Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 1, pp 97–105 | Cite as

Phase I study of BNC105P, carboplatin and gemcitabine in partially platinum-sensitive ovarian cancer patients in first or second relapse (ANZGOG-1103)

  • Kristina Lindemann
  • Philip J. Beale
  • Emma Rossi
  • Jeff C. Goh
  • Michelle M. Vaughan
  • Meaghan E. Tenney
  • Julie K. Martyn
  • Dirkje Sommeijer
  • Jose L. Iglesias
  • Gabriel Kremmidiotis
  • Jeremy Simpson
  • Elizabeth Doolin
  • Tina C. Lavranos
  • Annabell Leske
  • Anneso S. Veillard
  • David Espinoza
  • Martin R. Stockler
  • Danny RischinEmail author
  • For ANZGOG and HCRN Collaborative Groups
Original Article



The primary objective of this study was to determine the recommended dose of the vascular disrupting agent, BNC105P, in combination with gemcitabine and carboplatin in patients with ovarian cancer in first or second relapse with a minimum 4 month progression-free interval after last platinum.


Patients received carboplatin AUC4 on day 1 in combination with escalating doses of 800 or 1000 mg/m2 gemcitabine on days 1 and 8 and escalating doses of 12 or 16 mg/m2 BNC105P on days 2 and 9 every 21 days for a maximum for six cycles. Maintenance treatment with 16 mg/m2 BNC105P treatment continued for a maximum of six additional cycles. Patients were followed for safety and anti-tumor activity.


Fifteen patients were enrolled in the study. Adverse events were most commonly of hematological origin. Dose-limiting toxicities (thrombocytopenia and neutropenia) occurred in two patients at the dose level of 800 mg/m2 gemcitabine, carboplatin AUC4 and 16 mg/m2 BNC105P. No dose-limiting toxicities were observed at a dose level of gemcitabine 1000 mg/m2, carboplatin AUC4 and BNC105P 12 mg/m2. BNC105P as a single agent was well tolerated at a dose of 16 mg/m2 in maintenance treatment. Ten patients (67%) achieved a complete or partial response according to CA125 and/or RECIST response criteria, four of 13 (31%) responded by RECIST alone. The median progression-free survival was 5.9 months.


We have established that BNC105P 12 mg/m2 with gemcitabine 1000 mg/m2 and carboplatin AUC4 is the recommended dose level and has an acceptable toxicity profile. Further exploration of BNC105P in the ovarian cancer setting is planned.


BNC105P Vascular disrupting agent (VDA) Ovarian cancer Phase I Gemcitabine Carboplatin 



We thank Dave Cannon, NHMRC Clinical Trials Centre, for the administrative support during drafting and submission of the manuscript.


This trial was conducted by ANZGOG and HCRN with funding provided by Bionomics.

Compliance with ethical standards

Conflict of interest

Dr. Lindemann, Dr. Veillard, Dr. Espinoza. Dr. Sommeijer, Dr. Rossi, Dr. Simpson, Dr. Tenney, Dr. Goh and Dr. Vaughan declare that they have nothing to disclose. Dr. Lavranos, Ms. Doolin, Ms. Leske and Dr. Kremmidiotis report salary/stakeholder from Bionomics Limited, outside the submitted work. Dr. Iglesias reports salary from Bionomics Limited, outside the submitted work and has a patent on BNC105 pending. Dr. Martyn reports Grants and non-financial support from Bionomics, during the conduct of the study. Dr. Beale reports personal fees from Roche, personal fees from Astra Zeneca, Grants from Roche, outside the submitted work. Dr. Rischin reports a Grant from Bionomics to ANZGOG for the research costs of the study; in addition, Dr. Rischin has a patent B55 (US) BNC105 Triple Combination Patent Application pending and trial steering/scientific advisory committees—Bionomics, Merck, Amgen, Regeneron, Bristol-Myers—all uncompensated. Dr. Stockler reports Grants from Bionomics, during the conduct of the study; Grants from Bayer, Grants from BMS, Grants from Astra Zeneca, Grants from Specialised Therapeutics, Grants from Amgen, Grants from Astellas, Grants from Merck, outside the submitted work.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

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Supplementary material 1 (DOCX 18 KB)
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Supplementary material 2 (DOCX 26 KB)
280_2018_3706_MOESM3_ESM.docx (83 kb)
Supplementary material 3 (DOCX 83 KB)
280_2018_3706_MOESM4_ESM.docx (95 kb)
Supplementary material 4 (DOCX 95 KB)


  1. 1.
    Kumaran GC, Jayson GC, Clamp AR (2009) Antiangiogenic drugs in ovarian cancer. Br J Cancer 100(1):1–7. CrossRefPubMedGoogle Scholar
  2. 2.
    Ye Q, Chen HL (2013) Bevacizumab in the treatment of ovarian cancer: a meta-analysis from four phase III randomized controlled trials. Arch Gynecol Obstet 288(3):655–666. CrossRefPubMedGoogle Scholar
  3. 3.
    Gotlieb WH, Amant F, Advani S, Goswami C, Hirte H, Provencher D, Somani N, Yamada SD, Tamby JF, Vergote I (2012) Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 13(2):154–162. CrossRefPubMedGoogle Scholar
  4. 4.
    Colombo N (2012) A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol 125(1):42–47. CrossRefPubMedGoogle Scholar
  5. 5.
    Tew WP, Colombo N, Ray-Coquard I, Del Campo JM, Oza A, Pereira D, Mammoliti S, Matei D, Scambia G, Tonkin K, Shun Z, Sternas L, Spriggs DR (2014) Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study. Cancer 120(3):335–343. CrossRefPubMedGoogle Scholar
  6. 6.
    Ledermann JA, Embleton AC, Raja F, Perren TJ, Jayson GC, Rustin GJS, Kaye SB, Hirte H, Eisenhauer E, Vaughan M, Friedlander M, Gonzalez-Martin A, Stark D, Clark E, Farrelly L, Swart AM, Cook A, Kaplan RS, Parmar MKB, ICON6 Collaborators (2016) Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 387(10023):1066–1074. CrossRefPubMedGoogle Scholar
  7. 7.
    du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Harter P (2014) Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol 32(30):3374–3382. CrossRefPubMedGoogle Scholar
  8. 8.
    Gaya AM, Rustin GJ (2005) Vascular disrupting agents: a new class of drug in cancer therapy. Clin Oncol (R Coll Radiol) 17(4):277–290CrossRefGoogle Scholar
  9. 9.
    Huang X, Molema G, King S, Watkins L, Edgington TS, Thorpe PE (1997) Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature. Science 275(5299):547–550CrossRefGoogle Scholar
  10. 10.
    Blakey DC, Westwood FR, Walker M, Hughes GD, Davis PD, Ashton SE, Ryan AJ (2002) Antitumor activity of the novel vascular targeting agent ZD6126 in a panel of tumor models. Clin Cancer Res 8(6):1974–1983PubMedGoogle Scholar
  11. 11.
    Tozer GM, Kanthou C, Parkins CS, Hill SA (2002) The biology of the combretastatins as tumour vascular targeting agents. Int J Exp Pathol 83(1):21–38. doi:211 [pii]CrossRefGoogle Scholar
  12. 12.
    Ching LM, Goldsmith D, Joseph WR, Korner H, Sedgwick JD, Baguley BC (1999) Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice. Cancer Res 59(14):3304–3307PubMedGoogle Scholar
  13. 13.
    Kumar-Singh S, Vermeulen PB, Weyler J, Segers K, Weyn B, Van Daele A, Dirix LY, Van Oosterom AT, Van Marck E (1997) Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma. J Pathol 182(2):211–216.;2-D CrossRefPubMedGoogle Scholar
  14. 14.
    Zweifel M, Jayson GC, Reed NS, Osborne R, Hassan B, Ledermann J, Shreeves G, Poupard L, Lu SP, Balkissoon J, Chaplin DJ, Rustin GJ (2011) Phase II trial of combretastatin A4 phosphate, carboplatin, and paclitaxel in patients with platinum-resistant ovarian cancer. Ann Oncol 22(9):2036–2041. CrossRefPubMedGoogle Scholar
  15. 15.
    Rischin D, Bibby DC, Chong G, Kremmidiotis G, Leske AF, Matthews CA, Wong SS, Rosen MA, Desai J (2011) Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation. Clin Cancer Res 17(15):5152–5160. CrossRefPubMedGoogle Scholar
  16. 16.
    Leske AF, Beaumont DM, Lavranos TC, Gasic J, Kremmidiotis J (2011) Anti-tumor activity of the vascular disruption agent BNC105 in models of mesothelioma and lung cancer. In: American Association of Clinical Research, OrlandoGoogle Scholar
  17. 17.
    Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, du Bois A, Kristensen G, Jakobsen A, Sagae S, Greven K, Parmar M, Friedlander M, Cervantes A, Vermorken J, Gynecological Cancer I (2011) Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer Off J Int Gynecol Cancer Soc 21(2):419–423. CrossRefGoogle Scholar
  18. 18.
    National Cancer Institute, US Department of Health and Human Services (2009) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
  19. 19.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pal S, Azad A, Bhatia S, Drabkin H, Costello B, Sarantopoulos J, Kanesvaran R, Lauer R, Starodub A, Hauke R, Sweeney CJ, Hahn NM, Sonpavde G, Richey S, Breen T, Kremmidiotis G, Leske A, Doolin E, Bibby DC, Simpson J, Iglesias J, Hutson T (2015) A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma. Clin Cancer Res 21(15):3420–3427. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Pfisterer J, Plante M, Vergote I, du Bois A, Hirte H, Lacave AJ, Wagner U, Stahle A, Stuart G, Kimmig R, Olbricht S, Le T, Emerich J, Kuhn W, Bentley J, Jackisch C, Luck HJ, Rochon J, Zimmermann AH, Eisenhauer E (2006) Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24(29):4699–4707. CrossRefPubMedGoogle Scholar
  22. 22.
    Bilenker JH, Flaherty KT, Rosen M, Davis L, Gallagher M, Stevenson JP, Sun W, Vaughn D, Giantonio B, Zimmer R, Schnall M, O’Dwyer PJ (2005) Phase I trial of combretastatin a-4 phosphate with carboplatin. Clin Cancer Res 11(4):1527–1533. CrossRefPubMedGoogle Scholar
  23. 23.
    Anderson HL, Yap JT, Miller MP, Robbins A, Jones T, Price PM (2003) Assessment of pharmacodynamic vascular response in a phase I trial of combretastatin A4 phosphate. J Clin Oncol 21(15):2823–2830. CrossRefPubMedGoogle Scholar
  24. 24.
    Rustin GJ, Shreeves G, Nathan PD, Gaya A, Ganesan TS, Wang D, Boxall J, Poupard L, Chaplin DJ, Stratford MR, Balkissoon J, Zweifel M (2010) A Phase Ib trial of CA4P (combretastatin A-4 phosphate), carboplatin, and paclitaxel in patients with advanced cancer. Br J Cancer 102(9):1355–1360. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bionomics Investigators Brochure BNC105P, version 6, vol 6Google Scholar
  26. 26.
    Nowak AK, Brown C, Millward MJ, Creaney J, Byrne MJ, Hughes B, Kremmidiotis G, Bibby DC, Leske AF, Mitchell PL, Pavlakis N, Boyer M, Stockler MR (2013) A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced malignant pleural mesothelioma. Lung Cancer 81(3):422–427. CrossRefPubMedGoogle Scholar
  27. 27.
    Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, Gebski V, Heywood M, Vasey PA, Volgger B, Vergote I, Pignata S, Ferrero A, Sehouli J, Lortholary A, Kristensen G, Jackisch C, Joly F, Brown C, Le Fur N, du Bois A (2010) Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 28(20):3323–3329. CrossRefPubMedGoogle Scholar
  28. 28.
    Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B, Oh EY, Gaber MW, Finklestein D, Allen M, Frank A, Bayazitov IT, Zakharenko SS, Gajjar A, Davidoff A, Gilbertson RJ (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82. CrossRefGoogle Scholar
  29. 29.
    Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323. CrossRefPubMedGoogle Scholar
  30. 30.
    Inglis DJ, Lavranos TC, Beaumont DM, Leske AF, Brown CK, Hall AJ, Kremmidiotis G (2014) The vascular disrupting agent BNC105 potentiates the efficacy of VEGF and mTOR inhibitors in renal and breast cancer. Cancer Biol Ther 15(11):1552–1560. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Kristina Lindemann
    • 1
    • 2
    • 3
  • Philip J. Beale
    • 4
  • Emma Rossi
    • 5
  • Jeff C. Goh
    • 6
  • Michelle M. Vaughan
    • 7
  • Meaghan E. Tenney
    • 8
    • 9
  • Julie K. Martyn
    • 1
  • Dirkje Sommeijer
    • 10
    • 11
  • Jose L. Iglesias
    • 12
  • Gabriel Kremmidiotis
    • 13
  • Jeremy Simpson
    • 13
  • Elizabeth Doolin
    • 13
  • Tina C. Lavranos
    • 13
  • Annabell Leske
    • 13
  • Anneso S. Veillard
    • 1
  • David Espinoza
    • 1
  • Martin R. Stockler
    • 1
  • Danny Rischin
    • 14
    • 15
    Email author
  • For ANZGOG and HCRN Collaborative Groups
  1. 1.NHMRC Clinical Trials CentreSydneyAustralia
  2. 2.Division of Medicine, Department of Gynaecological OncologyOslo University HospitalOsloNorway
  3. 3.Institute of Clinical Medicine, Faculty of MedicineUniversity of OsloOsloNorway
  4. 4.Chris O’Brien LifehouseSydneyAustralia
  5. 5.Gynecologic Oncology, Department of Obstetrics and GynecologyUniversity of North CarolinaChapel HillUSA
  6. 6.Royal Brisbane and Women’s HospitalBrisbaneAustralia
  7. 7.Christchurch HospitalChristchurchNew Zealand
  8. 8.Northside HospitalUniversity Gynecologic OncologySandy SpringsUSA
  9. 9.University of Chicago MedicineChicagoUSA
  10. 10.Academic Medical CentreAmsterdamThe Netherlands
  11. 11.FlevohospitalAlmereThe Netherlands
  12. 12.ApobiologixTorontoCanada
  13. 13.Bionomics LtdThebartonAustralia
  14. 14.Peter MacCallum Cancer CentreMelbourneAustralia
  15. 15.Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia

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