Skip to main content

Advertisement

Log in

A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I

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

Abstract

Background

Cervix cancer (CC) represents the fourth most common cancer in women. Treatment involving cisplatin and radiotherapy has been the standard for locally advanced disease. Everolimus inhibits the aberrant activity of mTOR that is part of carcinogenesis in CC. Further everolimus inactivates the HPV E7 oncoprotein and inhibits its proliferation. Preclinical models have suggested that everolimus sensitizes tumoral cells and vasculature to cisplatin and radiotherapy.

Methods

In a 3 + 3 design, the trial aimed to treat three dose levels of at least three patients with daily doses of everolimus (2.5, 5 and 10 mg/day), cisplatin and radiotherapy delivered in a 9-week interval in CC patients, stage IIB, IIIA or IIIB. Patients received everolimus from day −7 up to the last day of brachytherapy. Primary objective was to evaluate safety, toxicity and the maximum-tolerated dose (MTD) of everolimus in association with cisplatin and radiotherapy. Pharmacokinetic (PK) parameters and response rates were analyzed as secondary objectives.

Results

Thirteen patients were enrolled, 6 at 2.5 mg, 3 at 5 mg and 4 at 10 mg. Four patients did not complete the planned schedule, 1 at 2.5 mg presented grade 4 acute renal failure interpreted as dose-limiting toxicity (DLT) and 3 at 10 mg: 1 with disease progression, and 2 with DLTs—1 grade 3 rash and 1 grade 4 neutropenia. PK results were characterized by dose-dependent increases in AUC and C max.

Conclusions

The MTD of everolimus in combination with cisplatin and radiotherapy has been defined as 5 mg/day. The data regarding safety and response rates support further studies.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Forman DBF, Brewster DH, Gombe Mbalawa C et al (2012) GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012. http://globocan.iarc.fr. Accessed 15 June 2015

  2. Whitney CW, Sause W, Bundy BN et al (1999) A randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stages IIB–IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecology Oncology Group and Southwest Oncology Group Study. J Clin Oncol 17:1339–1348

    CAS  PubMed  Google Scholar 

  3. Morris M, Eifel PJ, Lu J et al (1999) Pelvic radiation with concurrent chemotherapy versus pelvic and para-aortic radiation for high-risk cervical cancer: a randomized Radiation Therapy Oncologic Group clinical trial. N Engl J Med 340:1137–1143

    Article  CAS  PubMed  Google Scholar 

  4. Peters WA III, Liu PY, Barret RJ et al (2000) Cisplatin and 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive in high-risk early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: report of a phase III intergroup study. J Clin Oncol 18:1606–1613

    CAS  PubMed  Google Scholar 

  5. Rose PG, Bundy BN, Watkins EB et al (1999) Concurrent cisplatin based chemoradiation improves progression free and overall survival in an advanced cervical cancer: results of a randomized Gynecologic Oncology Group Study. N Engl J Med 340:1144–1153

    Article  CAS  PubMed  Google Scholar 

  6. Keys HM, Bundy BM, Stehman FBV et al (1999) Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340:1154–1161

    Article  CAS  PubMed  Google Scholar 

  7. Pearcey R, Brundage M, Drouin P et al (2002) Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20:966–972

    Article  CAS  PubMed  Google Scholar 

  8. Tierney JF, Vale C, Symonds P (2008) Concomitant and neoadjuvant chemotherapy for cervical cancer. Clin Oncol 20:401–416

    Article  CAS  Google Scholar 

  9. National Cancer Institute (1999) NCI Clinical Announcement. Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, MD, USA

  10. Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27(13):2278–2287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Husseinzadeh N, Husseinzadeh HD (2014) mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: a critical review. Gynecol Oncol 133(2):375–381

    Article  CAS  PubMed  Google Scholar 

  12. Bosch FX, Lorincz A, Muñoz N et al (2002) The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55(4):244–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bertelsen BI, Steine SJ, Sandvei R et al (2006) Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PI3KCA amplification and AKT phosphorylation. Int J Cancer 118:1877–1883

    Article  CAS  PubMed  Google Scholar 

  14. Oh KJ, Kalinina A, Park NH et al (2006) Deregulation of eiF4E: 4E-BP1 in differentiated human papillomavirus-containing cells leads to high levels of expression of the E7 oncoprotein. J Virol 80:7079–7088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Beuvink I, Boulay A, Fumagallo S et al (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120:747–759

    Article  CAS  PubMed  Google Scholar 

  16. Baselga J, Campone M, Piccart M et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529

    Article  CAS  PubMed  Google Scholar 

  17. Yao JC, Shah MH, Ito T et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364(6):514–523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Motzer RJ, Escudier B, Oudard S et al (2010) Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116(18):4256–4265

    Article  CAS  PubMed  Google Scholar 

  19. Brignol N, McMahon LM, Luo S et al (2001) High-throughput semi-automatic 96-well liquid/liquid extraction and liquid chromatography/mass spectrometric analysis of everolimus (RAD001) and cyclosporine A (CsA) in whole blood. Rapid Commun Mass Spectrom 15:898–907

    Article  CAS  PubMed  Google Scholar 

  20. Hu G, Liu W, Mendelsohn J et al (1997) Expression of epidermal growth factor receptor and human papillomavirus E6/E7 proteins in cervical carcinoma cells. J Natl Cancer Inst 89:1271–1276

    Article  CAS  PubMed  Google Scholar 

  21. Meira DD, de Almeida VH, Mororó JS et al (2009) Combination of cetuximab with chemoradiation, trastuzumab or MAPK inhibitors: mechanism of sensitisation of cervical cancer cells. Br J Cancer 101:782–791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meira DD, Nóbrega I, de Almeida VH et al (2009) Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathway. Eur J Cancer 45:1265–1273

    Article  CAS  PubMed  Google Scholar 

  23. Nogueira-Rodrigues A, Carmo CC, Viegas C et al (2008) Phase I trial of erlotinib combined with cisplatin and radiotherapy for patients with locally advanced cervical squamous cell cancer. Clin Cancer Res 14:6324–6329

    Article  CAS  PubMed  Google Scholar 

  24. Nogueira-Rodrigues A, Moralez G, Grazziotin R et al (2014) Phase 2 trial of erlotinib combined with cisplatin and radiotherapy in patients with locally advanced cervical cancer. Cancer 120(8):1187–1193

    Article  CAS  PubMed  Google Scholar 

  25. Fury MG, Lee NY, Sherman E et al (2013) A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. Int J Radiat Oncol Biol Phys 87:479–486

    Article  CAS  PubMed  Google Scholar 

  26. Chinnaiyan P, Won M, Wen PY et al (2013) RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 86:880–884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Sarkaria JN, Galanis E, Wu W et al (2011) North Central Cancer Treatment Group Phase I trial N057 K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 81:468–475

    Article  CAS  PubMed  Google Scholar 

  28. Deutsch E, Le Péchoux C, Faivre L et al (2015) Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer. Ann Oncol 26(6):1223–1229

    Article  CAS  PubMed  Google Scholar 

  29. Fury MG, Sherman E, Haque S et al (2012) A phase I study of everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors. Cancer Chemother Pharmacol 69:591–598

    Article  CAS  PubMed  Google Scholar 

  30. Moroney JW, Schlumbrecht MP, Helgason T et al (2011) A phase I trial of liposomal doxorubicin, bevacizumab, and temsirolimus in patients with advanced gynecologic and breast malignancies. Clin Cancer Res 17(21):6840–6846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Piha-Paul SA, Wheler JJ, Fu S et al (2014) Advanced gynecologic malignancies treated with a combination of the VEGF inhibitor bevacizumab and the mTOR inhibitor temsirolimus. Oncotarget 5(7):1846–1855

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tinker AV, Ellard S, Welch S et al (2013) Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol 130(2):269–274

    Article  CAS  PubMed  Google Scholar 

  33. Buxton EJ (1992) Experience with bleomycin, ifosfamide, and cisplatin in primary and recurrent cervical cancer. Semin Oncol 19:9–17

    CAS  PubMed  Google Scholar 

  34. Kumar L, Kaushal R, Nandy M et al (1994) Chemotherapy followed by radiotherapy versus radiotherapy alone in locally advanced cervical cancer: a randomized study. Gynecol Oncol 54:307–315

    Article  CAS  PubMed  Google Scholar 

  35. Leborgne F, Leborgne JH, Doldan R et al (1997) Induction chemotherapy and radiotherapy of advanced cancer of the cervix: a pilot study and phase III randomized trial. Int J Radiat Oncol Biol Phys 37:343–350

    Article  CAS  PubMed  Google Scholar 

  36. Classe JM, Rauche P, Rodier JF et al (2006) Surgery after concurrent chemoradiotherapy and brachytherapy for the treatment of advanced cervical cancer: morbidity and outcome: results of a multicenter study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer). Gynecol Oncol 102:523–529

    Article  CAS  PubMed  Google Scholar 

  37. Nogueira-Rodrigues A, Ferreira CG, Bergmann A et al (2014) Comparison of adenocarcinoma (ACA) and squamous cell carcinoma (SCC) of the uterine cervix in a sub-optimally screened cohort: a population-based epidemiologic study of 51,842 women in Brazil. Gynecol Oncol 135(2):292–296

    Article  PubMed  Google Scholar 

  38. O’Donnell A, Faivre S, Burris HA et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This phase I trial was funded by Novartis; Phoenix ClinicalTrials.gov identifier NCT01217177.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andréia Cristina de Melo.

Ethics declarations

Conflict of interest

Juliane Morando is a Novartis employee. All other authors have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Melo, A.C., Grazziotin-Reisner, R., Erlich, F. et al. A phase I study of mTOR inhibitor everolimus in association with cisplatin and radiotherapy for the treatment of locally advanced cervix cancer: PHOENIX I. Cancer Chemother Pharmacol 78, 101–109 (2016). https://doi.org/10.1007/s00280-016-3064-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-016-3064-0

Keywords

Navigation