Skip to main content

Advertisement

SpringerLink
Log in

TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

Methods

Sixty-seven patients received TAK-228 6–40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1.

Results

TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months.

Conclusion

TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors.

Clinicaltrials.gov identifier

NCT01351350.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Dazert E, Hall MN (2011) mTOR signaling in disease. Curr Opin Cell Biol 23:744–755

    Article  CAS  PubMed  Google Scholar 

  2. Hsieh AC, Liu Y, Edlind MP et al (2012) The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485:55–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wu R, Hu TC, Rehemtulla A et al (2011) Preclinical testing of PI3K/AKT/mTOR signaling inhibitors in a mouse model of ovarian endometrioid adenocarcinoma. Clin Cancer Res 17:7359–7372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35

    Article  CAS  PubMed  Google Scholar 

  5. Cantrell DA (2001) Phosphoinositide 3-kinase signalling pathways. J Cell Sci 114:1439–1445

    CAS  PubMed  Google Scholar 

  6. Fresno Vara JA, Casado E, de Castro J et al (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204

    Article  PubMed  Google Scholar 

  7. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37:217–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pene F, Claessens YE, Muller O et al (2002) Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene 21:6587–6597

    Article  CAS  PubMed  Google Scholar 

  9. Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 6:729–734

    Article  CAS  PubMed  Google Scholar 

  10. Liang J, Slingerland JM (2003) Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2:339–345

    Article  CAS  PubMed  Google Scholar 

  11. Benjamin D, Colombi M, Moroni C et al (2011) Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10:868–880

    Article  CAS  PubMed  Google Scholar 

  12. Vu C, Fruman DA (2010) Target of rapamycin signaling in leukemia and lymphoma. Clin Cancer Res 16:5374–5380

    Article  CAS  PubMed  Google Scholar 

  13. Robb VA, Karbowniczek M, Klein-Szanto AJ et al (2007) Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol 177(1):346–352

    Article  PubMed  Google Scholar 

  14. Dal CJ, Zancai P, Terrin L et al (2008) Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood 111(10):5142–5151

    Article  Google Scholar 

  15. Xiao L, Wang YC, Li WS et al (2009) The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res 28:152–158

    Article  PubMed  PubMed Central  Google Scholar 

  16. Matsubara S, Ding Q, Miyazaki Y et al (2013) mTOR plays critical roles in pancreatic cancer stem cells through specific and stemness-related functions. Sci Rep 3:3230

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mahadevan D, Chiorean EG, Harris WB et al (2012) Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer 48(18):3319–3327

    Article  CAS  PubMed  Google Scholar 

  18. Sarker D, Ang JE, Baird R et al (2015) First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res 21:77–86

    Article  CAS  PubMed  Google Scholar 

  19. Yang Q, Modi P, Newcomb T et al (2015) Idelalisib: first-in-class PI3K delta inhibitor for the treatment of chronic lymphocytic leukemia, small lymphocytic leukemia, and follicular lymphoma. Clin Cancer Res 21:1537–1542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Agarwal R, Koenig K, Rohren E et al (2014) Combined antiangiogenic and mammalian target of rapamycin inhibitor targeted therapy in metaplastic breast cancer harboring a PIK3CA mutation. J Breast Cancer 17:287–290

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bellmunt J, Puente J, de Garcia MJ et al (2014) SEOM clinical guidelines for the treatment of renal cell carcinoma. Clin Transl Oncol 16:1043–1050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Signorovitch J, Swallow E, Kantor E et al (2013) Everolimus and sunitinib for advanced pancreatic neuroendocrine tumors: a matching-adjusted indirect comparison. Exp Hematol Oncol 2:32

    Article  PubMed  PubMed Central  Google Scholar 

  23. Thoreen CC, Kang SA, Chang JW et al (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023–8032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wan X, Harkavy B, Shen N et al (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940

    Article  CAS  PubMed  Google Scholar 

  25. Carracedo A, Ma L, Teruya-Feldstein J et al (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118(9):3065–3074

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Figlin RA, Kaufmann I, Brechbiel J (2013) Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors. Int J Cancer 133(4):788–796

    Article  CAS  PubMed  Google Scholar 

  27. Carracedo A, Pandolfi PP (2008) The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 27(41):5527–5541

    Article  CAS  PubMed  Google Scholar 

  28. Feldman ME, Apsel B, Uotila A et al (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38

    Article  PubMed  Google Scholar 

  29. O’Reilly KE, Rojo F, She QB et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tabernero J, Rojo F, Calvo E et al (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603–1610

    Article  CAS  PubMed  Google Scholar 

  31. Korets SB, Musa F, Curtin J et al (2014) Dual mTORC1/2 inhibition in a preclinical xenograft tumor model of endometrial cancer. Gynecol Oncol 132(2):468–473

    Article  CAS  PubMed  Google Scholar 

  32. Zheng B, Mao JH, Qian L et al (2015) Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma. Cancer Lett 357(2):468–475

    Article  CAS  PubMed  Google Scholar 

  33. Ingels A, Zhao H, Thong AE et al (2014) Preclinical trial of a new dual mTOR inhibitor, MLN0128, using renal cell carcinoma tumorgrafts. Int J Cancer 134:2322–2329

    Article  CAS  PubMed  Google Scholar 

  34. Gokmen-Polar Y, Liu Y, Toroni RA et al (2012) Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. Breast Cancer Res Treat 136:673–682

    Article  PubMed  Google Scholar 

  35. Lou HZ, Weng XC, Pan HM et al (2014) The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells. Biochem Biophys Res Commun 450:973–978

    Article  CAS  PubMed  Google Scholar 

  36. Zhang H, Dou J, Yu Y et al (2015) mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling. Apoptosis 20:50–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Slotkin EK, Patwardhan PP, Vasudeva SD et al (2015) MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma. Mol Cancer Ther 14:395–406

    Article  CAS  PubMed  Google Scholar 

  38. Kannan K, Fabrey R, Cooper J et al (2013) MLN0128, an investigational mTORC1/2 inhibitor, demonstrates potent antitumor activity alone and in combination with paclitaxel in preclinical models of endometrial cancer. Mol Cancer Ther 12 (abstract B198)

  39. Chiang CT, Yeh PY, Gao M et al (2010) Combinations of mTORC1 inhibitor RAD001 with gemcitabine and paclitaxel for treating non-Hodgkin lymphoma. Cancer Lett 298(2):195–203

    Article  CAS  PubMed  Google Scholar 

  40. Shafer A, Zhou C, Gehrig PA et al (2010) Rapamycin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction of apoptosis. Int J Cancer 126(5):1144–1154

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Miller TW, Forbes JT, Shah C et al (2009) Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res 15(23):7266–7276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Garcia-Garcia C, Ibrahim YH, Serra V et al (2012) Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 18:2603–2612

    Article  CAS  PubMed  Google Scholar 

  43. Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247

    Article  CAS  PubMed  Google Scholar 

  44. Ghobrial I et al (2016) MLN0128, an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström’s macroglobulinemia. Am J Hematol 91:400–405

    Article  CAS  PubMed  Google Scholar 

  45. Infante J, Tabernero J, Cervantes A et al (2013) A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies. Mol Cancer Ther 12 (abstract C252)

  46. Shapiro GI, Rodon J, Bedell C et al (2014) Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors. Clin Cancer Res 20(1):233–245

    Article  CAS  PubMed  Google Scholar 

  47. Rodon J, Dienstmann R, Serra V et al (2013) Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 10(3):143–153

    Article  CAS  PubMed  Google Scholar 

  48. Infante J, Tabernero J, Burris H et al (2012) A phase I, open label, dose-escalation study of an oral mammalian target of rapamycin inhibitor INK128 administered once daily in patients with advanced malignancies. Cancer Res 72 (abstract 5588)

  49. Tabernero J, Cervantes A, Gordon M et al (2012) A phase I, open label, dose escalation study of oral mammalian target of rapamycin inhibitor INK128 administered by intermittent dosing regimens in patients with advanced malignancies. Cancer Res 72 (abstract CT-02)

  50. Xu R, Nakano K, Iwasaki H et al (2011) Dual blockade of phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways overcomes paclitaxel-resistance in colorectal cancer. Cancer Lett 306:151–160

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank all the study participants and their families, as well as the investigators and site staff involved in the study. The authors also acknowledge Ana Limon of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, who contributed to the editorial and scientific content of the manuscript. The authors would also like to acknowledge the writing support of Dawn L. Lee of FireKite, an Ashfield company, part of UDG Healthcare plc, in the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., and complied with Good Publication Practice 3 guidelines (Battisti et al., Ann Intern Med 2015;163:461–4).

Author information

Author notes

  1. S. Pant

    Present address: The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Authors and Affiliations

  1. Sarah Cannon Research Institute, 250 25th Avenue North, #100, Nashville, TN, 37203, USA

    Howard A. Burris III, C. D. Kurkjian, L. Hart, S. Pant, P. B. Murphy, S. F. Jones & J. R. Infante

  2. Tennessee Oncology PLLC, Nashville, TN, USA

    Howard A. Burris III, P. B. Murphy & J. R. Infante

  3. Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    C. D. Kurkjian & S. Pant

  4. Florida Cancer Specialists, Fort Myers, FL, USA

    L. Hart

  5. Millennium Pharmaceuticals, Inc., A Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    R. Neuwirth, C. G. Patel & F. Zohren

Authors
  1. Howard A. Burris III
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. D. Kurkjian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. Hart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Pant
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P. B. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. F. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Neuwirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. G. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. F. Zohren
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. R. Infante
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Howard A. Burris III.

Ethics declarations

Funding

This study was funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Conflict of interest

HA Burris, S Pant, PB Murphy, and SF Jones disclose no potential conflicts of interest. CD Kurkjian participated in an advisory board meeting for Halozyme Therapeutics Inc. (consultant/advisory role). L Hart discloses research funding to institution from Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. JR Infante discloses participation in a consultant/advisory role for Takeda on behalf of institution. R Neuwirth, CG Patel, and F Zohren are employees of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. CG Patel and F Zohren also disclose stock ownership (Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited).

Ethical approval and informed consent

The study was approved by the institutional review board at each site and conducted per the Declaration of Helsinki, the International Conference on Harmonisation, and Good Clinical Practice guidelines. All patients provided written informed consent.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burris, H.A., Kurkjian, C.D., Hart, L. et al. TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Cancer Chemother Pharmacol 80, 261–273 (2017). https://doi.org/10.1007/s00280-017-3343-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-017-3343-4

Keywords

Search

Navigation