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A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE)

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Abstract

Purpose

VEGF, mTOR, and EGFR inhibitors have demonstrated anti-tumor and anti-angiogenic effects alone and in combination with each other. This study evaluated the safety, tolerability, and pharmacokinetics of bevacizumab, everolimus, and erlotinib combination.

Methods

Doublet therapy consisted of bevacizumab at 10 mg/kg every 14 days and everolimus 5 mg daily which escalated to 10 mg daily. Erlotinib 75 mg daily was added to the phase II dose recommended phase II dose (RPTD) of bevacizumab and everolimus. Dose-limiting toxicity (DLT) was assessed in cycle 1.

Results

Forty-eight patients with advanced solid malignancies were evaluable for DLT and efficacy. No DLTs were observed in the doublet dose escalation. Two DLTs (grade 3 mucositis and grade 3 rash) were observed with the addition of erlotinib 75 mg daily. Consequently, triplet doses were adjusted and were better tolerated. Four patients had a partial response. Median progression-free survival (PFS) for the doublet therapy was 6.0 months (0.5 to 32+ months) and 5.5 months (0.8 to 27+ months) for the triplet therapy. Systemic exposure of everolimus was significantly higher in combination with erlotinib (476 ± 161 ng h/mL) compared to when given alone (393 ± 156 ng h/mL; P = 0.020).

Conclusions

The RPTD for the doublet therapy is bevacizumab 10 mg/kg every 14 days and everolimus 10 mg daily, and the RPTD for the triplet therapy is bevacizumab 5 mg/kg every 14 days, everolimus 5 mg and erlotinib 75 mg daily. Prolonged disease stability was demonstrated in tumors known to respond to mTOR inhibition and potentially resistant to VEGF blockade.

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References

  1. Ciardiello F, Tortora G (2003) Epidermal growth factor receptor (EGFR) as a target in cancer therapy: understanding the role of receptor expression and other molecular determinants that could influence the response to anti-EGFR drugs. Eur J Cancer 39:1348–1354

    Article  CAS  PubMed  Google Scholar 

  2. Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174

    Article  CAS  PubMed  Google Scholar 

  3. Grant S (2008) Cotargeting survival signaling pathways in cancer. The Journal of clinical investigation 118:3003–3006

    Article  CAS  PubMed  Google Scholar 

  4. Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027

    Article  CAS  PubMed  Google Scholar 

  5. Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27:2278–2287

    Article  CAS  PubMed  Google Scholar 

  6. Fukumura D, Jain RK (2007) Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize. J Cell Biochem 101:937–949

    Article  CAS  PubMed  Google Scholar 

  7. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014

    Article  CAS  PubMed  Google Scholar 

  8. Kerbel RS (2008) Tumor angiogenesis. N Engl J Med 358:2039–2049

    Article  CAS  PubMed  Google Scholar 

  9. Hainsworth JD, Sosman JA, Spigel DR, Edwards DL, Baughman C, Greco A (2005) Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23:7889–7896

    Article  CAS  PubMed  Google Scholar 

  10. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892–5899

    Article  CAS  PubMed  Google Scholar 

  11. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342

    Article  CAS  PubMed  Google Scholar 

  12. Saltz LB, Lenz HJ, Kindler HL, Hochster HS, Wadler S, Hoff PM, Kemeny NE, Hollywood EM, Gonen M, Quinones M, Morse M, Chen HX (2007) Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol 25:4557–4561

    Article  CAS  PubMed  Google Scholar 

  13. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550

    Article  CAS  PubMed  Google Scholar 

  14. Wu W, Onn A, Isobe T, Itasaka S, Langley RR, Shitani T, Shibuya K, Komaki R, Ryan AJ, Fidler IJ, Herbst RS, O’Reilly MS (2007) Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade. Mol Cancer Ther 6:471–483

    Article  CAS  PubMed  Google Scholar 

  15. Goudar RK, Shi Q, Hjelmeland MD, Keir ST, McLendon RE, Wikstrand CJ, Reese ED, Conrad CA, Traxler P, Lane HA, Reardon DA, Cavenee WK, Wang XF, Bigner DD, Friedman HS, Rich JN (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4:101–112

    CAS  PubMed  Google Scholar 

  16. Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, Iwata KK, Gibson NW, Griffin G (2006) Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther 5:2676–2684

    Article  CAS  PubMed  Google Scholar 

  17. Buck E, Eyzaguirre A, Haley JD, Gibson NW, Cagnoni P, Iwata KK (2006) Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER-3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity. Mol Cancer Ther 5:2051–2059

    Article  CAS  PubMed  Google Scholar 

  18. Bianco R, Garofalo S, Rosa R, Damiano V, Gelardi T, Daniele G, Marciano R, Ciardiello F, Tortora G (2008) Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs. Br J Cancer 98:923–930

    Article  CAS  PubMed  Google Scholar 

  19. O’Reilly T, Lane HA, Wood JM, Schnell C, Littlewood-Evans A, Brueggen J, McSheehy PM (2010) Everolimus and PTK/ZK show synergistic growth inhibition in the orthotopic BL16/BL6 murine melanoma model. Cancer Chemother Pharmacol. Published online 30 May 2010

  20. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC (1997) Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 89:1138–1147

    Article  CAS  PubMed  Google Scholar 

  21. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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. Journal of the National Cancer Institute 92:205–216

    CAS  Google Scholar 

  22. Brignol N, McMahon LM, Luo S, Tse FL (2001) High-throughput semi-automated 96-well liquid/liquid extraction and liquid chromatography/mass spectrometric analysis of everolimus (RAD 001) and cyclosporin a (CsA) in whole blood. Rapid Commun Mass Spectrom 15:898–907

    Article  CAS  PubMed  Google Scholar 

  23. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ (2006) Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res 12:2166–2171

    Article  CAS  PubMed  Google Scholar 

  24. Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG, Krug LM, Pao W, Pizzo B, Rizvi NA, Miller VA (2007) Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 110:599–605

    Article  CAS  PubMed  Google Scholar 

  25. Papadimitrakopoulou V, Blumenschein GR, Leighl NB, Bennouna J, Soria JC, Burris I HA, Dimitrijevic S, Kunz T, Di Scala L, Johnson BE (2008) A phase 1/2 study investigating the combination of RAD001 (R) (everolimus) and erlotinib (E) as 2nd and 3rd line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy (C): Phase 1 results. J Clin Oncol 26: May 20 suppl abst 8051

    Google Scholar 

  26. Robins HI, Wen PY, Chang SM, Kuhn J, Lamborn K, Cloughesy T, Glibert MR, Yung WK, Dancey J, Prados MD (2007) Phase I study of erlotinib and CCI-779 (temsirolimus) for patients with recurrent malignant gliomas (MG) (NABTC 04–02). J Clin Oncol 25: 18 S June 20 suppl abst 2057

  27. Howard LA, Bullock KE, Bendell JC, Uronis HE, Vlahovic G, Blobe GC, Riedel RF, Nixon AB, Gockerman JP, Hurwitz HI (2009) Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors. J Clin Oncol 27: 15S abstr 3551

    Google Scholar 

  28. Flechner SM (2008) Reviewing the evidence for de novo immunosuppression with sirolimus. Transpl Proc 40:S25–S28

    Article  CAS  Google Scholar 

  29. Chawla SP, Tolcher AW, Staddon AP, Schuetze S, D’Amato GZ, Blay JY, Loewy J, Kan R, Demetri GD (2007) Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial. J Clin Oncol 25: 18S (June Suppl abstr10076)

  30. Duran I, Le L, Saltman D, Kortmansky J, Kocha W, Singh D, Pond GR, Peralba JM, Dancey J, Siu LL (2005) A phase II trial of temsirolimus in metastatic neuroendocrine carcinomas (NECs) J Clin Oncol: 16S (June 1 Suppl abstr 3096)

  31. Raymond E, Niccoli P, Raoul J, Bang Y, Borbath I, Lombard-Bohas C, Valle JW, Patyna S, Chao RC, Lu D (2010) Cox proportional hazard analysis of sunitinib (SU) efficacy across subgroups of patients (pts) with progressive pancreatic neuroendocrine tumors (NET). J Clin Oncol 28: 15S (abstr 4031)

  32. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  CAS  PubMed  Google Scholar 

  33. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111

    Article  PubMed  Google Scholar 

  34. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O’Toole T, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356:2271–2281

    Article  CAS  PubMed  Google Scholar 

  35. 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 (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456

    Article  CAS  PubMed  Google Scholar 

  36. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124

    Article  CAS  PubMed  Google Scholar 

  37. Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, Jacobs C, Mares JE, Landgraf AN, Rashid A, Meric-Bernstam F (2008) Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol 26:4311–4318

    Article  PubMed  Google Scholar 

  38. Sternberg CN, Szczylik C, Lee E, Salman PV, Mardiak J, Davis ID, Pandite L, Chen M, McCann L, Hawki R (2009) A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). J Clin Oncol 27: 15S abstr 5021

    Google Scholar 

  39. Yao J, Shah M, Ito T, Lombard-Bohas C, Wolin E, Van Cutsem E, Hobday T, Sachs C, Hoosen S, Lincy J, David Lebwohl, Oberg K (2010) Everolimus versus placebo in patients with advanced pancreatic neuroendocrine tumors (pNET) (RADIANT-3). Presented at the World Congress on Gastrointestinal Cancer, July 2010 Poster O-0028

  40. Sankhala KK, Chawla SP, Iagaru A, Dellamaggiora R, Chua V, Daly S, Bedrosian CL, Edwards GK, Cohen S, Demetri GD, Group ASS (2005) Early response evaluation of therapy with AP23573 (an mTOR inhibitor) in sarcoma using [18F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan J Clin Oncol 23: 16S June 1 Suppl abstr 9028

  41. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson III AB (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544

    Article  CAS  PubMed  Google Scholar 

  42. Saltz LB, Rosen LS, Marshall JL, Belt RJ, Hurwitz HI, Eckhardt SG, Bergsland EK, Haller DG, Lockhart AC, Rocha Lima CM, Huang X, DePrimo SE, Chow-Maneval E, Chao RC, Lenz HJ (2007) Phase II trial of sunitinib in patients with metastatic colorectal cancer after failure of standard therapy. J Clin Oncol 25:4793–4799

    Article  CAS  PubMed  Google Scholar 

  43. Fuchs CS, Tabernero JM, Hwang J, Bajetta E, Sharma S, DelPrete SA, Arrowsmith ER, Ryan DP, Hoosen S Multicenter phase II study of RAD001 in patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). 2009 Gastrointestinal Cancers Symposium abstr 446

  44. Townsley CA, Major P, Siu LL, Dancey J, Chen E, Pond GR, Nicklee T, Ho J, Hedley D, Tsao M, Moore MJ, Oza AM (2006) Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94:1136–1143

    Article  CAS  PubMed  Google Scholar 

  45. Bullock KE, Hurwitz HI, Uronis HE, Morse MA, Blobe GC, Hsu SD, Zafar SY, Nixon AB, Howard LA, Bendell JC (2009) Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC). J Clin Oncol 27: 15S abstr 4080

    Google Scholar 

  46. Kovarik JM, Hartmann S, Hubert M, Berthier S, Schneider W, Rosenkranz B, Rordorf C (2002) Pharmacokinetic and pharmacodynamic assessments of HMG-CoA reductase inhibitors when coadministered with everolimus. J Clin Pharmacol 42:222–228

    Article  CAS  PubMed  Google Scholar 

  47. Ling J, Johnson KA, Miao Z, Rakhit A, Pantze MP, Hamilton M, Lum BL, Prakash C (2006) Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers. Drug metabolism and disposition: the biological fate of chemicals 34:420–426

    CAS  Google Scholar 

  48. Zevin S, Benowitz NL (1999) Drug interactions with tobacco smoking. An update. Clinical pharmacokinetics 36:425–438

    Article  CAS  Google Scholar 

  49. Li J, Zhao M, He P, Hidalgo M, Baker SD (2007) Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res 13:3731–3737

    Article  CAS  PubMed  Google Scholar 

  50. OSI Pharmaceuticals I, Genentech Inc., F. Hoffman-La Roche Ltd (2007) Tarceva Investigator’s Brochure

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Acknowledgments

The authors would like to thank the patients, their families, and our phase I research staff: Shawna Savage, Jill Ashton, Christy Arrowood, Dorris Lockamy, Catherine Lowe, Sharon Norman, Neal Kaplan, Kathy Coleman, and Denise Morgan.

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Author notes

  1. Karen E. Bullock

    Present address: United States Navy, Portsmouth, VA, 23708, USA

  2. Islam Younis

    Present address: United States Food and Drug Administration, Silver Spring, MD, 20993, USA

  3. Joanne J. Lager

    Present address: Sanofi-aventis, Malvern, PA, 19355, USA

  4. Johanna C. Bendell

    Present address: Sarah Cannon Research Institute, Nashville, TN, 37203, USA

Authors and Affiliations

  1. Duke University Medical Center, Seeley G. Mudd Bldg, 10 Bryan Searle Drive, Box 3052, Durham, NC, 27710, USA

    Karen E. Bullock, Hope E. Uronis, Michael A. Morse, Gerard C. Blobe, S. Yousuf Zafar, Jon P. Gockerman, Joanne J. Lager, Roxanne Truax, Kellen L. Meadows, Leigh A. Howard, Margot M. O’Neill, Gloria Broadwater, Herbert I. Hurwitz & Johanna C. Bendell

  2. Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, 26506, USA

    William P. Petros & Islam Younis

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  1. Karen E. Bullock
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Corresponding author

Correspondence to Herbert I. Hurwitz.

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Bullock, K.E., Petros, W.P., Younis, I. et al. A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE). Cancer Chemother Pharmacol 67, 465–474 (2011). https://doi.org/10.1007/s00280-010-1507-6

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  • DOI: https://doi.org/10.1007/s00280-010-1507-6

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