Skip to main content

Advertisement

SpringerLink
Log in

A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors

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

Summary

Purpose To determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetic and pharmacodynamic profiles of the tripeptide epoxyketone proteasome inhibitor oprozomib in patients with advanced refractory or recurrent solid tumors. Methods Patients received escalating once daily (QD) or split doses of oprozomib on days 1–5 of 14-day cycles (C). The split-dose arm was implemented and compared in fasted (C1) and fed (C2) states. Pharmacokinetic samples were collected during C1 and C2. Proteasome inhibition was evaluated in red blood cells and peripheral blood mononuclear cells. Results Forty-four patients (QD, n = 25; split dose, n = 19) were enrolled. The most common primary tumor types were non–small cell lung cancer (18 %) and colorectal cancer (16 %). In the 180-mg QD cohort, two patients experienced DLTs: grade 3 vomiting and dehydration; grade 3 hypophosphatemia (n = 1 each). In the split-dose group, three DLTs were observed (180-mg cohort: grade 3 hypophosphatemia; 210-mg cohort: grade 5 gastrointestinal hemorrhage and grade 3 hallucinations (n = 1 each). In the QD and split-dose groups, the MTD was 150 and 180 mg, respectively. Common adverse events (all grades) included nausea (91 %), vomiting (86 %), and diarrhea (61 %). Peak concentrations and total exposure of oprozomib generally increased with the increasing dose. Oprozomib induced dose-dependent proteasome inhibition. Best response was stable disease. Conclusions While generally low-grade, clinically relevant gastrointestinal toxicities occurred frequently with this oprozomib formulation. Despite dose-dependent increases in pharmacokinetics and pharmacodynamics, single-agent oprozomib had minimal antitumor activity in this patient population with advanced solid tumors.

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

Similar content being viewed by others

References

  1. Glickman MH, Ciechanover A (2002) The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428

    Article  CAS  PubMed  Google Scholar 

  2. Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5:417–421

    Article  CAS  PubMed  Google Scholar 

  3. Adams J (2004) The proteasome: a suitable antineoplastic target. Nat Rev Cancer 4:349–360

    Article  CAS  PubMed  Google Scholar 

  4. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617

    Article  CAS  PubMed  Google Scholar 

  5. Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al. (2015) Ixazomib, an Investigational Oral Proteasome Inhibitor (PI), in Combination with Lenalidomide and Dexamethasone (IRd), Significantly Extends Progression-Free Survival (PFS) for Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): The Phase 3 Tourmaline-MM1 Study (NCT01564537). American Society of Hematology Annual Meeting; Orlando, FL; December 5–8. Abstract 727

  6. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S et al (2012) A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 120:2817–2825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Engel RH, Brown JA, Von Roenn JH, O’Regan RM, Bergan R, Badve S et al (2007) A phase II study of single agent bortezomib in patients with metastatic breast cancer: a single institution experience. Cancer Invest 25:733–737

    Article  CAS  PubMed  Google Scholar 

  8. Papadopoulos KP, Burris HA III, Gordon M, Lee P, Sausvlle EA, Rosen PJ et al (2013) A phase I/II study of carfilzomib 2-10-min infusion in patients with advanced solid tumors. Cancer Chemother Pharmacol 72:861–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Rosenberg JE, Halabi S, Sanford BL, Himelstein AL, Atkins JN, Hohl RJ et al (2008) Phase II study of bortezomib in patients with previously treated advanced urothelial tract transitional cell carcinoma: CALGB 90207. Ann Oncol 19:946–950

    Article  CAS  PubMed  Google Scholar 

  10. Shah MA, Power DG, Kindler HL, Holen KD, Kemeny MM, Ilson DH et al (2011) A multicenter, phase II study of bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma. Invest New Drugs 29:1475–1481

    Article  CAS  PubMed  Google Scholar 

  11. Smith DC, Kalebic T, Infante JR, Siu LL, Sullivan D, Vlahovic G et al (2015) Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies. Invest New Drugs 33:652–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhou HJ, Aujay MA, Bennett MK, Dajee M, Demo SD, Fang Y et al (2009) Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 52:3028–3038

    Article  CAS  PubMed  Google Scholar 

  13. Hurchla MA, Garcia-Gomez A, Hornick MC, Ocio EM, Li A, Blanco JF et al (2013) The epoxyketone-based proteasome inhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolic activity in addition to anti-myeloma effects. Leukemia 27:430–440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Roccaro AM, Sacco A, Aujay M, No HT, Azab AK, Azab F et al (2010) Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood 115:4051–4060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chauhan D, Singh AV, Aujay M, Kirk CJ, Bandi M, Ciccarelli B et al (2010) A novel orally active proteasome inhibitor ONX 0912 triggers in vitro and in vivo cytotoxicity in multiple myeloma. Blood 116:4906–4915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zang Y, Thomas SM, Chan ET, Kirk CJ, Freilino ML, DeLancey HM et al (2012) The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4. Autophagy 8:1873–1874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubenstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European organization for research and treatment of cancer, national cancer institute of the United States, national cancer institute of Canada. J Natl Cancer Inst 92:205–216

    Article  CAS  PubMed  Google Scholar 

  18. U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events, version 4.02 (2009) In: [Internet]. Bethesda, MD: U.S. Department of Health and Human Services. 2013 [cited 2013 June 2]. Available from: http://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf

Download references

Acknowledgments

The authors thank all of the patients and their families and caregivers who contributed to this study; the investigators and staff from the additional participating study sites; all of the participating research nurses and data coordinators; Darrin Bomba and Tina Woo (Onyx Pharmaceuticals, Inc.) for clinical operations support; Sandra Dixon (Onyx Pharmaceuticals, Inc.) for statistical support; Ying Ou (Onyx Pharmaceuticals, Inc.) for her assistance analyzing the pharmacokinetic data; and Janet Anderl (Onyx Pharmaceuticals, Inc.) for her assistance running and analyzing the pharmacodynamic assays. This work was supported by Onyx Pharmaceuticals, Inc., an Amgen subsidiary. Editorial assistance was provided by BlueMomentum, a division of KnowledgePoint360 Group and funded by Onyx Pharmaceuticals, Inc., an Amgen subsidiary.

Author information

Authors and Affiliations

  1. Sarah Cannon Research Institute/Tennessee Oncology, 250 25th Avenue North, Nashville, TN, 37203, USA

    Jeffrey R. Infante, Howard A. Burris III & Johanna C. Bendell

  2. Pinnacle Oncology Hematology, Scottsdale, AZ, USA

    David S. Mendelson & Michael S. Gordon

  3. South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA

    Anthony W. Tolcher & Kyriakos P. Papadopoulos

  4. Onyx Pharmaceuticals, Inc., an Amgen Subsidiary, South San Francisco, CA, USA

    Heidi H. Gillenwater, Shirin Arastu-Kapur & Hansen L. Wong

Authors
  1. Jeffrey R. Infante
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David S. Mendelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Howard A. Burris III
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Johanna C. Bendell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anthony W. Tolcher
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael S. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heidi H. Gillenwater
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shirin Arastu-Kapur
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hansen L. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kyriakos P. Papadopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey R. Infante.

Ethics declarations

Conflicts of interest

Jeffrey R. Infante, David S. Mendelson, Howard A. Burris III, Johanna C. Bendell, Michael S. Gordon, and KPP have no relevant conflicts of interest to disclose. Anthony W. Tolcher has received research funding from GSK. Heidi H. Gillenwater, Shirin Arastu-Kapur, and Hansen L. Wong are employed by Onyx.

Ethical statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Financial support

Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, California.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 130 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Infante, J.R., Mendelson, D.S., Burris, H.A. et al. A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors. Invest New Drugs 34, 216–224 (2016). https://doi.org/10.1007/s10637-016-0327-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-016-0327-x

Keywords

Search

Navigation