL. V-SRC induces expression of hypoxia-inducible factor 1 (HIF-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1: involvement of HIF-1 in tumor progression. Cancer Res. 1997 Dec 1;57(23):5328-35.

  PMID: 9393757 BACKGROUND

• Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. doi: 10.1200/JCO.2005.02.027.

  PMID: 16110015 BACKGROUND

• Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004 Jun;4(6):423-36. doi: 10.1038/nrc1369. No abstract available.

  PMID: 15170445 BACKGROUND

• Kieser A, Weich HA, Brandner G, Marme D, Kolch W. Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene. 1994 Mar;9(3):963-9.

  PMID: 8108142 BACKGROUND

• Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993 Apr 29;362(6423):841-4. doi: 10.1038/362841a0.

  PMID: 7683111 BACKGROUND

• Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000 Apr;105(8):R15-24. doi: 10.1172/JCI8829.

  PMID: 10772661 BACKGROUND

• Konecny GE, Meng YG, Untch M, Wang HJ, Bauerfeind I, Epstein M, Stieber P, Vernes JM, Gutierrez J, Hong K, Beryt M, Hepp H, Slamon DJ, Pegram MD. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res. 2004 Mar 1;10(5):1706-16. doi: 10.1158/1078-0432.ccr-0951-3.

  PMID: 15014023 BACKGROUND

• Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y. Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000 Oct 1;60(19):5565-70.

  PMID: 11034104 BACKGROUND

• Leyland-Jones B, Gelmon K, Ayoub JP, Arnold A, Verma S, Dias R, Ghahramani P. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003 Nov 1;21(21):3965-71. doi: 10.1200/JCO.2003.12.109. Epub 2003 Sep 24.

  PMID: 14507946 BACKGROUND

• Linderholm BK, Lindahl T, Holmberg L, Klaar S, Lennerstrand J, Henriksson R, Bergh J. The expression of vascular endothelial growth factor correlates with mutant p53 and poor prognosis in human breast cancer. Cancer Res. 2001 Mar 1;61(5):2256-60.

  PMID: 11280795 BACKGROUND

• Liu CD, Tilch L, Kwan D, McFadden DW. Vascular endothelial growth factor is increased in ascites from metastatic pancreatic cancer. J Surg Res. 2002 Jan;102(1):31-4. doi: 10.1006/jsre.2001.6307.

  PMID: 11792148 BACKGROUND

• Marty M, Espie M, Cottu PH, Cuvier C, Lerebours F. Optimizing chemotherapy for patients with advanced breast cancer. Oncology. 1999 Jul;57 Suppl 1:21-6. doi: 10.1159/000055265.

  PMID: 10436413 BACKGROUND

• Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Anton A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. doi: 10.1200/JCO.2005.04.173. Epub 2005 May 23.

  PMID: 15911866 BACKGROUND

• Mayer LD, Tai LC, Ko DS, Masin D, Ginsberg RS, Cullis PR, Bally MB. Influence of vesicle size, lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res. 1989 Nov 1;49(21):5922-30.

  PMID: 2790807 BACKGROUND

• Menard S, Casalini P, Tomasic G, Pilotti S, Cascinelli N, Bufalino R, Perrone F, Longhi C, Rilke F, Colnaghi MI. Pathobiologic identification of two distinct breast carcinoma subsets with diverging clinical behaviors. Breast Cancer Res Treat. 1999 May;55(2):169-77. doi: 10.1023/a:1006262324959.

  PMID: 10481944 BACKGROUND

• 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. doi: 10.1200/JCO.2005.05.098.

  PMID: 15681523 BACKGROUND

• Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. doi: 10.1056/NEJMoa072113.

  PMID: 18160686 BACKGROUND

• Miwa M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, Shimma N, Umeda I, Ishitsuka H. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer. 1998 Jul;34(8):1274-81. doi: 10.1016/s0959-8049(98)00058-6.

  PMID: 9849491 BACKGROUND

• Moghaddam A, Zhang HT, Fan TP, Hu DE, Lees VC, Turley H, Fox SB, Gatter KC, Harris AL, Bicknell R. Thymidine phosphorylase is angiogenic and promotes tumor growth. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):998-1002. doi: 10.1073/pnas.92.4.998.

  PMID: 7532308 BACKGROUND

• Mross K, Niemann B, Massing U, Drevs J, Unger C, Bhamra R, Swenson CE. Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study. Cancer Chemother Pharmacol. 2004 Dec;54(6):514-24. doi: 10.1007/s00280-004-0825-y. Epub 2004 Aug 21.

  PMID: 15322827 BACKGROUND

• Mukhopadhyay D, Tsiokas L, Sukhatme VP. Wild-type p53 and v-Src exert opposing influences on human vascular endothelial growth factor gene expression. Cancer Res. 1995 Dec 15;55(24):6161-5.

  PMID: 8521408 BACKGROUND

• Paterson MC, Dietrich KD, Danyluk J, Paterson AH, Lees AW, Jamil N, Hanson J, Jenkins H, Krause BE, McBlain WA, et al. Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer. Cancer Res. 1991 Jan 15;51(2):556-67.

  PMID: 1670762 BACKGROUND

• Petit AM, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, Kerbel RS. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997 Dec;151(6):1523-30.

  PMID: 9403702 BACKGROUND

• Piccart M. Treatment of advanced breast cancer: current status. Anticancer Drugs. 1996 Aug;7 Suppl 2:5-7.

  PMID: 8862702 BACKGROUND

• Piccart MJ, Di Leo A. Future perspectives of docetaxel (Taxotere) in front-line therapy. Semin Oncol. 1997 Aug;24(4 Suppl 10):S10-27-S10-33.

  PMID: 9275004 BACKGROUND

• Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 1995 Oct 15;55(20):4575-80.

  PMID: 7553632 BACKGROUND

• 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. doi: 10.1158/1078-0432.CCR-05-2603.

  PMID: 16707611 BACKGROUND

• 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.

  PMID: 9041202 BACKGROUND

• Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. doi: 10.1056/NEJMoa052122.

  PMID: 16236738 BACKGROUND

• Ross JS, Fletcher JA. The HER-2/neu oncogene in breast cancer: prognostic factor, predictive factor, and target for therapy. Stem Cells. 1998;16(6):413-28. doi: 10.1002/stem.160413.

  PMID: 9831867 BACKGROUND

• Schaller G, Fuchs I, Gonsch T, Weber J, Kleine-Tebbe A, Klare P, Hindenburg HJ, Lakner V, Hinke A, Bangemann N. Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. J Clin Oncol. 2007 Aug 1;25(22):3246-50. doi: 10.1200/JCO.2006.09.6826. Epub 2007 Jun 18.

  PMID: 17577021 BACKGROUND

• Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D'Amato RJ, Kerbel RS. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell. 2005 Jan;7(1):101-11. doi: 10.1016/j.ccr.2004.11.023.

  PMID: 15652753 BACKGROUND

• Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999 Aug;26(4 Suppl 12):60-70.

  PMID: 10482195 BACKGROUND

• Stemmler HJ, Kahlert S, Siekiera W, Untch M, Heinrich B, Heinemann V. Prolonged survival of patients receiving trastuzumab beyond disease progression for HER2 overexpressing metastatic breast cancer (MBC). Onkologie. 2005 Nov;28(11):582-6. doi: 10.1159/000088296.

  PMID: 16249644 BACKGROUND

• Sumizawa T, Furukawa T, Haraguchi M, Yoshimura A, Takeyasu A, Ishizawa M, Yamada Y, Akiyama S. Thymidine phosphorylase activity associated with platelet-derived endothelial cell growth factor. J Biochem. 1993 Jul;114(1):9-14. doi: 10.1093/oxfordjournals.jbchem.a124146.

  PMID: 8407883 BACKGROUND

• Sweeney CJ, Miller KD, Sissons SE, Nozaki S, Heilman DK, Shen J, Sledge GW Jr. The antiangiogenic property of docetaxel is synergistic with a recombinant humanized monoclonal antibody against vascular endothelial growth factor or 2-methoxyestradiol but antagonized by endothelial growth factors. Cancer Res. 2001 Apr 15;61(8):3369-72.

  PMID: 11309294 BACKGROUND

• Swenson CE, Bolcsak LE, Batist G, Guthrie TH Jr, Tkaczuk KH, Boxenbaum H, Welles L, Chow SC, Bhamra R, Chaikin P. Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer. Anticancer Drugs. 2003 Mar;14(3):239-46. doi: 10.1097/00001813-200303000-00008.

  PMID: 12634619 BACKGROUND

• Theodoulou M, Batist G, Campos S, Winer E, Welles L, Hudis C. Phase I study of nonpegylated liposomal doxorubicin plus trastuzumab in patients with HER2-positive breast cancer. Clin Breast Cancer. 2009 May;9(2):101-7. doi: 10.3816/CBC.2009.n.019.

  PMID: 19433391 BACKGROUND

• Toi M, Hoshina S, Taniguchi T, Yamamoto Y, Ishitsuka H, Tominaga T. Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase in human breast cancer. Int J Cancer. 1995 Apr 21;64(2):79-82. doi: 10.1002/ijc.2910640202.

  PMID: 7542228 BACKGROUND

• Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004 Jun 1;64(11):3731-6. doi: 10.1158/0008-5472.CAN-04-0074.

  PMID: 15172975 BACKGROUND

• Tripathy D, Slamon DJ, Cobleigh M, Arnold A, Saleh M, Mortimer JE, Murphy M, Stewart SJ. Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol. 2004 Mar 15;22(6):1063-70. doi: 10.1200/JCO.2004.06.557.

  PMID: 15020607 BACKGROUND

• Vukelja SJ, Lombardo FA, James WD, Weiss RB. Pyridoxine for the palmar-plantar erythrodysesthesia syndrome. Ann Intern Med. 1989 Oct 15;111(8):688-9. doi: 10.7326/0003-4819-111-8-688. No abstract available.

  PMID: 2529807 BACKGROUND

• Vukelja SJ, Baker WJ, Burris HA 3rd, Keeling JH, Von Hoff D. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with taxotere. J Natl Cancer Inst. 1993 Sep 1;85(17):1432-3. doi: 10.1093/jnci/85.17.1432. No abstract available.

  PMID: 8102408 BACKGROUND

• Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest. 1995 Apr;95(4):1789-97. doi: 10.1172/JCI117857.

  PMID: 7535799 BACKGROUND

• Xeloda® (Capecitabine) Investigator Brochure, 9th Version August 2007

  BACKGROUND

• Yap R, Veliceasa D, Emmenegger U, Kerbel RS, McKay LM, Henkin J, Volpert OV. Metronomic low-dose chemotherapy boosts CD95-dependent antiangiogenic effect of the thrombospondin peptide ABT-510: a complementation antiangiogenic strategy. Clin Cancer Res. 2005 Sep 15;11(18):6678-85. doi: 10.1158/1078-0432.CCR-05-0621.

  PMID: 16166447 BACKGROUND

• Yen L, You XL, Al Moustafa AE, Batist G, Hynes NE, Mader S, Meloche S, Alaoui-Jamali MA. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene. 2000 Jul 20;19(31):3460-9. doi: 10.1038/sj.onc.1203685.

  PMID: 10918604 BACKGROUND

• Amadori D, Gasparini G, Ardizzoni A, Comella G, Saracchini S, Barone C, Bordonaro R, et al. Phase II study of liposomal doxorubicin (Myocet®), docetaxel and trastuzumab combination as first line treatment of patients with HER-2/neu positive locally advanced or metastatic breast cancer. Cancer Res 2009; 69 (Suppl.): (2).January 15, 3149

  RESULT

• Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126(3 Suppl):204S-233S. doi: 10.1378/chest.126.3_suppl.204S.

  PMID: 15383473 RESULT

• Antón A, Ruiz-Simón A, Plazaola A, Calvo L, Segui M. A, Santabella A, Muňoz M, et al. Phase II study of a 3-weekly liposome-encapsulated doxorubicin/docetaxel/pegfilgrastim in combination with weekly trastuzumab as primary treatment in HER2 positive (HER+) early stage cancer patients (II-IIIa). GEICAM 2003-03 study. Cancer Res 2009; 69 (Suppl.): (2).January 15, 5117

  RESULT

• Avastin® (Bevacizumab) Investigator Brochure, Fifteenth Version: November 2007

  RESULT

• Balazsovits JA, Mayer LD, Bally MB, Cullis PR, McDonell M, Ginsberg RS, Falk RE. Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor efficacy of doxorubicin. Cancer Chemother Pharmacol. 1989;23(2):81-6. doi: 10.1007/BF00273522.

  PMID: 2491964 RESULT

• Bartsch R, Wenzel C, Hussian D, Pluschnig U, Sevelda U, Koestler W, Altorjai G, Locker GJ, Mader R, Zielinski CC, Steger GG. Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: an observational study. BMC Cancer. 2006 Mar 15;6:63. doi: 10.1186/1471-2407-6-63.

  PMID: 16539726 RESULT

• Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, Gnant M, Zielinski CC, Steger GG. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. doi: 10.1200/JCO.2007.11.9776. Epub 2007 Aug 6.

  PMID: 17679724 RESULT

• Barton GJ, Ponting CP, Spraggon G, Finnis C, Sleep D. Human platelet-derived endothelial cell growth factor is homologous to Escherichia coli thymidine phosphorylase. Protein Sci. 1992 May;1(5):688-90. doi: 10.1002/pro.5560010514. No abstract available.

  PMID: 1304367 RESULT

• Batist G, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol. 2001 Mar 1;19(5):1444-54. doi: 10.1200/JCO.2001.19.5.1444.

  PMID: 11230490 RESULT

• Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS. Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res. 2003 Aug 1;63(15):4342-6.

  PMID: 12907602 RESULT

• Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, Osterwalder B. Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer. 2001 Oct 1;92(7):1759-68. doi: 10.1002/1097-0142(20011001)92:73.0.co;2-a.

  PMID: 11745247 RESULT

• Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, Osterwalder B, Burger HU, Brown CS, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999 Feb;17(2):485-93. doi: 10.1200/JCO.1999.17.2.485.

  PMID: 10080589 RESULT

• Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res. 1999 Sep-Oct;19(5B):4203-14.

  PMID: 10628376 RESULT

• Budman DR, Meropol NJ, Reigner B, Creaven PJ, Lichtman SM, Berghorn E, Behr J, Gordon RJ, Osterwalder B, Griffin T. Preliminary studies of a novel oral fluoropyrimidine carbamate: capecitabine. J Clin Oncol. 1998 May;16(5):1795-802. doi: 10.1200/JCO.1998.16.5.1795.

  PMID: 9586893 RESULT

• Phase II trial of the anti-VEGF antibody bevacizumab in combination with vinorelbine for refractory advanced breast cancer [abstract 446]. Breast Cancer Res Treat 2002;76:S115

  RESULT

• Browder T, Butterfield CE, Kraling BM, Shi B, Marshall B, O'Reilly MS, Folkman J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000 Apr 1;60(7):1878-86.

  PMID: 10766175 RESULT

• Chan S, Friedrichs K, Noel D, Pinter T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, Gonzalez Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. doi: 10.1200/JCO.1999.17.8.2341.

  PMID: 10561296 RESULT

• Epstein M, Ayala R, Tchekmedyian N et al. HER-2/neu-overexpressing human breast cancer xenografts exhibit increased angiogenic potential mediated by vascular endothelial growth factor (VEGF). Breast Cancer Res. Treat. 2002; 76: S143

  RESULT

• Extra JM, Antoine EC, Vincent-Salomon A et al. Favourable effect of trastuzumab (Herceptin®) treatment in metastatic breast cancer patients: results from the French Hermine cohort study. Poster presentation, 2006 SABCS, San Antonio, Texas

  RESULT

• Hambleton J, Novotny F, Hurwitz H et al. Bevacizumab (Avastin) does not increase the incidence of bleeding in patients with metastatic colorectal cancer receiving simultaneous anticoagulation. ASCO New Orleans 2004,Abstract 3528

  RESULT

• Herceptin® (Trastuzumab) Investigator Brochure, Version: October 5, 2007

  RESULT

• Jackisch C, Eustermann H, Schoenegg W et al. Routine clinical usage of trastuzumab (Herceptin®) in advanced breast cancer in Germany from 2001 to 2006. 2007; Poster Presentation, SABCS

  RESULT

• Jain RK. Antiangiogenic therapy for cancer: current and emerging concepts. Oncology (Williston Park). 2005 Apr;19(4 Suppl 3):7-16.

  PMID: 15934498 RESULT

• Kabbinavar FF, Wong JT, Ayala RE et al. The effect of antibody to vascular endothelia growth factor and cisplatin on the growth of lung tumors in nude mice [abstract]. Proc Am Assoc Cancer Res 1995; 36:488

  RESULT

• Ménard S (on behalf of the Demetra Group). Observational Demetra study: Survival of metastatic breast carcinoma patients after treatment with trastuzumab. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1062)

  RESULT

• Miles D, Chan A, Romieu G et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J Clin Oncol 26:2008 (May 20 Suppl; abstr LBA1011). Presented at the 2008 ASCO Annual Meeting

  RESULT

• Myers CE. Anthracyclines. In: Chabner B, ed. Pharmacologic principles of cancer treatment. Philadelphia: Saunders 1982: xii, 457 p

  RESULT

• O'Shaughnessy J, Blackwell KL, Burstein H et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. J Clin Oncol 26: 2008 (May 20 suppl; abstr 1015)

  RESULT

• Pegram MD, Reese DM. Combined biological therapy of breast cancer using monoclonal antibodies directed against HER2/neu protein and vascular endothelial growth factor. Semin Oncol. 2002 Jun;29(3 Suppl 11):29-37. doi: 10.1053/sonc.2002.34053.

  PMID: 12138395 RESULT

• Pegram M, Chan D, Dichmann RA et al., Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first-line treatment of HER2-amplified breast cancer. 2006; Poster Presentation, SABCS

  RESULT

• Potchoiba MJ, West M, Smolarek TA, Macaione G, Santacroce E, Lundeen GR. Tissue distribution of doxorubicin in the free and liposomal forms in male Beagles. Proc Am Assoc Cancer Res 1996; 37:A2675

  RESULT

• Rugo H, Dickler MN, Scott JH et al. Change in circulating endothelial cells (CEC) and tumor cells (CTC) in patients (pts) receiving bevacizumab and erlotinib for metastatic breast cancer (MBC) predicts stable disease at first evaluation [abstract 525]. J Clin Oncol 2005;23:10s

  RESULT

• Schippinger W, Lileg B, Ploner F, Weitzer W, Bauernhofer TH, Samonigg H. Neoadjuvant chemotherapy with non-pegylated liposomal doxorubicin, docetaxel and trastuzumab in HER-2/neu overexpressing breast cancer. Ann Oncol 2007; 18 (Suppl 9): 28p

  RESULT

• Shweiki D, Itin A, Soffer D et al. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature (Lond.) 1992; 359: 843-845.Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the Her-2/neu oncogene. Science 1987; 235:177-182

  RESULT

• Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707-12. doi: 10.1126/science.2470152.

  PMID: 2470152 RESULT

• Sledge GW, Miller KD, Moisa CF et al. Safety and efficacy of capecitabine plus bevacizumab as first-line treatment in metastatic breast cancer J Clin Oncol 2007; 25: 35s ASCO abstract 1013

  RESULT

• Traina TA, Dickler MN, Caravelli JF et al. A phase II trial of letrozole in combination with bevacizumab, an anti-VEGF antibody, in patients with hormone receptor-positive metastatic breast cancer [abstract 2030]. Breast Cancer Res Treat 2005;94:S93

  RESULT

• Tycznski JE, Bray F and. Parkin DM. Breast cancer in Europe. International Agency for Research on Cancer: European Network of Cancer Registries Cancer Fact Sheet 2002; 2

  RESULT

• Venturini M, Bighin C, Puglisi F, Olmeo N, Aitini E, Colucci G, Garrone O, Paccagnella A, Marini G, Crino L, Mansutti M, Baconnet B, Barbato A, Del Mastro L. A multicentre Phase II study of non-pegylated liposomal doxorubicin in combination with trastuzumab and docetaxel as first-line therapy in metastatic breast cancer. Breast. 2010 Oct;19(5):333-8. doi: 10.1016/j.breast.2010.01.018. Epub 2010 Feb 24.

  PMID: 20185313 RESULT

• Von Minckwitz G, Zielinski C, Maarteense E et al. Capecitabine vs. capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: The TBP phase III study (GBG 26/BIG 3-05). J Clin Oncol 26: 2008 (May 20 suppl; abstr 1025)

  RESULT

• Yardley DA, Hart L, Badarinath S et al. Preliminary results of a multicenter study of bevacizumab with 3 docetaxel-based adjuvant breast cancer regimens. San Antonio Breast Cancer Symposium, 2007, Poster Presentation

  RESULT

Related Links

• ABCSG official website

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Trastuzumab; Docetaxel; Bevacizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Guenther Steger, MD

  Austrian Breast & Colorectal Cancer Study Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2011
• First Posted: June 6, 2011
• Study Start: June 1, 2011
• Primary Completion: April 1, 2014
• Study Completion: April 1, 2014
• Last Updated: May 13, 2014

Record last verified: 2014-05

Locations

AU (11)