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Development of Molecularly Targeted Agents in Early Phase Clinical Trials

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Phase I Oncology Drug Development

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Abstract

There are a significant number of signaling networks that play a key role in living organisms, but which are commonly hijacked during oncogenesis. The identification of these drivers of cancer has led to the clinical development and subsequent regulatory approval of multiple molecularly targeted agents. Nonetheless, drug resistance is almost inevitable due to the development of signaling crosstalk, disruption of negative feedback loops and other mechanisms. In order to overcome these challenges, there has been an expansion of clinical trials investigating novel therapies and rational combinations of different targeted agents. Here, we describe the features of successful early phase clinical trials: strong scientific rationale leading to their initiation; robust preclinical data from model systems; inclusion of pharmacokinetic (PK) and pharmacodynamic (PD) proof-of-mechanism studies; use of optimal trial designs; and incorporation of predictive biomarkers of response to optimize patient selection to these trials. Such approaches may optimize and accelerate the drug development process and lead to monotherapy and combination strategies that benefit patients with different cancers.

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References

  1. Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013;31:1592–605.

    Article  CAS  PubMed  Google Scholar 

  2. Paller CJ, Bradbury PA, Ivy SP, et al. Design of phase I combination trials: recommendations of the clinical trial design task force of the NCI investigational drug steering committee. Clin Cancer Res. 2014;20:4210–7.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Kummar S, Chen HX, Wright J, et al. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov. 2010;9:843–56.

    Article  CAS  PubMed  Google Scholar 

  4. Sever R, Brugge JS. Signal transduction in cancer. Cold Spring Harb Perspect Med. 2015;5:a006098.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13:871–82.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Porta R, Borea R, Coelho A, et al. FGFR a promising druggable target in cancer: molecular biology and new drugs. Crit Rev Oncol Hematol. 2017;113:256–67.

    Article  PubMed  Google Scholar 

  7. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–310.

    Article  CAS  PubMed  Google Scholar 

  8. Morgensztern D, McLeod HL. PI3K/Akt/mTOR pathway as a target for cancer therapy. Anti-Cancer Drugs. 2005;16:797–803.

    Article  CAS  PubMed  Google Scholar 

  9. Cecchi F, Rabe DC, Bottaro DP. Targeting the HGF/met signaling pathway in cancer. Eur J Cancer. 2010;46:1260–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Thomas SJ, Snowden JA, Zeidler MP, et al. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer. 2015;113:365–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Yuan X, Wu H, Xu H, et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 2015;369:20–7.

    Article  CAS  PubMed  Google Scholar 

  12. Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res. 2014;2:823–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2016;36:1461.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Neel DS, Bivona TG. Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma. Precis Oncol. 2017;1:3.

    Article  Google Scholar 

  15. Soria J-C, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non–small-cell lung cancer. N Engl J Med. 2018;378:113–25.

    Article  CAS  PubMed  Google Scholar 

  16. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  CAS  PubMed  Google Scholar 

  17. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Swain SM, Baselga J, Kim S-B, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Humphrey RW, Brockway-Lunardi LM, Bonk DT, et al. Opportunities and challenges in the development of experimental drug combinations for cancer. J Natl Cancer Inst. 2011;103:1222–6.

    Article  CAS  PubMed  Google Scholar 

  21. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Shih H-P, Zhang X, Aronov AM. Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications. Nat Rev Drug Discov. 2017;17:19.

    Article  PubMed  CAS  Google Scholar 

  23. Tuntland T, Ethell B, Kosaka T, et al. Implementation of pharmacokinetic and pharmacodynamic strategies in early research phases of drug discovery and development at Novartis Institute of Biomedical Research. Front Pharmacol. 2014;5:174.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Garralda E, Dienstmann R, Tabernero J. Pharmacokinetic/pharmacodynamic modeling for drug development in oncology. Am Soc Clin Oncol Educ Book. 2017:210–5.

    Google Scholar 

  25. Zang Y, Lee JJ. Adaptive clinical trial designs in oncology. Chin Clin Oncol. 2014;3:49.

    PubMed Central  PubMed  Google Scholar 

  26. Standing JF. Understanding and applying pharmacometric modelling and simulation in clinical practice and research. Br J Clin Pharmacol. 2017;83:247–54.

    Article  PubMed  Google Scholar 

  27. Banerji U, Workman P. Critical parameters in targeted drug development: the pharmacological audit trail. Semin Oncol. 2016;43:436–45.

    Article  CAS  PubMed  Google Scholar 

  28. Sweeney C, Percent IJ, Babu S, et al. Phase 1b/2 study of enzalutamide (ENZ) with LY3023414 (LY) or placebo (PL) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) after progression on abiraterone. Proc Am Soc Clin Oncol. 2019;37:5009.

    Article  Google Scholar 

  29. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor–positive advanced breast cancer. N Engl J Med. 2011;366:520–9.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Hirakawa A, Asano J, Sato H, et al. Master protocol trials in oncology: review and new trial designs. Contemp Clin Trials Commun. 2018;12:1–8.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Cook N, Hansen AR, Siu LL, et al. Early phase clinical trials to identify optimal dosing and safety. Mol Oncol. 2015;9:997–1007.

    Article  CAS  PubMed  Google Scholar 

  32. Parchment RE, Doroshow JH. Pharmacodynamic endpoints as clinical trial objectives to answer important questions in oncology drug development. Semin Oncol. 2016;43:514–25.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Kurnit KC, Ileana Dumbrava EE, Litzenburger BC, et al. Precision oncology decision support: current approaches and strategies for the future. Clin Cancer Res. 2018;24:2719–31.

    Article  PubMed Central  PubMed  Google Scholar 

  34. Yan W-T, Cui X, Chen Q, et al. Circulating tumor cell status monitors the treatment responses in breast cancer patients: a meta-analysis. Sci Rep. 2017;7:43464.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Araujo DV, Bratman SV, Siu LL. Designing circulating tumor DNA-based interventional clinical trials in oncology. Genome Med. 2019;11:22.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34:1402–18.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the gynecological cancer intergroup (GCIG). Int J Gynecol Cancer. 2011;21:419–23.

    Article  PubMed  Google Scholar 

  38. Gayed I, Vu T, Iyer R, et al. The role of 18F-FDG PET in staging and early prediction of response to therapy of recurrent gastrointestinal stromal tumors. J Nucl Med. 2004;45:17–21.

    CAS  PubMed  Google Scholar 

  39. Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer. N Engl J Med. 2012;366:109–19.

    Article  CAS  PubMed  Google Scholar 

  40. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376:629–40.

    Article  CAS  PubMed  Google Scholar 

  41. Wilhelm-Benartzi CS, Mt-Isa S, Fiorentino F, et al. Challenges and methodology in the incorporation of biomarkers in cancer clinical trials. Crit Rev Oncol Hematol. 2017;110:49–61.

    Article  PubMed  Google Scholar 

  42. Torti D, Trusolino L. Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med. 2011;3:623–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365:1273–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Solomon BJ, Mok T, Kim D-W, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371:2167–77.

    Article  PubMed  CAS  Google Scholar 

  45. Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Robson M, Im S-A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523–33.

    Article  CAS  PubMed  Google Scholar 

  48. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382–92.

    Article  CAS  PubMed  Google Scholar 

  49. Kummar S, Williams PM, Lih CJ, et al. Application of molecular profiling in clinical trials for advanced metastatic cancers. J Natl Cancer Inst. 2015;107:djv003.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  50. Mayo C, Bertran-Alamillo J, Molina-Vila MA, et al. Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications. Pharmacogenomics. 2012;13:789–802.

    Article  CAS  PubMed  Google Scholar 

  51. Tolcher AW, Baird RD, Patnaik A, et al. A phase I dose-escalation study of oral MK-2206 (allosteric AKT inhibitor) with oral selumetinib (AZD6244; MEK inhibitor) in patients with advanced or metastatic solid tumors. J Clin Oncol. 2011;29:–3004.

    Google Scholar 

  52. Al-Lazikani B, Banerji U, Workman P. Combinatorial drug therapy for cancer in the post-genomic era. Nat Biotechnol. 2012;30:679–92.

    Article  CAS  PubMed  Google Scholar 

  53. Garnett MJ, McDermott U. The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response. Curr Opin Genet Dev. 2014;24:114–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Wong AHH, Li H, Jia Y, et al. Drug screening of cancer cell lines and human primary tumors using droplet microfluidics. Sci Rep. 2017;7:9109.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  55. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473–82.

    Article  CAS  PubMed  Google Scholar 

  56. Baselga J, Bradbury I, Eidtmann H, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379:633–40.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371:1877–88.

    Article  PubMed  CAS  Google Scholar 

  58. US Food Drug Administration: US Food and Drug Administration Approved Drugs. 2018. www.fda.gov

  59. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol. 2015;26:1883–9.

    Article  PubMed  Google Scholar 

  60. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947–57.

    Article  CAS  PubMed  Google Scholar 

  61. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.

    Article  CAS  PubMed  Google Scholar 

  62. Morrissey K, Yuraszeck T, Li CC, et al. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci. 2016;9:89–104.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  63. Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621–81.

    Article  CAS  PubMed  Google Scholar 

  64. Hamberg P, Verweij J. Phase I drug combination trial design: walking the tightrope. J Clin Oncol. 2009;27:4441–3.

    Article  PubMed  Google Scholar 

  65. Storer BE. Design and analysis of phase I clinical trials. Biometrics. 1989;45:925–37.

    Article  CAS  PubMed  Google Scholar 

  66. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101:708–20.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  67. LoRusso PM, Boerner SA, Seymour L. An overview of the optimal planning, design, and conduct of phase I studies of new therapeutics. Clin Cancer Res. 2010;16:1710–8.

    Article  CAS  PubMed  Google Scholar 

  68. Cook T, DeMets DL. Review of draft FDA adaptive design guidance. J Biopharm Stat. 2010;20:1132–42.

    Article  PubMed  Google Scholar 

  69. Fukushige S, Matsubara K, Yoshida M, et al. Localization of a novel v-erbB-related gene, c-erbB-2, on human chromosome 17 and its amplification in a gastric cancer cell line. Mol Cell Biol. 1986;6:955–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Madarnas Y, Trudeau M, Franek JA, et al. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev. 2008;34:539–57.

    Article  CAS  PubMed  Google Scholar 

  71. Mariani G, Fasolo A, De Benedictis E, et al. Trastuzumab as adjuvant systemic therapy for HER2-positive breast cancer. Nat Clin Pract Oncol. 2009;6:93–104.

    Article  CAS  PubMed  Google Scholar 

  72. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.

    Article  CAS  PubMed  Google Scholar 

  73. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.

    Article  CAS  PubMed  Google Scholar 

  74. Untch M, Muscholl M, Tjulandin S, et al. First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the herceptin, cyclophosphamide, and epirubicin (HERCULES) trial. J Clin Oncol. 2010;28:1473–80.

    Article  CAS  PubMed  Google Scholar 

  75. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23:4265–74.

    Article  CAS  PubMed  Google Scholar 

  76. Hamberg P, Bos MMEM, Braun HJJ, et al. Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial. Clin Breast Cancer. 2011;11:103–13.

    Article  CAS  PubMed  Google Scholar 

  77. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2–positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264–71.

    Article  CAS  PubMed  Google Scholar 

  78. Valero V, Forbes J, Pegram MD, et al. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011;29:149–56.

    Article  CAS  PubMed  Google Scholar 

  79. Franklin MC, Carey KD, Vajdos FF, et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317–28.

    Article  CAS  PubMed  Google Scholar 

  80. Nami B, Maadi H, Wang Z. Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer. Cancers. 2018;10:342.

    Article  CAS  PubMed Central  Google Scholar 

  81. Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009;69:9330–6.

    Article  CAS  PubMed  Google Scholar 

  82. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13:25–32.

    Article  CAS  PubMed  Google Scholar 

  83. von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377:122–31.

    Article  Google Scholar 

  84. Colombino M, Capone M, Lissia A, et al. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30:2522–9.

    Article  PubMed  Google Scholar 

  85. Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18:3242–9.

    Article  CAS  PubMed  Google Scholar 

  86. Yuan J, Ng WH, Lam PYP, et al. The dimer-dependent catalytic activity of RAF family kinases is revealed through characterizing their oncogenic mutants. Oncogene. 2018;37:5719–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Lavoie H, Therrien M. Regulation of RAF protein kinases in ERK signalling. Nat Rev Mol Cell Biol. 2015;16:281–98.

    Article  CAS  PubMed  Google Scholar 

  88. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707–14.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.

    Article  CAS  PubMed  Google Scholar 

  90. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.

    Article  CAS  PubMed  Google Scholar 

  91. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30–9.

    Article  PubMed  CAS  Google Scholar 

  93. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.

    Article  CAS  PubMed  Google Scholar 

  94. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36:7–13.

    Article  CAS  PubMed  Google Scholar 

  95. Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Huang Z, Wu Y, Zhou X, et al. Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review. Future Oncol. 2015;11:1687–99.

    Article  CAS  PubMed  Google Scholar 

  97. Seeliger H, Guba M, Kleespies A, et al. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev. 2007;26:611–21.

    Article  PubMed  Google Scholar 

  98. O’Reilly T, McSheehy PMJ, Brueggen J, et al. In vivo antitumor activity of RAD001 (everolimus) in 58 specialized human tumor xenograft models. Cancer Res. 2008;68:–2917.

    Google Scholar 

  99. Lane H, Tanaka C, Kovarik J, et al. Preclinical and clinical pharmacokinetic/pharmacodynamic (PK/PD) modeling to help define an optimal biological dose for the oral mTOR inhibitor, RAD001, in oncology. Proc Am Soc Clin Oncol. 2003;22:237.

    Google Scholar 

  100. Mabuchi S, Altomare DA, Cheung M, et al. RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res. 2007;13:4261–70.

    Article  CAS  PubMed  Google Scholar 

  101. Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11:5319–28.

    Article  CAS  PubMed  Google Scholar 

  102. O’Donnell A, Faivre S, Burris HA 3rd, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol. 2008;26:1588–95.

    Article  PubMed  CAS  Google Scholar 

  103. Okamoto I, Doi T, Ohtsu A, et al. Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol. 2010;40:17–23.

    Article  PubMed  Google Scholar 

  104. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–56.

    Article  CAS  PubMed  Google Scholar 

  105. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376:354–66.

    Article  CAS  PubMed  Google Scholar 

  108. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931–9.

    Article  CAS  PubMed  Google Scholar 

  109. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122:664–71.

    Article  CAS  PubMed  Google Scholar 

  110. Boss DS, Glen H, Beijnen JH, et al. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br J Cancer. 2012;106:1598–604.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Fuereder T, Jaeger-Lansky A, Hoeflmayer D, et al. mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and improves anti-tumor activity against gastric cancer in vivo. Cancer Lett. 2010;296:249–56.

    Article  CAS  PubMed  Google Scholar 

  112. Mariniello B, Rosato A, Zuccolotto G, et al. Combination of sorafenib and everolimus impacts therapeutically on adrenocortical tumor models. Endocr Relat Cancer. 2012;19:527–39.

    Article  CAS  PubMed  Google Scholar 

  113. Wang Z, Zhou J, Fan J, et al. Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma. Clin Cancer Res. 2008;14:5124–30.

    Article  CAS  PubMed  Google Scholar 

  114. Adachi Y, Matsuki M, Yamaguchi A, et al. Abstract 3264: Lenvatinib in combination with everolimus demonstrated enhanced antiangiogenesis and antitumor activity in human RCC xenograft models. Cancer Res. 2016;76:–3264.

    Google Scholar 

  115. Kimura T, Adachi Y, Matsuki M, et al. The antitumor activity of lenvatinib (LEN) in combination with everolimus (EVE) in human renal cell carcinoma (RCC) xenograft models is dependent on VEGFR and FGFR signaling. Ann Oncol. 2016;27:vi2.

    Article  Google Scholar 

  116. Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2012;118:1868–76.

    Article  CAS  PubMed  Google Scholar 

  117. Powles T, Foreshew S-JS, Shamash J, et al. A phase Ib study investigating the combination of everolimus and dovitinib in vascular endothelial growth factor refractory clear cell renal cancer. Eur J Cancer. 2014;50:2057–64.

    Article  CAS  PubMed  Google Scholar 

  118. Harzstark AL, Small EJ, Weinberg VK, et al. A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer. 2011;117:4194–200.

    Article  CAS  PubMed  Google Scholar 

  119. Leonetti A, Leonardi F, Bersanelli M, et al. Clinical use of lenvatinib in combination with everolimus for the treatment of advanced renal cell carcinoma. Ther Clin Risk Manag. 2017;13:799–806.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  120. Barata PC, Rini BI. Treatment of renal cell carcinoma: current status and future directions. CA Cancer J Clin. 2017;67:507–24.

    Article  PubMed  Google Scholar 

  121. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–8.

    Article  CAS  PubMed  Google Scholar 

  122. Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743–8.

    Article  CAS  PubMed  Google Scholar 

  123. Zurita AJ, Jonasch E, Wang X, et al. A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol. 2012;23:46–52.

    Article  CAS  PubMed  Google Scholar 

  124. Rini BI, Quinn DI, Baum M, et al. Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Target Oncol. 2015;10:45–53.

    Article  PubMed  Google Scholar 

  125. Wei S, Fu N, Sun Y, et al. Targeted contrast-enhanced ultrasound imaging of angiogenesis in an orthotopic mouse tumor model of renal carcinoma. Ultrasound Med Biol. 2014;40:1250–9.

    Article  PubMed  Google Scholar 

  126. Farber NJ, Kim CJ, Modi PK, et al. Renal cell carcinoma: the search for a reliable biomarker. Transl Cancer Res. 2017;6:620–32.

    Article  CAS  PubMed  Google Scholar 

  127. Duda DG, Munn LL, Jain RK. Can we identify predictive biomarkers for antiangiogenic therapy of cancer using mathematical modeling? J Natl Cancer Inst. 2013;105:762–5.

    Article  PubMed Central  PubMed  Google Scholar 

  128. Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6:327–38.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Tsimberidou A-M, Kurzrock R, Anderson KC, et al. Targeted therapy in translational cancer research: John Wiley & Sons; 2015.

    Google Scholar 

  130. US Food Drug Administration: CFR-code of federal regulations title 21. Current good manufacturing practice for finished pharmaceuticals Part 211, 2015.

    Google Scholar 

  131. Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1432–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. US Food Drug Administration: Codevelopment of two or more unmarketed investigational drugs for use in combination. www.fda.gov, 2015.

  133. US Food Drug Administration: Guideline on clinical development of fixed combination medicinal products. www.ema.europa.eu, 2017.

  134. US Food Drug Administration: Center for Biologics Evaluation and Research (CBER) Foreign Inspectional Collaborations. www.fda.gov, 2018.

  135. Ott PA, Hodi FS, Kaufman HL, et al. Combination immunotherapy: a road map. J Immunother Cancer. 2017;5:16.

    Article  PubMed Central  PubMed  Google Scholar 

  136. Zappasodi R, Merghoub T, Wolchok JD. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell. 2018;33:581–98.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345–56.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  138. Motzer RJ, Powles T, Atkins MB, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2018;36:578.

    Article  Google Scholar 

  139. Schmidt C. The benefits of immunotherapy combinations. Nature. 2017;552:S67–s69.

    Article  CAS  PubMed  Google Scholar 

  140. Klauschen F, Andreeff M, Keilholz U, et al. The combinatorial complexity of cancer precision medicine. Onco Targets Ther. 2014;1:504–9.

    Google Scholar 

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Authors and Affiliations

  1. Tulane Medical School, Deming Department of Medicine, Section of Hematology and Medical Oncology, New Orleans, LA, USA

    Pedro C. Barata

  2. Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap

  3. Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap

  4. The Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap

  5. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap

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  1. Pedro C. Barata
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  2. Timothy A. Yap
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Correspondence to Timothy A. Yap .

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Editors and Affiliations

  1. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Timothy A. Yap

  2. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jordi Rodon

  3. University of Texas MD Anderson Cancer Center, Houston, TX, USA

    David S. Hong

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Barata, P.C., Yap, T.A. (2020). Development of Molecularly Targeted Agents in Early Phase Clinical Trials. In: Yap, T.A., Rodon, J., Hong, D.S. (eds) Phase I Oncology Drug Development. Springer, Cham. https://doi.org/10.1007/978-3-030-47682-3_12

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