A phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (BEE)
- 234 Downloads
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.
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.
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).
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.
KeywordsBevacizumab Everolimus Erlotinib Phase I Advanced cancer
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.
- 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 23:5892–5899CrossRefPubMedGoogle 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 350:2335–2342CrossRefPubMedGoogle 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 25:4557–4561CrossRefPubMedGoogle 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 6:471–483CrossRefPubMedGoogle 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 4:101–112PubMedGoogle 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 5:2676–2684CrossRefPubMedGoogle 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 5:2051–2059CrossRefPubMedGoogle 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 2010Google 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 92:205–216Google 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 8051Google 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 2057Google Scholar
- 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 3551Google 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)Google Scholar
- 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)Google Scholar
- 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)Google Scholar
- 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 356:125–134CrossRefPubMedGoogle 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 370:2103–2111CrossRefPubMedGoogle 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 356:2271–2281CrossRefPubMedGoogle 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 372:449–456CrossRefPubMedGoogle 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 26:4311–4318CrossRefPubMedGoogle 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 5021Google 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-0028Google Scholar
- 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 9028Google Scholar
- 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 25:1539–1544CrossRefPubMedGoogle 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 25:4793–4799CrossRefPubMedGoogle 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 446Google 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 4080Google 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 34:420–426Google Scholar
- 50.OSI Pharmaceuticals I, Genentech Inc., F. Hoffman-La Roche Ltd (2007) Tarceva Investigator’s BrochureGoogle Scholar