Skip to main content

Advertisement

SpringerLink
Log in

A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort

  • PHASE I STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

JI-101 is an oral multi-kinase inhibitor that targets vascular endothelial growth factor receptor type 2 (VEGFR-2), platelet derived growth factor receptor β (PDGFR-β), and ephrin type-B receptor 4 (EphB4). None of the currently approved angiogenesis inhibitors have been reported to inhibit EphB4, and therefore, JI-101 has a novel mechanism of action. We conducted a pilot trial to assess the pharmacokinetics (PK), tolerability, and efficacy of JI-101 in combination with everolimus in advanced cancers, and pharmacodynamics (PD), tolerability, and efficacy of JI-101 in ovarian cancer. This was the first clinical study assessing anti-tumor activity of JI-101 in a combinatorial regimen. In the PK cohort, four patients received single agent 10 mg everolimus on day 1, 10 mg everolimus and 200 mg JI-101 combination on day 8, and single agent 200 mg JI-101 on day 15. In the PD cohort, eleven patients received single agent JI-101 at 200 mg twice daily for 28 day treatment cycles. JI-101 was well tolerated as a single agent and in combination with everolimus. No serious adverse events were observed. Common adverse events were hypertension, nausea, and abdominal pain. JI-101 increased exposure of everolimus by approximately 22 %, suggestive of drug-drug interaction. The majority of patients had stable disease at their first set of restaging scans (two months), although no patients demonstrated a response to the drug per RECIST criteria. The novel mechanism of action of JI-101 is promising in ovarian cancer treatment and further prospective studies of this agent may be pursued in a less refractory patient population or in combination with cytotoxic chemotherapy.

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

Similar content being viewed by others

References

  1. Velleca M, Brittelli D, Elkin L, et al. (2009) Preclinical and preliminary phase 1 trial results of JI-101: A novel, oral tyrosine kinase inhibitor that selectively targets VEGFR2, EphB4, and PDGFRβ. NCI - EORTC Int Conf Molec Targ Cancer Therapeut. November 15–19, Boston, MA USA, Abstract no: B11

  2. Sharma S, Miller L, Gordon M, et al. (2010) Phase I study of JI-101, a novel oral tyrosine kinase inhibitor that selectively targets EphB4, VEGFR2 and PDGFRß. Poster presentation at 22nd EORTC-NCI-AACR Symp Molec Targ Cancer Therapeut. November 16–19, Berlin, Abstract no: 400

  3. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grunwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A, Group R-S (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372(9637):449–456. doi:10.1016/S0140-6736(08)61039-9

    Article  CAS  PubMed  Google Scholar 

  4. Gurav SD, Gilibili RR, Jeniffer S, Mohd Z, Giri S, Govindarajan R, Srinivas NR, Mullangi R (2012) Pharmacokinetics, tissue distribution and identification of putative metabolites of JI-101 - a novel triple kinase inhibitor in rats. Arzneimittelforschung 62(1):27–34. doi:10.1055/s-0031-1295427

    Article  CAS  PubMed  Google Scholar 

  5. Burger RA (2007) Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol 25(20):2902–2908. doi:10.1200/JCO.2007.12.1509

    Article  CAS  PubMed  Google Scholar 

  6. Spannuth WA, Mangala LS, Stone RL, Carroll AR, Nishimura M, Shahzad MM, Lee SJ, Moreno-Smith M, Nick AM, Liu R, Jennings NB, Lin YG, Merritt WM, Coleman RL, Vivas-Mejia PE, Zhou Y, Krasnoperov V, Lopez-Berestein G, Gill PS, Sood AK (2010) Converging evidence for efficacy from parallel EphB4-targeted approaches in ovarian carcinoma. Mol Cancer Ther 9(8):2377–2388. doi:10.1158/1535-7163.MCT-10-0200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX, Gynecologic Oncology G (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365(26):2473–2483. doi:10.1056/NEJMoa1104390

    Article  CAS  PubMed  Google Scholar 

  8. Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade-Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stahle A, Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM, Investigators I (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365(26):2484–2496. doi:10.1056/NEJMoa1103799

    Article  CAS  PubMed  Google Scholar 

  9. Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD (2009) Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol : Off J Am Soc Clin Oncol 27(7):1069–1074. doi:10.1200/JCO.2008.18.9043

    Article  CAS  Google Scholar 

  10. Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol : Off J Am Soc Clin Oncol 20(21):4368–4380

    Article  CAS  Google Scholar 

  11. Alam SM, Fujimoto J, Jahan I, Sato E, Tamaya T (2008) Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers. Br J Cancer 98(4):845–851. doi:10.1038/sj.bjc.6604216

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133(1):38–52. doi:10.1016/j.cell.2008.03.011

    Article  CAS  PubMed  Google Scholar 

  13. DeGeorge JJ, Ahn CH, Andrews PA, Brower ME, Giorgio DW, Goheer MA, Lee-Ham DY, McGuinn WD, Schmidt W, Sun CJ, Tripathi SC (1998) Regulatory considerations for preclinical development of anticancer drugs. Cancer Chemother Pharmacol 41(3):173–185

    Article  CAS  PubMed  Google Scholar 

  14. Tang XX, Brodeur GM, Campling BG, Ikegaki N (1999) Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma. J Clin Oncol : Off J Am Soc Clin Oncol 5(2):455–460

    CAS  Google Scholar 

  15. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a gynecologic oncology group study (2007). J Clin Oncol 25(3):5165–5171

    Article  CAS  PubMed  Google Scholar 

  16. Kumar SR, Masood R, Spannuth WA, Singh J, Scehnet J, Kleiber G, Jennings N, Deavers M, Krasnoperov V, Dubeau L, Weaver FA, Sood AK, Gill PS (2007) The receptor tyrosine kinase EphB4 is overexpressed in ovarian cancer, provides survival signals and predicts poor outcome. Br J Cancer 96(7):1083–1091. doi:10.1038/sj.bjc.6603642

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the study participants and their families, as well as the research coordinators. We would like to acknowledge Joely Straseski, PhD, who analyzed the plasma VEGF samples.

Funding

This work was supported by a grant from Vanthys Pharmaceutical Development.

Conflict of interest

Neeraj Agarwal: Research support to the institution from Amgen, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Imclone, Medivation, Takeda, Novartis, Pfizer.

Sunil Sharma: Research support to the institution from Novartis, Spectrum, GlaxoSmithKline, Merrimack, Millennium, Takeda, Amgen, LSK Biopartners, Mirati, MedImmune, Johnson & Johnson, Gilead Sciences, Plexxikon, Celgene, Sanofi, Onyx, Bayer; and financial interest in Beta Cat Pharmaceuticals, Salarius, and ConverGene.

Theresa L. Werner: Research support to the institution from Abbvie, Amgen, Bayer, GlaxoSmithKline, Novartis, Roche-Genentech, Pfizer.

The other authors have declared no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Medicine, Oncology Division, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA

    Theresa L. Werner, Mark L. Wade, Neeraj Agarwal, Jesal Patel, Aaron Luebke & Sunil Sharma

  2. Department of Oncologic Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA

    Kenneth Boucher

  3. Department of Medicine, Oncology Division, University of Utah School of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Suite 2100, Salt Lake City, UT, 84112, USA

    Theresa L. Werner

Authors
  1. Theresa L. Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark L. Wade
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Neeraj Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kenneth Boucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jesal Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aaron Luebke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sunil Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theresa L. Werner.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Werner, T.L., Wade, M.L., Agarwal, N. et al. A pilot study of JI-101, an inhibitor of VEGFR-2, PDGFR-β, and EphB4 receptors, in combination with everolimus and as a single agent in an ovarian cancer expansion cohort. Invest New Drugs 33, 1217–1224 (2015). https://doi.org/10.1007/s10637-015-0288-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-015-0288-5

Keywords

Search

Navigation