Investigational New Drugs

, Volume 31, Issue 4, pp 891–899 | Cite as

Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib

  • Grace K. Dy
  • Jeffrey R. Infante
  • S. Gail Eckhardt
  • Silvia Novello
  • Wen Wee Ma
  • Suzanne F. Jones
  • Anne Huff
  • Qiong Wang
  • A. Benjamin Suttle
  • Lone H. Ottesen
  • Alex A. Adjei
  • Howard A. BurrisIII


Introduction As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. Methods Escalating doses of pazopanib (400–800 mg once daily [QD]) plus erlotinib (100–150 mg QD) doses were evaluated in cohorts of 3–6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). Results The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib (N = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. Conclusions Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination.


Pazopanib Erlotinib Pharmacokinetics Solid tumors Non-small-cell lung cancer 



We thank Jane Saiers, PhD, The WriteMedicine, Inc., and Jerome F. Sah, PhD, ProEd Communications, Inc., for their medical editorial assistance with this manuscript. Financial support for this study and medical editorial assistance was provided by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania.

Ethical standards

This study complied with the laws of the countries in which it was conducted (United States and Italy), and the study was approved by the respective institutional ethics committees.

Conflicts of interest

AH, QW, ABS, and LHO are employees of GlaxoSmithKline and hold company stock. JRI has been an uncompensated consultant for GlaxoSmithKline and his organization has received grants for research and consultant/advisor roles. All other authors report no financial conflicts of interest.


  1. 1.
    Bertino EM, Otterson GA (2010) Benefits and limitations of antiangiogenic agents in patients with non-small cell lung cancer. Lung Cancer 70:233–246. doi: 10.1016/j.lungcan.2010.08.018 PubMedCrossRefGoogle Scholar
  2. 2.
    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 20:4368–4380PubMedCrossRefGoogle Scholar
  3. 3.
    Sandler A, Herbst R (2006) Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin Cancer Res 12:4421s–4425sPubMedCrossRefGoogle Scholar
  4. 4.
    Pennell NA, Lynch TJ Jr (2009) Combined inhibition of the VEGFR and EGFR signaling pathways in the treatment of NSCLC. Oncologist 14:399–411PubMedCrossRefGoogle Scholar
  5. 5.
    Scagliotti GV, Krzakowski M, Szczesna A et al (2010) Sunitinib (SU) in combination with erlotinib (E) for the treatment of advanced/metastatic nonsmall cell lung cancer (NSCLC): a phase III study. Ann Oncol 21(Suppl 8):viii3. doi: 10.1093/annonc/mdq601, Abstract LBA6Google Scholar
  6. 6.
    Herbst RS, Ansari R, Bustin F et al (2011) Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 377:1846–1854PubMedCrossRefGoogle Scholar
  7. 7.
    Hainsworth J, Herbst R (2008) A phase III, multicenter, placebo-controlled, double-blind, randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin®) in combination with erlotinib (Tarceva®) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). J Thorac Oncol 3:S302Google Scholar
  8. 8.
    Heath EI, Chiorean EG, Sweeney CJ et al (2010) A phase I study of the pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients with advanced solid tumors. Clin Pharmacol Ther 88:818–823PubMedCrossRefGoogle Scholar
  9. 9.
    Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068. doi: 10.1200/JCO.2009.23.9764 PubMedCrossRefGoogle Scholar
  10. 10.
    U.S. Department of Health and Human Services Food & Drug Administration (2009) Pazopanib [approval notice for renal cell carcinoma]. Accessed March 30 2012
  11. 11.
    van der Graaf WT, Blay JY, Chawla SP et al (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886. doi: 10.1016/S0140-6736(12)60651-5 PubMedCrossRefGoogle Scholar
  12. 12.
    U.S. Department of Health and Human Services Food & Drug Administration (2012) Pazopanib [approval notice for soft tissue sarcoma]. Accessed July 7 2012
  13. 13.
    Friedlander M, Hancock KC, Rischin D et al (2010) A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 119:32–37PubMedCrossRefGoogle Scholar
  14. 14.
    Altorki N, Lane ME, Bauer T et al (2010) Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol 28:3131–3137PubMedCrossRefGoogle Scholar
  15. 15.
    Monk BJ, Mas Lopez L, Zarba JJ et al (2010) Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol 28:3562–3569PubMedCrossRefGoogle Scholar
  16. 16.
    Reguart N, Cardona AF, Rosell R (2010) Role of erlotinib in first-line and maintenance treatment of advanced non-small-cell lung cancer. Cancer Manag Res 2:143–156PubMedGoogle Scholar
  17. 17.
    Therasse P, Arbuck SG, Eisenhauer EA 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 92:205–216PubMedCrossRefGoogle Scholar
  18. 18.
    Lang JM, Harrison MR (2010) Pazopanib for the treatment of patients with advanced renal cell carcinoma. Clin Med Insights Oncol 4:95–105PubMedGoogle Scholar
  19. 19.
    LaPlant KD, Louzon PD (2010) Pazopanib: an oral multitargeted tyrosine kinase inhibitor for use in renal cell carcinoma. Ann Pharmacother 44:1054–1060PubMedCrossRefGoogle Scholar
  20. 20.
    Reck M, Mok T, Wolf J, Heigener D, Wu YL (2011) Reviewing the safety of erlotinib in non-small cell lung cancer. Expert Opin Drug Saf 10:147–157PubMedCrossRefGoogle Scholar
  21. 21.
    Sleijfer S, Ray-Coquard I, Papai Z et al (2009) Pazopanib, a multi-kinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC study 62043). J Clin Oncol 27:3126–3132PubMedCrossRefGoogle Scholar
  22. 22.
    Goh BC, Reddy NJ, Dandamudi UB et al (2010) An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5 + 1 cocktail in patients with advanced solid tumors. Clin Pharmacol Ther 88:652–659PubMedCrossRefGoogle Scholar
  23. 23.
    Duckett DR, Cameron MD (2010) Metabolism considerations for kinase inhibitors in cancer treatment. Expert Opin Drug Metab Toxicol 6:1175–1193PubMedCrossRefGoogle Scholar
  24. 24.
    Rosell R, Carcereny E, Gervais R et al (2012) Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 13:239–246. doi: 10.1016/S1470-2045(11)70393-X PubMedCrossRefGoogle Scholar
  25. 25.
    Zhou C, Wu YL, Chen G et al (2011) Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 12:735–742. doi: 10.1016/S1470-2045(11)70184-X PubMedCrossRefGoogle Scholar
  26. 26.
    Natale RB, Thongprasert S, Greco FA et al (2011) Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 29:1059–1066PubMedCrossRefGoogle Scholar
  27. 27.
    Wedge SR, Ogilvie DJ, Dukes M et al (2002) ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645–4655PubMedGoogle Scholar
  28. 28.
    Scagliotti GV (2007) Potential role of multi-targeted tyrosine kinase inhibitors in non-small-cell lung cancer. Ann Oncol 18(Suppl 10):x32–x41PubMedCrossRefGoogle Scholar
  29. 29.
    Kabbinavar FF, Miller VA, Johnson BE, O'Connor PG, Soh C (2010) Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 28(15s):544, Abstract 7526Google Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Grace K. Dy
    • 1
  • Jeffrey R. Infante
    • 2
  • S. Gail Eckhardt
    • 3
  • Silvia Novello
    • 4
  • Wen Wee Ma
    • 5
  • Suzanne F. Jones
    • 2
  • Anne Huff
    • 6
  • Qiong Wang
    • 6
  • A. Benjamin Suttle
    • 7
  • Lone H. Ottesen
    • 8
  • Alex A. Adjei
    • 5
  • Howard A. BurrisIII
    • 9
  1. 1.Roswell Park Cancer InstituteBuffaloUSA
  2. 2.Sarah Cannon Research InstituteNashvilleUSA
  3. 3.Division of Medical OncologyUniversity of Colorado School of MedicineAuroraUSA
  4. 4.Department of Clinical & Biological SciencesUniversity of TurinOrbassanoItaly
  5. 5.Department of MedicineRoswell Park Cancer InstituteBuffaloUSA
  6. 6.GlaxoSmithKline PharmaceuticalsCollegevilleUSA
  7. 7.GlaxoSmithKline PharmaceuticalsResearch Triangle ParkUSA
  8. 8.GlaxoSmithKline PharmaceuticalsUxbridgeUK
  9. 9.Sarah Cannon Research InstituteNashvilleUSA

Personalised recommendations