Skip to main content

Advertisement

SpringerLink
Log in

A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors

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

Summary

Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16–25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14–120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.

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
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Qualified researchers may request access to individual patient level data through the ClinicalStudyDataRequest platform (www.clinicalstudydatarequest.com). Further details on Roche’s criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

References

  1. Vassilev LT (2007) MDM2 inhibitors for cancer therapy. Trends Mol Med 13(1):23–31

    Article  CAS  Google Scholar 

  2. Ding Q, Zhang Z, Liu JJ, Jiang N, Zhang J, Ross TM, Chu XJ, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassilev LT, Graves B (2013) Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem 56(14):5979–5983

    Article  CAS  Google Scholar 

  3. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659):844–848

    Article  CAS  Google Scholar 

  4. Yee K, Martinelli G, Vey N, Dickinson MJ, Seiter K, Assouline S, Drummond M, Yoon S-S, Kasner M, Lee J-H, Kelly KR, Blotner S, Higgins B, Middleton S, Nichols G, Chen G, Zhong H, Pierceall WE, Zhi J, Chen L-C (2014) Phase 1/1b study of RG7388, a potent MDM2 antagonist, in acute myelogenous leukemia (AML) patients (Pts) [abstract]. Blood 124(21):116

    Article  Google Scholar 

  5. Siu LL, Italiano AI, Miller WH, Blay J-Y, Gietema JA, Bang Y-J, Mileshkin LR, Hirte HW, Reckner M, Higgins B, Jukofsky L, Blotner S, Zhi J, Middleton S, Nichols GL, Chen LC (2014) Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors [abstract]. J Clin Oncol 32(15 suppl):abstract 2535

  6. Higgins B, Tovar C, Glen K, Railkar A, Filipovic Z, Qureshi F, Vu B, Ehrlich G, Fishlock D, Chen L-C, Middleton S, Nichols G, Packman K, Vassilev L (2014) Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration [abstract]. Mol Cancer Ther 14(12 suppl 2):abstract 156

  7. Razak A, Gore L, Britten CD, Miller WH, Uy GL, Nichols G, Middleton S, Blotner S, Zhi J, Jukofsky L, Pierceall W, Higgins B, Chen LC (2016) A phase I study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, for intravenous (IV) administration in patients with advanced solid tumors. Eur J Cancer 69:S21–S22

    Article  Google Scholar 

  8. O'Quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 46(1):33–48

    Article  CAS  Google Scholar 

  9. Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT (2003) Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol Cancer Ther 2(10):1023–1029

  10. Ray-Coquard I, Blay JY, Italiano A, Le Cesne A, Penel N, Zhi J, Heil F, Rueger R, Graves B, Ding M, Geho D, Middleton SA, Vassilev LT, Nichols GL, Bui BN (2012) Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 13(11):1133–1140

  11. Andreeff M, Kelly KR, Yee K, Assouline S, Strair R, Popplewell L, Bowen D, Martinelli G, Drummond MW, Vyas P, Kirschbaum M, Iyer SP, Ruvolo V, González GM, Huang X, Chen G, Graves B, Blotner S, Bridge P, Jukofsky L, Middleton S, Reckner M, Rueger R, Zhi J, Nichols G, Kojima K (2016) Results of the phase i trial of RG7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res 22(4):868–876

  12. Montesinos P, Esteve J, Konopleva M, Martinelli G, Ottmann O, Rodriguez-Veiga R, Röllig C, Wei A, Vey N, Chiu I, Monnet A, Ott MG, Fenaux P (2019) MIRROS: an ongoing randomized phase 3 trial of idasanutlin + ARA-C in patients with relapsed or refractory acute myeloid leukemia [abstract]. J Clin Oncol 37(15 suppl):abstract TPS7063

Download references

Acknowledgements

We thank the participants of the study. Special thanks to Steven Middleton, Gwen Nichols, William Pierceall, Jianguo Zhi, Lori Jukofsky, Patricia Delora, David Stephen Ward, and Ene Kelly and in the memory of Zoran Filipovic.

Funding

This study was funded by F. Hoffmann-La Roche Ltd. The sponsor was responsible for the clinical operations oversight, data management, medical monitoring, drug supply, statistical analysis, drug safety process, medical writing, and journal article processing charges. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Author information

Authors and Affiliations

  1. Princess Margaret Cancer Centre and Mount Sinai Hospital, Toronto, ON, Canada

    Albiruni R. Abdul Razak

  2. Division of Oncology and Hematology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Albiruni R. Abdul Razak

  3. Jewish General Hospital, Rossy Cancer Network and McGill University, Montreal, Quebec, Canada

    Wilson H. Miller Jr

  4. Washington University School of Medicine, St. Louis, MO, USA

    Geoffrey L. Uy

  5. Pharma Research and Early Development, Roche Innovation Center, New York, NY, USA

    Steven Blotner, Brian Higgins & Lin-Chi Chen

  6. Pharma Research and Early Development, Roche Innovation Center, Welwyn Garden City, UK

    Anne-Marie Young

  7. University of Colorado, Aurora, CO, USA

    Lia Gore

Authors
  1. Albiruni R. Abdul Razak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wilson H. Miller Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Geoffrey L. Uy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven Blotner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne-Marie Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brian Higgins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin-Chi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lia Gore
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Medical Writing, Editorial, and Other Assistance.

Support for third-party writing assistance for this manuscript, furnished by writer Christine Gould, PhD, CMPP, of Health Interactions, Inc., was provided by F. Hoffmann-La Roche Ltd. and Genentech, Inc.

Corresponding author

Correspondence to Albiruni R. Abdul Razak.

Ethics declarations

Conflict of interest

All authors report support of the parent study and funding of editorial support from F. Hoffmann-La Roche. SB, A-MY, BH, and L-CC are employees of Roche. ARR has received research funding from Genentech/Roche. WHM has served as a consultant for Amgen, BMS, GSK, Merck, Novartis and Roche; has received research funding to his institution from Amgen, AstraZeneca, BMS, MedImmune, Merck, MethylGene, Novartis, Pfizer and Roche; and has received honoraria from BMS, GSK, Merck, Novartis and Roche. LG has served as a consultant for Amgen, Genentech/Roche and Novartis; has stock with Amgen, Anchiano, Blueprint Medicines, Celgene, Clovis, Mirati and Sanofi; and has a spouse employed with Anchiano.

Ethical approval

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.

Informed consent

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

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Abdul Razak, A.R., Miller, W.H., Uy, G.L. et al. A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors. Invest New Drugs 38, 1156–1165 (2020). https://doi.org/10.1007/s10637-019-00869-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-019-00869-2

Keywords

Search

Navigation