Blockade of Insulin-like growth factor type-1 receptor with cixutumumab (IMC-A12): A novel approach to treatment for multiple cancers

Current Drug Targets

Volumn 12, Issue 14, 2011, Pages 2016-2033

  Rowinsky, Eric K ^a,b   Schwartz, Jonathan D ^a   Zojwalla, Naseem ^a,c   Youssoufian, Hagop ^a,d   Fox, Floyd ^a   Pultar, Philippe ^a,e   Novosyadlyy, Ruslan ^a   Cosaert, Jan ^a   Ludwig, Dale L ^a  

^a ELI LILLY AND COMPANY   (United States)

^b Oncodrugs   (United States)

^c ONYX PHARMACEUTICALS   (United States)

^d Ziopharm Oncology Inc   (United States)

^e AGENNIX INC   (United States)

Author keywords

Cixutumumab; IGF 1R; IMC A12; Insulin like growth factor receptor type 1; Monoclonal antibody

Indexed keywords

CIXUTUMUMAB; IMMUNOGLOBULIN F(AB) FRAGMENT; IMMUNOGLOBULIN G1; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; SOMATOMEDIN C RECEPTOR;

ADVANCED CANCER; ANTIBODY SCREENING; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AREA UNDER THE CURVE; BACTERIOPHAGE; BINDING ASSAY; BREAST CANCER; CANCER CELL DESTRUCTION; CANCER COMBINATION CHEMOTHERAPY; CANCER HORMONE THERAPY; CANCER INHIBITION; CANCER RADIOTHERAPY; CANCER REGRESSION; CANCER SURVIVAL; DOWN REGULATION; DRUG MECHANISM; DRUG METABOLISM; DRUG RECEPTOR BINDING; DRUG TOLERABILITY; EVENT FREE SURVIVAL; HUMAN; IC 50; INTERNALIZATION; MAXIMUM PLASMA CONCENTRATION; MOLECULAR CLONING; MOLECULARLY TARGETED THERAPY; MONOTHERAPY; MULTIPLE MYELOMA; NONHUMAN; PHARMACOLOGICAL BLOCKING; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); POLYMERASE CHAIN REACTION; PROSTATE CANCER; PROTEIN DEGRADATION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR;

ANIMALS; ANTIBODIES, MONOCLONAL; DRUG RESISTANCE, NEOPLASM; HUMANS; INSULIN-LIKE GROWTH FACTOR I; NEOPLASMS; RECEPTOR, IGF TYPE 1;

EID: 84855904697     PISSN: 13894501     EISSN: 18735592     Source Type: Journal    
DOI: 10.2174/138945011798829401     Document Type: Review

References (139)

1. McKian KP, Haluska P. Cixutumumab. Expert Opin Investig Drugs 2009; 18: 1025-33.
2. Rowinsky EK, Youssoufian H, Tonra JR, et al. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res 2007; 13: 5549s-55s.
3. Ryan PD, Goss PE. The emerging role of the insulin-like growth factor pathway as a therapeutic target in cancer. Oncologist 2008; 13: 16-24.
4. Samani AA, Yakar S, LeRoith D, et al. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007; 28: 20-47.
5. Miller BS, Yee D. Type I insulin-like growth factor receptor as a therapeutic target in cancer. Cancer Res 2005; 65: 10123-7.
6. Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 2003; 349: 2211-22.
7. Woods KA, Camacho-Hubner C, Savage MO, et al. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 1996; 335: 1363-7.
8. Feldman EL, Sullivan KA, Kim B, et al. Insulin-like growth factors regulate neuronal differentiation and survival. Neurobiol Dis 1997; 4: 201-14.
9. Garcia-Segura LM, Cardona-Gomez GP, Chowen JA, et al. Insulin-like growth factor-I receptors and estrogen receptors interact in the promotion of neuronal survival and neuroprotection. J Neurocytol 2000; 29: 425-37.
10. McMullen JR, Shioi T, Huang WY, et al. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110alpha) pathway. J Biol Chem 2004; 279: 4782-93.
11. Ruan W, Newman CB, Kleinberg DL. Intact and amino-terminally shortened forms of insulin-like growth factor I induce mammary gland differentiation and development. Proc Natl Acad Sci USA 1992; 89: 10872-6.
12. Ruan W, Powell-Braxton L, Kopchick JJ, et al. Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development. Endocrinology 1999; 140: 1984-9.
13. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 2007; 6: 1-12.
14. Rubini M, Hongo A, D'Ambrosio C, et al. The IGF-I receptor in mitogenesis and transformation of mouse embryo cells: role of receptor number. Exp Cell Res 1997; 230: 284-92.
15. Cullen KJ, Yee D, Sly WS, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 1990; 50: 48-53.
16. Lee AV, Yee D. Insulin-like growth factors and breast cancer. Biomed Pharmacother 1995; 49: 415-21.
17. Quinn KA, Treston AM, Unsworth EJ, et al. Insulin-like growth factor expression in human cancer cell lines. J Biol Chem 1996; 271: 11477-83.
18. Wu Y, Yakar S, Zhao L, et al. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 2002; 62: 1030-5.
19. All-Ericsson C, Girnita L, Seregard S, et al. Insulin-like growth factor-1 receptor in uveal melanoma: a predictor for metastatic disease and a potential therapeutic target. Invest Ophthalmol Vis Sci 2002; 43: 1-8.
20. Ge NL, Rudikoff S. Insulin-like growth factor I is a dual effector of multiple myeloma cell growth. Blood 2000; 96: 2856-61.
21. Nickerson T, Chang F, Lorimer D, et al. In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulinlike growth factor I (IGF-I) and IGF-I receptor (IGF-IR). Cancer Res 2001; 61: 6276-80.
22. Yee D, Morales FR, Hamilton TC, et al. Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer. Cancer Res 1991; 51: 5107-12.
23. Pollak M. Insulin-like growth factor physiology and cancer risk. Eur J Cancer 2000; 36: 1224-8.
24. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998; 351: 1393-6.
25. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998; 279: 563-6.
26. Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999; 91: 620-5.
27. Yu H, Spitz MR, Mistry J, et al. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-control analysis. J Natl Cancer Inst 1999; 91: 151-6.
28. Cheng I, Stram DO, Penney KL, et al. Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst 2006; 98: 123-34.
29. Wagner K, Hemminki K, Israelsson E, et al. Polymorphisms in the IGF-1 and IGFBP 3 promoter and the risk of breast cancer. Breast Cancer Res Treat 2005; 92: 133-40.
30. Zecevic M, Amos CI, Gu X, et al. IGF1 gene polymorphism and risk for hereditary nonpolyposis colorectal cancer. J Natl Cancer Inst 2006; 98: 139-43.
31. Yaginuma Y, Nishiwaki K, Kitamura S, et al. Relaxation of insulin-like growth factor-II gene imprinting in human gynecologic tumors. Oncology 1997; 54: 502-7.
32. Cui H, Cruz-Correa M, Giardiello FM, et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 2003; 299: 1753-5.
33. Sarfstein R, Maor S, Reizner N, et al. Transcriptional regulation of the insulin-like growth factor-I receptor gene in breast cancer. Mol Cell Endocrinol 2006; 252: 241-6.
34. Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer 2004; 4: 505-18.
35. McCampbell AS, Broaddus RR, Loose DS, et al. Overexpression of the insulin-like growth factor I receptor and activation of the AKT pathway in hyperplastic endometrium. Clin Cancer Res 2006; 12: 6373-8.
36. Abe S, Funato T, Takahashi S, et al. Increased expression of insulin-like growth factor I is associated with Ara-C resistance in leukemia. Tohoku J Exp Med 2006; 209: 217-28.
37. Allen GW, Saba C, Armstrong EA, et al. Insulin-like growth factor-I receptor signaling blockade combined with radiation. Cancer Res 2007; 67: 1155-62.
38. Camirand A, Lu Y, Pollak M. Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med Sci Monit 2002; 8: BR521-6.
39. Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoel MJ, et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer 2006; 119: 2557-66.
40. Gee JM, Robertson JF, Gutteridge E, et al. Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer 2005; 12(suppl 1): S99-S111.
41. Wan X, Helman LJ. Effect of insulin-like growth factor II on protecting myoblast cells against cisplatin-induced apoptosis through p70 S6 kinase pathway. Neoplasia 2002; 4: 400-8.
42. Wiseman LR, Johnson MD, Wakeling AE, et al. Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur J Cancer 1993; 29A: 2256-64.
43. Dunn SE, Hardman RA, Kari FW, et al. Insulin-like growth factor 1 (IGF-1) alters drug sensitivity of HBL100 human breast cancer cells by inhibition of apoptosis induced by diverse anticancer drugs. Cancer Res 1997; 57: 2687-93.
44. Gooch JL, Van Den Berg CL, Yee D. Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death-proliferative and anti-apoptotic effects. Breast Cancer Res Treat 1999; 56: 1-10.
45. Lee JY, Han CY, Yang JW, et al. Induction of glutathione transferase in insulin-like growth factor type I receptoroverexpressed hepatoma cells. Mol Pharmacol 2007; 72: 1082-93.
46. Yee D, Favoni RE, Lebovic GS, et al. Insulin-like growth factor I expression by tumors of neuroectodermal origin with the t(11;22) chromosomal translocation. A potential autocrine growth factor. J Clin Invest 1990; 86: 1806-14.
47. Eckstein N, Servan K, Hildebrandt B, et al. Hyperactivation of the Insulin-like growth factor receptor I signaling pathway is an essential event for cisplatin resistance of ovarian cancer cells. Cancer Res 2009; 69: 2996-3003.
48. Huang GS, Brouwer-Visser J, Ramirez MJ. Insulin-like growth factor 2 expression modulates taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin Cancer Res 2010; 16: 2999-3010.
49. Ibanez de Caceres I, Cortes-Sempere M, Moratilla C, et al. IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small cell lung cancer. 2010; 29: 1681-90.
50. Turner BC, Haffty BG, Narayanan L, et al. Insulin-like growth factor-I receptor overexpression mediates cellular radioresistance and local breast cancer recurrence after lumpectomy and radiation. Cancer Res 1997; 57: 3079-83.
51. Riesterer O, Yang Q, Raju U, et al. Combination of anti-IGF-1R antibody A12 and ionizing radiation in upper respiratory tract cancers. Int J Radiat Oncol Biol Phys. 2011; 79:1179-87.
52. Rochester MA, Riedemann J, Hellawell GO, et al. Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer. Cancer Gene Ther 2005; 12: 90-100.
53. Massarweh S, Osborne CK, Creighton CJ, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 2008; 68: 826-33.
54. Campbell RA, Bhat-Nakshatri P, Patel NM, et al. Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α: a new model for anti-estrogen resistance. J Biol Chem 2001; 276: 9817-24.
55. Wu JD, Haugk K, Coleman I, et al. Combined in vivo effect of A12, a type 1 insulin-like growth factor receptor antibody, and docetaxel against prostate cancer tumors. Clin Cancer Res 2006; 12: 6153-60.
56. Culig Z, Hobisch A, Cronauer MV, et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994; 54: 5474-8.
57. Chakravarti A, Loeffler JS, Dyson NJ. Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 2002; 62: 200-7.
58. Lu Y, Zi X, Zhao Y, et al. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 2001; 93: 1852-7.
59. Haluska P, Carboni JM, TenEyck C, et al. HER receptor signaling confers resistance to the insulin-like growth factor-I receptor inhibitor, BMS-536924. Mol Cancer Ther 2008; 7: 2589-98.
60. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500-8.
61. Dai N, Rapley J, Angel M, et al. mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes Dev 2011; 25: 1159-72.
62. Racanelli AC, Rothbart SB, Heyer CL, Moran RG. Therapeutics by cytotoxic metabolite accumulation: pemetrexed causes ZMP accumulation, AMPK activation, and mammalian target of rapamycin inhibition. Cancer Res 2009; 69: 5467-74.
63. Rothbart SB, Racanelli AC, Moran RG. Pemetrexed indirectly activates the metabolic kinase AMPK in human carcinomas. Cancer Res 2010; 70: 10299-309.
64. Yuen JS, Macaulay VM. Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Expert Opin Ther Targets 2008; 12: 589-603.
65. Burtrum D, Zhu Z, Lu D, et al. A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks liganddependent signaling and inhibits human tumor growth in vivo. Cancer Res 2003; 63: 8912-21.
66. Lu D, Zhang H, Ludwig D, et al. Simultaneous blockade of both the epidermal growth factor receptor and the insulin-like growth factor receptor signaling pathways in cancer cells with a fully human recombinant bispecific antibody. J Biol Chem 2004; 279: 2856-65.
67. Allen G, Armstrong E, Modhia F, et al. Inhibition of insulin-like growth factor-1 receptor signaling impairs proliferation of head and neck, lung, prostate, and breast cancer cells. The 96th Annual Meeting of the American Association for Cancer Research; Anaheim/Orange County, CA, April 16-20, 2005.
68. Wu K, Zhou L, Zhang K, et al. A humanized insulin-like growth factor I receptor antibody inhibits multiple myeloma cell growth in vivo through anti-angiogenesis. The 96th Annual Meeting of the American Association for Cancer Research; Anaheim/Orange County, CA, April 16-20, 2005.
69. Burtrum D, Pytowski B, Ludwig DL. Abrogation of PTEN does not confer resistance to anti-IGF-IR targeted therapy in IGF responsive tumor cells. The 98th Annual Meeting of the American Association for Cancer Research; Los Angeles, CA, April 14-18, 2007.
70. Wu J, Higgins L, Haugk K, et al. Blocking IGF-1R poses differential effects on androgen-dependent and androgenindependent human prostate cancer. The 96th Annual Meeting of the American Association for Cancer Research; Anaheim/Orange County, CA, April 16-20, 2005.
71. Wu JD, Odman A, Higgins LM, et al. In vivo effects of the human type I insulin-like growth factor receptor antibody A12 on androgen-dependent and androgen-independent xenograft human prostate tumors. Clin Cancer Res 2005; 11: 3065-74.
72. Haugk K, Coleman I, Wu JD, et al. TSC-22 is a potential proapoptotic prostate tumor suppressor gene regulated by androgen and IGF-1R signaling in prostate epithelium. The 97th Annual Meeting of the American Association for Cancer Research; Washington, DC, April 1-5, 2006.
73. Haugk K, Woodke L, Sun S, et al. Determinants of response to type 1 insulin-like growth factor receptor inhibition by human monoclonal antibodies in prostate cancer. The 15th Annual SPORE Investigators' Workshop; Boston, MA, July 7-10, 2007.
74. Wu KD, Zhou L, Burtrum D, et al. Antibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis. Cancer Immunol Immunother 2007; 56: 343-57.
75. Houghton PJ, Morton CL, Gorlick R, et al. Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2010; 54: 921-6.
76. Plymate SR, Wu JD, Odman A, et al. Inhibition of IGF-1R signaling with the human monoclonal antibody A12 enhances the therapeutic effect of docetaxel in prostate cancer. The 96th Annual Meeting of the American Association for Cancer Research; Anaheim/Orange County, CA, April 16-20, 2005.
77. Plymate SR, Lavoie N, Haugk K, et al. IGF-1R as a target with the human monoclonal antibody A12 in prostate cancer. The 2006 Prostate Cancer Inter-SPORE Meeting; Houston, TX, February 4-6, 2006.
78. Wang Z, Chakravarty G, Kim S, et al. Growth-inhibitory effects of human anti-insulin-like growth factor-I receptor antibody (A12) in an orthotopic nude mouse model of anaplastic thyroid carcinoma. Clin Cancer Res 2006; 12: 4755-65.
79. Yeh J, Litz J, Hauck P, et al. Selective inhibition of SCLC growth by the A12 anti-IGF-1R monoclonal antibody correlates with inhibition of Akt. The 98th Annual Meeting of the American Association for Cancer Research; Los Angeles, CA, April 14-18, 2007.
80. Ludwig DL, Tonra JR, Burtrum D, et al. Potent anti-tumor activity of IGF-I receptor antagonist antibody IMC-A12 alone and in combination with CPT-11. The 95th Annual Meeting of the American Association for Cancer Research; Orlando, FL, March 27-31, 2004.
81. Plymate SR, Haugk K, Coleman I, et al. An antibody targeting the type I insulin-like growth factor receptor enhances the castration induced response in androgen-dependent prostate cancer. Clin Cancer Res 2007; 13: 6429-39.
82. Lee AV, Cui X, Oesterreich S. Cross-talk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res 2001; 7(Suppl): 4429s-35s; discussion 11s-12s.
83. Best CJM, Ludwig DL, Steeg PS. Breast cancer cell lines resistant to either tamoxifen or Herceptin exhibit sensitivity to the anti-IGF receptor antibody A12 in vitro. The 97th Annual Meeting of the American Association for Cancer Research; Washington, DC, April 1-5, 2006.
84. van der Veeken J, Oliveira S, Schiffelers RM, et al. Crosstalk between epidermal growth factor receptor-and insulin-like growth factor-1 receptor signaling: implications for cancer therapy. Curr Cancer Drug Targets 2009; 9: 748-60.
85. Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res 2009; 15: 5445-56.
86. Prewett M, Damoci C, Bassi R, et al. IMC-A12 enhances the efficacy of cetuximab + gemcitabine therapy in human pancreatic carcinoma xenografts. The 98th Annual Meeting of the American Association for Cancer Research; Los Angeles, CA, April 14-18, 2007.
87. Barnes CJ, Kumar R. Novel mechanistic insights from a preclinical model targeting insulin-like growth factor receptor 1. The 97th Annual Meeting of the American Association for Cancer Research; Washington, DC, April 1-5, 2006.
88. Barnes CJ, Ohshiro K, Rayala SK, et al. Insulin-like growth factor receptor as a therapeutic target in head and neck cancer. Clin Cancer Res 2007; 13: 4291-9.
89. Tonra JR, Corcoran E, Deevi DS, et al. Prioritization of EGFR/IGF-IR/VEGFR2 combination targeted therapies utilizing cancer models. Anticancer Research 2009; 29; 1999-2008.
90. Bertrand FE, Steelman LS, Chappell WH, et al. Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells. Leukemia 2006; 20: 1254-60.
91. Kolb EA, Gorlick R, Maris JM, et al. Combination testing (stage 2) of the anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program [published online ahead of print May 31 2011]. Pediatr Blood Cancer 2011 http://www.ncbi.nlm.nih.gov/pubmed/21630428. Accessed Nov 2, 2011.
92. Rothenberg ML, Poplin E, LoRusso P, et al. Pharmacokinetic (PK) and pharmacodynamic (PD) results of phase I studies of IMC-A12, a fully human insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in patients with advanced solid malignancies. The 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; Geneva, Switzerland, October 21-24, 2008.
93. US National Institutes of Health. Paclitaxel With or Without Cixutumumab as Second-Line Therapy in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer. NCT01142388. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
94. US National Institutes of Health. IMC-A12 in combination with temsirolimus (CCI-779) in patients with advanced cancers. NCT00678769. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
95. US National Institutes of Health. A study of IMC-A12 in patients with tumors who no longer respond to standard therapy or for whom no standard therapy is available. NCT00785538. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
96. Higano C, LoRusso P, Gordon M, et al. A phase I study of the recombinant human IgG1 anti-IGF-1R monoclonal antibody (Mab) IMC-A12, administered on a weekly basis to patients with advanced solid tumors: Interim analysis [poster]. Presented at: 19th AACR-NCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics; San Francisco, CA, October 22-26, 2007.
97. Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. The 3rd Meeting of the American Society of Clinical Oncology Prostate Cancer Symposium; Orlando, FL, February 22-24, 2007.
98. Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. The 43rd Annual Meeting of the American Society of Clinical Oncology; Chicago, IL, June 1-5, 2007.
99. US National Institutes of Health. A study of IMC-A12 every 2 weeks in patients with tumors who no longer respond to treatment or no treatment is available. NCT00785941. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
100. Rothenberg ML, Poplin E, Sandler AB, et al. Phase I doseescalation study of the anti-IGF-1R recombinant human IgG1 monoclonal antibody (Mab) IMC-A12, administered every other week to patients with advanced solid tumors. The 19th AACRNCI-EORTC Symposium on Molecular Targets and Cancer Therapeutics; San Francisco, CA, October 22-26, 2007.
101. US National Institutes of Health. IMC-A12 in treating young patients with relapsed or refractory Ewing sarcoma/peripheral primitive neuroectodermal tumor or other solid tumor. NCT00609141. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
102. Malempati S, Weigel B, Ingle AM, et al. A phase I trial and pharmacokinetic study of IMC-A12 in pediatric patients with relapsed/refractory solid tumors. The 45th Annual Meeting of the American Society of Clinical Oncology; Orlando, FL, May 29-June 2, 2009.
103. US National Institutes of Health. Cixutumumab and temsirolimus in treating young patients with solid tumors that have recurred or not responded to treatment. NCT00880282. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
104. US National Institutes of Health. Cixutumumab in treating patients with relapsed or refractory solid tumors. NCT00831844. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
105. US National Institutes of Health. Phase I dose escalation trial evaluating the safety and tolerability of AZD6244 and IMC-A12 in subjects with advanced solid malignancies. NCT01061749. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
106. US National Institutes of Health. A study of IMC-A12 in advanced solid tumors. NCT01007032. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
107. US National Institutes of Health. A phase I study of IMC-A12 in combination with temsirolimus in pediatric patients with recurrent or refractory solid tumors. NCT01182883. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
108. US National Institutes of Health. A study for safety and effectiveness of IMCA12 by itself or combined with antiestrogens to treat metastatic breast cancer in patients who progressed on antiestrogen therapy. NCT00728949. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
109. US National Institutes of Health. Capecitabine and lapatinib with or without cixutumumab in treating patients with previously treated HER2-positive stage IIIB, stage IIIC, or stage IV breast cancer. NCT00684983. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
110. US National Institutes of Health. IMC-A12 and temsirolimus in treating patients with locally recurrent or metastatic breast cancer. NCT00699491. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
111. US National Institutes of Health. Study using IMC-A12 with or without cetuximab in patients with metastatic colorectal cancer who have failed a treatment regimen that consisted of a prior anti-EGFR therapy. NCT00503685. Available at: www.clinicaltrials. gov. Accessed November 2, 2011.
112. US National Institutes of Health. A study of irinotecan and cetuximab with or without IMC-A12 for treatment of people with colon or rectum cancer who got worse after their first treatment with oxaliplatin and bevacizumab. NCT00845039. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
113. US National Institutes of Health. Study of IMC-A12, alone or in combination with cetuximab, in patients with recurrent or metastatic squamous cell carcinoma (MSCC) of the head and neck. NCT00617734. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
114. US National Institutes of Health. Preoperative treatment with cetuximab and/or IMC-A12. NCT00957853. Available at: www.clinicaltrials.gov. Accessed August 10, 2009.
115. US National Institutes of Health. A study of IMC-A12 in combination with sorafenib in patients with advanced cancer of the liver. NCT00906373. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
116. US National Institutes of Health. IMC-A12 in treating patients with advanced liver cancer. NCT00639509. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
117. US National Institutes of Health. Cixutumumab and sorafenib tosylate in treating patients with advanced liver cancer. NCT01008566. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
118. US National Institutes of Health. A study to test IMC-A12 with and without other standard chemotherapies in patients with lung cancer who have not received chemotherapy before. NCT00870870. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
119. US National Institutes of Health. BATTLE-FL: Front-line biomarker-integrated treatment study in non small cell lung cancer. NCT01263782. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
120. US National Institutes of Health. Paclitaxel, carboplatin, and bevacizumab with or without cixutumumab in treating patients with stage IIIB or stage IV non-small cell lung cancer. NCT00955305. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
121. US National Institutes of Health. Erlotinib with or without IMCA12 in treating patients with stage III or stage IV non-small cell lung cancer. NCT00778167. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
122. US National Institutes of Health. Phase II study of IMC-A12 in patients with mesothelioma who have been previously treated with chemotherapy. NCT01160458. Available at: www.clinicaltrials. gov. Accessed November 2, 2011.
123. US National Institutes of Health. Cixutumumab, everolimus, and octreotide acetate in treating patients with advanced low-or intermediate-grade neuroendocrine cancer. NCT01204476. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
124. US National Institutes of Health. Multicenter study of IMC-A12 in combination with depot octreotide in patients with carcinoid or islet cell cancer. NCT00781911. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
125. US National Institutes of Health. Mitotane with or without IMCA12 in treating patients with recurrent, metastatic, or primary adrenocortical cancer that cannot be removed by surgery. NCT00778817. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
126. US National Institutes of Health. Multicenter phase ll study of IMC-A12 in patients with thymoma and thymic carcinoma who have been previously treated with chemotherapy. NCT00965250. Available at www.clinicaltrials.gov. Accessed November 2, 2011.
127. US National Institutes of Health. Gemcitabine and erlotinib with or without monoclonal antibody therapy in treating patients with metastatic pancreatic cancer that cannot be removed by surgery. NCT00617708. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
128. US National Institutes of Health. Study using IMC-A12 or IMC-1121B plus mitoxantrone and prednisone in metastatic androgenindependent prostate cancer, following disease progression on docetaxel-based chemotherapy. NCT00683475. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
129. US National Institutes of Health. Study of effectiveness of IMCA12 antibody combined with hormone therapy prior to surgery to treat prostate cancer. NCT00769795. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
130. US National Institutes of Health. Study with IMC-A12 in patients who have not previously been treated with chemotherapy with metastatic prostate cancer. NCT00520481. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
131. Higano C, Alumkal J, Ryan CJ, et al. A phase II study evaluating the efficacy and safety of single agent IMC A12, a monoclonal antibody (mAb), against the insulin-like growth factor-1 receptor (IGF-1R), as monotherapy in patients with metastatic, asymptomatic castration-resistant prostate cancer (CRPC) [poster]. Presented at: 45th Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, FL. Abstract 5142.
132. US National Institutes of Health. Bicalutamide and goserelin or leuprolide acetate with or without cixutumumab in treating patients with newly diagnosed metastatic prostate cancer. NCT01120236. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
133. US National Institutes of Health. Cixutumumab and temsirolimus in treating patients with metastatic prostate cancer. NCT01026623. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
134. US National Institutes of health: A five-tier, open-label study of IMC-A12 in advanced sarcoma. NCT00668148. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.!
135. Schöffski P, Adkins D, Blay J-Y, et al. Phase 2 Trial of the Anti-IGF-IR Antibody Cixutumumab in Patients with Advanced or Metastatic Soft Tissue Sarcoma and Ewing Family of Tumors (Poster). 2011 CTOS and MSTS conference. Chicago, IL, October 26-29, 2011.
136. US National Institutes of Health. Temsirolimus and cixutumumab in treating patients with locally advanced, metastatic, or recurrent soft tissue sarcoma or bone sarcoma NCT01016015. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
137. US National Institutes of Health. Monoclonal antibody IMC-A12 and doxorubicin in treating patients with unresectable, locally advanced, or metastatic soft tissue sarcoma. NCT00720174. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
138. US National Institutes of Health. Temozolomide, cixutumumab, and combination chemotherapy in treating patients with metastatic rhabdomyosarcoma. NCT01055314. Available at: www.clinicaltrials.gov. Accessed November 2, 2011.
139. Naing A, LoRusso P, Mills G, et al. Phase I study combining an IGFR inhibitor (IMC-A12) and an mTOR inhibitor (temsirolimus) in patients with solid tumors or lymphoma. The 45th Annual Meeting of the American Society of Clinical Oncology; Orlando, FL, May 29-June 2, 2009.