Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer’s decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug–drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507. doi:10.1056/NEJMra0708126

    Article  CAS  PubMed  Google Scholar 

  2. Bolos V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363. doi:10.1210/er.2006-0046

    Article  CAS  PubMed  Google Scholar 

  3. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678–689. doi:10.1038/nrm2009

    Article  CAS  PubMed  Google Scholar 

  4. Nefedova Y, Gabrilovich D (2008) Mechanisms and clinical prospects of Notch inhibitors in the therapy of hematological malignancies. Drug Resist Updat 11:210–218. doi:10.1016/j.drup.2008.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li YM, Eberhart CG (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66:7445–7452. doi:10.1158/0008-5472.CAN-06-0858

    Article  CAS  PubMed  Google Scholar 

  6. Aster JC, Pear WS, Blacklow SC (2008) Notch signaling in leukemia. Annu Rev Pathol 3:587–613. doi:10.1146/annurev.pathmechdis.3.121806.154300

    Article  CAS  PubMed  Google Scholar 

  7. Staal FJ, Langerak AW (2008) Signaling pathways involved in the development of T-cell acute lymphoblastic leukemia. Haematologica 93:493–497. doi:10.3324/haematol.12917

    Article  CAS  PubMed  Google Scholar 

  8. Chen Y, De Marco MA, Graziani I, Gazdar AF, Strack PR, Miele L, Bocchetta M (2007) Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res 67:7954–7959. doi:10.1158/0008-5472.CAN-07-1229

    Article  CAS  PubMed  Google Scholar 

  9. Konishi J, Kawaguchi KS, Vo H, Haruki N, Gonzalez A, Carbone DP, Dang TP (2007) Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 67:8051–8057. doi:10.1158/0008-5472.CAN-07-1022

    Article  CAS  PubMed  Google Scholar 

  10. Peacock CD, Watkins DN (2008) Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 26:2883–2889. doi:10.1200/JCO.2007.15.2702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kanamori M, Kawaguchi T, Nigro JM, Feuerstein BG, Berger MS, Miele L, Pieper RO (2007) Contribution of Notch signaling activation to human glioblastoma multiforme. J Neurosurg 106:417–427. doi:10.3171/jns.2007.106.3.417

    Article  PubMed  Google Scholar 

  12. Shih AH, Holland EC (2006) Notch signaling enhances nestin expression in gliomas. Neoplasia 8:1072–1082. doi:10.1593/neo.06526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J, Wang CY (2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8:13–23. doi:10.1016/j.ccr.2005.06.004

    Article  CAS  PubMed  Google Scholar 

  14. Li JL, Sainson RC, Oon CE, Turley H, Leek R, Sheldon H, Bridges E, Shi W, Snell C, Bowden ET, Wu H, Chowdhury PS, Russell AJ, Montgomery CP, Poulsom R, Harris AL (2011) DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res 71:6073–6083. doi:10.1158/0008-5472.CAN-11-1704

    Article  CAS  PubMed  Google Scholar 

  15. Soeda A, Hara A, Kunisada T, Yoshimura S, Iwama T, Park DM (2015) The evidence of glioblastoma heterogeneity. Sci Rep 5:7979. doi:10.1038/srep07979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Park DM, Li J, Okamoto H, Akeju O, Kim SH, Lubensky I, Vortmeyer A, Dambrosia J, Weil RJ, Oldfield EH, Park JK, Zhuang Z (2007) N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation. Cell Cycle 6:467–470

    Article  CAS  PubMed  Google Scholar 

  17. Wu J, Wiegand R, LoRusso P, Li J (2011) Validation and implementation of a liquid chromatography/tandem mass spectrometry assay for quantitation of the total and unbound RO4929097, a gamma-secretase inhibitor targeting Notch signaling, in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 879:1537–1543. doi:10.1016/j.jchromb.2011.03.045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shah VP, Midha KK, Findlay JW, Hill HM, Hulse JD, McGilveray IJ, McKay G, Miller KJ, Patnaik RN, Powell ML, Tonelli A, Viswanathan CT, Yacobi A (2000) Bioanalytical method validation—a revisit with a decade of progress. Pharm Res 17:1551–1557

    Article  CAS  PubMed  Google Scholar 

  19. Gabrielsson J (1994) Pharmacokinetic/pharmacodynamic data analysis: concepts and applications. Swedish Pharmaceutical Press, Uppsala

    Google Scholar 

  20. Lacey LF, Keene ON, Pritchard JF, Bye A (1997) Common noncompartmental pharmacokinetic variables: are they normally or log-normally distributed? J Biopharm Stat 7:171–178. doi:10.1080/10543409708835177

    Article  CAS  PubMed  Google Scholar 

  21. Mizuta E, Tsubotani A (1985) Preparation of mean drug concentration–time curves in plasma. A study on the frequency distribution of pharmacokinetic parameters. Chem Pharm Bull (Tokyo) 33:1620–1632

    Article  CAS  Google Scholar 

  22. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105:6392–6397. doi:10.1073/pnas.0802047105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bolos V, Mira E, Martinez-Poveda B, Luxan G, Canamero M, Martinez AC, Manes S, de la Pompa JL (2013) Notch activation stimulates migration of breast cancer cells and promotes tumor growth. Breast Cancer Res 15:R54. doi:10.1186/bcr3447

    Article  PubMed  PubMed Central  Google Scholar 

  24. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9:617–628. doi:10.1016/j.devcel.2005.09.010

    Article  CAS  PubMed  Google Scholar 

  25. Qiang L, Wu T, Zhang HW, Lu N, Hu R, Wang YJ, Zhao L, Chen FH, Wang XT, You QD, Guo QL (2012) HIF-1alpha is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway. Cell Death Differ 19:284–294. doi:10.1038/cdd.2011.95

    Article  CAS  PubMed  Google Scholar 

  26. Androutsellis-Theotokis A, Leker RR, Soldner F, Hoeppner DJ, Ravin R, Poser SW, Rueger MA, Bae SK, Kittappa R, McKay RD (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826. doi:10.1038/nature04940

    Article  CAS  PubMed  Google Scholar 

  27. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay R, Engh J, Iwama T, Kunisada T, Kassam A (2009) Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α. Oncogene 28:3949–3959

    Article  CAS  PubMed  Google Scholar 

  28. Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG (2010) Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres. Am J Pathol 177:1491–1502. doi:10.2353/ajpath.2010.091021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hovinga KE, Shimizu F, Wang R, Panagiotakos G, Van Der Heijden M, Moayedpardazi H, Correia AS, Soulet D, Major T, Menon J, Tabar V (2010) Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem cells 28:1019–1029. doi:10.1002/stem.429

    Article  CAS  PubMed  Google Scholar 

  30. Villa JC, Chiu D, Brandes AH, Escorcia FE, Villa CH, Maguire WF, Hu CJ, de Stanchina E, Simon MC, Sisodia SS, Scheinberg DA, Li YM (2014) Nontranscriptional role of Hif-1alpha in activation of gamma-secretase and notch signaling in breast cancer. Cell Rep 8:1077–1092. doi:10.1016/j.celrep.2014.07.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Diaz-Padilla I, Hirte H, Oza AM, Clarke BA, Cohen B, Reedjik M, Zhang T, Kamel-Reid S, Ivy SP, Hotte SJ, Razak AA, Chen EX, Brana I, Wizemann M, Wang L, Siu LL, Bedard PL (2013) A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest New Drugs 31:1182–1191. doi:10.1007/s10637-013-0001-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tolcher AW, Messersmith WA, Mikulski SM, Papadopoulos KP, Kwak EL, Gibbon DG, Patnaik A, Falchook GS, Dasari A, Shapiro GI, Boylan JF, Xu ZX, Wang K, Koehler A, Song J, Middleton SA, Deutsch J, Demario M, Kurzrock R, Wheler JJ (2012) Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 30:2348–2353. doi:10.1200/JCO.2011.36.8282

    Article  CAS  PubMed  Google Scholar 

  33. Shih T, Lindley C (2006) Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28:1779–1802. doi:10.1016/j.clinthera.2006.11.015

    Article  CAS  PubMed  Google Scholar 

  34. Sahebjam S, Bedard PL, Castonguay V, Chen Z, Reedijk M, Liu G, Cohen B, Zhang WJ, Clarke B, Zhang T, Kamel-Reid S, Chen H, Ivy SP, Razak AR, Oza AM, Chen EX, Hirte HW, McGarrity A, Wang L, Siu LL, Hotte SJ (2013) A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503). Br J Cancer 109:943–949. doi:10.1038/bjc.2013.380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xu R, Shimizu F, Hovinga K, Beal K, Karimi S, Droms L, Peck KK, Gutin P, Iorgulescu JB, Kaley T, DeAngelis L, Pentsova E, Nolan C, Grommes C, Chan T, Bobrow D, Hormigo A, Cross JR, Wu N, Takebe N, Panageas K, Ivy P, Supko JG, Tabar V, Omuro A (2016) Molecular and clinical effects of Notch inhibition in glioma patients: a phase 0/I trial. Clin Cancer Res. doi:10.1158/1078-0432.CCR-16-0048

    Google Scholar 

Download references

Funding

CA UM1 137443 awarded to ABTC.

Author information

Authors and Affiliations

  1. Department of Medicine, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA

    Edward Pan

  2. Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Jeffrey G. Supko

  3. Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Thomas J. Kaley

  4. Department of Neurological Surgery, University of California, San Francisco, CA, USA

    Nicholas A. Butowski

  5. Department of Neurology, University of California, Los Angeles, CA, USA

    Timothy Cloughesy

  6. Neuro-Oncology Branch, CCR, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Jinkyu Jung & Deric M. Park

  7. Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Serena Desideri, Stuart Grossman & Xiaobu Ye

Authors
  1. Edward Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey G. Supko
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas J. Kaley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicholas A. Butowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Timothy Cloughesy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinkyu Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Serena Desideri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stuart Grossman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaobu Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Deric M. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Edward Pan or Deric M. Park.

Ethics declarations

Conflict of interest

Timothy F. Cloughesy has been compensated by Roche/Genentech for consulting work and expert testimony. No other authors report conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 17 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pan, E., Supko, J.G., Kaley, T.J. et al. Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma. J Neurooncol 130, 571–579 (2016). https://doi.org/10.1007/s11060-016-2263-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-016-2263-1

Keywords

Search

Navigation