Skip to main content

Advertisement

SpringerLink
Log in

Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies

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

Summary

Purpose. Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. Methods. Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. Results. Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. Conclusions. Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

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

Similar content being viewed by others

Availability of data and materials

Data will be available upon reasonable request.

References

  1. Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–591. https://doi.org/10.1038/nrc2403

    Article  CAS  PubMed  Google Scholar 

  2. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603. https://doi.org/10.1038/nrc2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. https://doi.org/10.1038/35052073

    Article  CAS  PubMed  Google Scholar 

  4. Wedge SR et al (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65(10):4389–4400. https://doi.org/10.1158/0008-5472.can-04-4409

    Article  CAS  PubMed  Google Scholar 

  5. Garland LL et al (2011) Phase II Study of Cediranib in Patients with Malignant Pleural Mesothelioma: SWOG S0509. J Thorac Oncol 6(11):1938–1945. https://doi.org/10.1097/jto.0b013e318229586e

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bender D et al (2015) A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol 138(3):507–512. https://doi.org/10.1016/j.ygyno.2015.07.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hirte H et al (2015) A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California Phase II Consortia. Gynecol Oncol 138(1):55–61

    Article  CAS  Google Scholar 

  8. Matulonis UA et al (2009) Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27(33):5601–5606. https://doi.org/10.1200/jco.2009.23.2777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cohen JW et al (2019) Cediranib phase-II study in children with metastatic alveolar soft-part sarcoma (ASPS). Pediatr Blood Cancer 66(12):e27987. https://doi.org/10.1002/pbc.27987

    Article  PubMed  PubMed Central  Google Scholar 

  10. Judson I et al (2019) Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial. Lancet Oncol 20(7):1023–1034. https://doi.org/10.1016/s1470-2045(19)30215-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kummar S et al (2013) Cediranib for metastatic alveolar soft part sarcoma. J Clin Oncol 31(18):2296–2302

    Article  CAS  Google Scholar 

  12. Batchelor TT et al (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28(17):2817–2823. https://doi.org/10.1200/jco.2009.26.3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dahut WL et al (2013) Phase II clinical trial of cediranib in patients with metastatic castration-resistant prostate cancer. BJU Int 111(8):1269–1280. https://doi.org/10.1111/j.1464-410x.2012.11667.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ryan CJ et al (2007) Phase I dose escalation and pharmacokinetic study of AZD2171, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinase, in patients with hormone refractory prostate cancer (HRPC). Invest New Drugs 25(5):445–451. https://doi.org/10.1007/s10637-007-9050-y

    Article  CAS  PubMed  Google Scholar 

  15. Drevs J et al (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25(21):3045–3054. https://doi.org/10.1200/jco.2006.07.2066

    Article  CAS  PubMed  Google Scholar 

  16. Yamamoto N et al (2009) Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 64(6):1165–1172. https://doi.org/10.1007/s00280-009-0979-8

    Article  CAS  PubMed  Google Scholar 

  17. Mulders P et al (2012) Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study. Eur J Cancer 48(4):527–537. https://doi.org/10.1016/j.ejca.2011.12.022

    Article  CAS  PubMed  Google Scholar 

  18. Batchelor TT et al (2013) Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31(26):3212–3218. https://doi.org/10.1200/jco.2012.47.2464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu JF et al (2014) Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol 15(11):1207–1214. https://doi.org/10.1016/s1470-2045(14)70391-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu JF et al (2019) Overall survival and updated progression-free survival outcomes in a randomized phase II study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer. Ann Oncol 30(4):551–557. https://doi.org/10.1093/annonc/mdz018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liu JF et al (2020) A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer. J Clin Oncol. 38

  22. Goss GD et al (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 28(1):49–55. https://doi.org/10.1200/jco.2009.22.9427

    Article  CAS  PubMed  Google Scholar 

  23. Schmoll HJ et al (2012) Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol 30(29):3588–3595. https://doi.org/10.1200/jco.2012.42.5355

    Article  CAS  PubMed  Google Scholar 

  24. Hoff PM et al (2012) Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, phase III study (HORIZON II). J Clin Oncol 30(29):3596–3603. https://doi.org/10.1200/jco.2012.42.6031

    Article  CAS  PubMed  Google Scholar 

  25. Cunningham D et al (2013) Cediranib with mFOLFOX6 vs bevacizumab with mFOLFOX6 in previously treated metastatic colorectal cancer. Br J Cancer 108(3):493–502. https://doi.org/10.1038/bjc.2012.545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Laurie SA et al (2014) Randomised, double-blind trial of carboplatin and paclitaxel with daily oral cediranib or placebo in patients with advanced non-small cell lung cancer: NCIC Clinical Trials Group study BR29. Eur J Cancer 50(4):706–712. https://doi.org/10.1016/j.ejca.2013.11.032

    Article  CAS  PubMed  Google Scholar 

  27. Yeh TC et al (2007) Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res 13(5):1576–1583. https://doi.org/10.1158/1078-0432.ccr-06-1150

    Article  CAS  PubMed  Google Scholar 

  28. Gross AM et al (2020) Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 382(15):1430–1442. https://doi.org/10.1056/nejmoa1912735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Adjei AA et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol 26(13):2139–2146. https://doi.org/10.1200/jco.2007.14.4956

    Article  CAS  PubMed  Google Scholar 

  30. Banerji U et al (2010) The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res 16(5):1613–1623. https://doi.org/10.1158/1078-0432.ccr-09-2483

    Article  CAS  PubMed  Google Scholar 

  31. Bekaii-Saab T et al (2011) Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol 29(17):2357–2363. https://doi.org/10.1200/jco.2010.33.9473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bennouna J et al (2011) A Phase II, open-label, randomised study to assess the efficacy and safety of the MEK1/2 inhibitor AZD6244 (ARRY-142886) versus capecitabine monotherapy in patients with colorectal cancer who have failed one or two prior chemotherapeutic regimens. Invest New Drugs 29(5):1021–1028

    Article  CAS  Google Scholar 

  33. Bodoky G et al (2012) A phase II open-label randomized study to assess the efficacy and safety of selumetinib (AZD6244 [ARRY-142886]) versus capecitabine in patients with advanced or metastatic pancreatic cancer who have failed first-line gemcitabine therapy. Invest New Drugs 30(3):1216–1223. https://doi.org/10.1007/s10637-011-9687-4

    Article  CAS  PubMed  Google Scholar 

  34. Catalanotti F et al (2013) Phase II trial of MEK inhibitor selumetinib (AZD6244, ARRY-142886) in patients with BRAFV600E/K-mutated melanoma. Clin Cancer Res 19(8):2257–2264. https://doi.org/10.1158/1078-0432.ccr-12-3476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hayes DN et al (2012) Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res 18(7):2056–2065. https://doi.org/10.1158/1078-0432.ccr-11-0563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jänne PA et al (2013) Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14(1):38–47. https://doi.org/10.1016/s1470-2045(12)70489-8

    Article  PubMed  Google Scholar 

  37. Jänne PA et al (2017) Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non-Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial. JAMA 317(18):1844–1853. https://doi.org/10.1001/jama.2017.3438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Takahashi O et al (2012) Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis. Clin Cancer Res 18(6):1641–1654. https://doi.org/10.1158/1078-0432.ccr-11-2324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Oken MM et al (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655

    Article  CAS  Google Scholar 

  40. Fan SK, Venook AP, Lu Y (2009) Design issues in dose-finding Phase I trials for combinations of two agents. J Biopharm Stat 19(3):509–523. https://doi.org/10.1080/10543400902802433

    Article  PubMed  Google Scholar 

  41. Yuan Z, Chappell R, Bailey H (2007) The continual reassessment method for multiple toxicity grades: a Bayesian quasi-likelihood approach. Biometrics 63(1):173–179. https://doi.org/10.1111/j.1541-0420.2006.00666.x

    Article  CAS  PubMed  Google Scholar 

  42. Health UDo, Services H (2009) National cancer Institute. In: Common Terminology criteria for adverse events (CTCAE) version 4.0. National Institutes of Health/National Cancer Institute. p. 1e194

  43. Eisenhauer EA et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–47. https://doi.org/10.1016/j.ejca.2008.10.026

  44. Carvajal RD et al (2014) Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: a randomized clinical trial. JAMA 311(23):2397–2405. https://doi.org/10.1001/jama.2014.6096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Azad NS et al (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26(22):3709–3714. https://doi.org/10.1200/jco.2007.10.8332

    Article  CAS  PubMed  Google Scholar 

  46. Castellano D et al (2013) Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: a phase II study of Spanish Neuroendocrine Tumour Group (GETNE0801). Eur J Cancer 49(18):3780–3787. https://doi.org/10.1016/j.ejca.2013.06.042

    Article  CAS  PubMed  Google Scholar 

  47. Galanis E et al (2013) Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. Clin Cancer Res 19(17):4816–4823. https://doi.org/10.1158/1078-0432.ccr-13-0708

    Article  CAS  PubMed  Google Scholar 

  48. Mina LA et al (2013) A phase II study of combined VEGF inhibitor (bevacizumab+sorafenib) in patients with metastatic breast cancer: Hoosier Oncology Group Study BRE06-109. Invest New Drugs 31(5):1307–1310. https://doi.org/10.1007/s10637-013-9976-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mahalingam D et al (2014) Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma. Cancer Chemother Pharmacol 74(1):77–84. https://doi.org/10.1007/s00280-014-2479-8

    Article  CAS  PubMed  Google Scholar 

  50. Hong DS et al (2014) Dual inhibition of the vascular endothelial growth factor pathway: a phase 1 trial evaluating bevacizumab and AZD2171 (cediranib) in patients with advanced solid tumors. Cancer 120(14):2164–2173. https://doi.org/10.1002/cncr.28701

    Article  CAS  PubMed  Google Scholar 

  51. Trarbach T et al (2012) Phase I open-label study of cediranib, an oral inhibitor of VEGF signalling, in combination with the oral Src inhibitor saracatinib in patients with advanced solid tumours. Invest New Drugs 30(5):1962–1971. https://doi.org/10.1007/s10637-011-9754-x

    Article  CAS  PubMed  Google Scholar 

  52. van Cruijsen H et al (2010) Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. Eur J Cancer 46(5):901–911. https://doi.org/10.1016/j.ejca.2009.12.023

    Article  CAS  PubMed  Google Scholar 

  53. Sahebjam S et al (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(4):943–949. https://doi.org/10.1038/bjc.2013.380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Supported by the Mayo Clinic U01 (CA069912) and Mayo Clinic UM1 (CA186686) grants.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Mayo Clinic, Rochester, MN, 55905, USA

    Joleen M. Hubbard, Erin L. Schenk, Charles Erlichman, Alex Adjei, Paul Haluska & Brian A. Costello

  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, 55905, USA

    Jun Yin, Rui Qin, Carrie Strand & Jack Fiskum

  3. Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA

    Erin L. Schenk

  4. Division of Oncology Research, Mayo Clinic, Rochester, MN, 55905, USA

    Joel M. Reid

  5. VA Medical Center, Washington, DC, 20422, USA

    Michael Menefee

  6. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, 55905, USA

    Grace Lin

  7. Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of fHealth, Bethesda, MD, 20892, USA

    L. Austin Doyle & Percy Ivy

  8. Bristol Myers Squibb, Lawrenceville, NJ, 08648, USA

    Paul Haluska

Authors
  1. Joleen M. Hubbard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erin L. Schenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rui Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joel M. Reid
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carrie Strand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jack Fiskum
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Menefee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Grace Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. L. Austin Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Percy Ivy
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Charles Erlichman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alex Adjei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Paul Haluska
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Brian A. Costello
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to this work.

Corresponding author

Correspondence to Brian A. Costello.

Ethics declarations

Ethics approval and consent to participate

The clinical trial protocol was approved by the Mayo Clinic institutional review board and all patients provided written informed consent before participating in the study.

Consent for publication

Not Applicable.

Conflicts of interest

Authors’ Disclosure of Potential Conflicts of Interests: None.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 12 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hubbard, J.M., Yin, J., Schenk, E.L. et al. Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies. Invest New Drugs 40, 115–123 (2022). https://doi.org/10.1007/s10637-021-01175-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-021-01175-6

Keywords

Search

Navigation