Skip to main content

Advertisement

SpringerLink
Log in

A phase I study of temsirolimus plus carboplatin plus paclitaxel for patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC)

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

Abstract

Purpose

The mammalian target of rapamycin complex 1 (mTORC1) is aberrantly activated in many head and neck squamous cell carcinomas (HNSCCs). This phase I study combines the mTORC1 inhibitor temsirolimus with carboplatin and paclitaxel.

Methods

This was a single institution phase I study for patients with R/M HNSCC with a standard 3 + 3 design. Three doses of temsirolimus were planned: 15, 20, and 25 mg. Due to excessive toxicity with the original study regimen, the protocol was amended to carboplatin AUC 1.5, paclitaxel 80 mg/m2, and temsirolimus (according to dose escalation plan), all on days 1 and 8 of a 21-day cycle.

Results

18 patients (14 male, 4 female) enrolled, with median age 56 years (range 33–78). The most common toxicities were anemia, leukopenia, thrombocytopenia, and hyperglycemia. Among all patients treated, the confirmed objective partial response (cPR) rate was 22 %. DLT was not exceeded among 6 patients treated at dose level 3 of the revised protocol, and 4 of 6 subjects treated at this dose level had cPRs.

Conclusion

The phase II recommended regimen is temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2, all on days 1 and 8 of a 21-day cycle. A phase II study of this regimen in R/M HNSCC is ongoing.

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

Similar content being viewed by others

References

  1. Aissat N, Le Tourneau C, Ghoul A, Serova M, Bieche I, Lokiec F, Raymond E, Faivre S (2008) Antiproliferative effects of rapamycin as a single agent and in combination with carboplatin and paclitaxel in head and neck cancer cell lines. Cancer Chemother Pharmacol 62:305–313

    Article  PubMed  CAS  Google Scholar 

  2. Amornphimoltham P, Patel V, Sodhi A, Nikitakis NG, Sauk JJ, Sausville EA, Molinolo AA, Gutkind JS (2005) Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res 65:9953–9961

    Article  PubMed  CAS  Google Scholar 

  3. Andre F, Campone M, O’Regan R, Manlius C, Massacesi C, Sahmoud T, Mukhopadhyay S, Soria J-C, Naughton M, Hurvitz SA (2010) Phase I study of everolimus plus weekly paclitaxel and trastuzumab in patients with metastatic breast cancer pretreated with trastuzumab. J Clin Oncol 28:5110–5115

    Article  PubMed  CAS  Google Scholar 

  4. Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, Tester WJ (2008) Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 26:468–473

    Article  PubMed  CAS  Google Scholar 

  5. Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O’Reilly E, Natt F, Hall J, Lane HA, Thomas G (2005) The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damage induced apoptosis though inhibition of p21 translation. Cell 120:747–759

    Article  PubMed  CAS  Google Scholar 

  6. Campone M, Levy V, Bourbouloux E, Berton Riguad D, Bootle D, Dutreix C, Zoellner U, Shand N, Calvo F, Raymond E (2009) Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumors. Br J Cancer 100:315–321

    Article  PubMed  CAS  Google Scholar 

  7. Faried LS, Faried A, Kanuma T, Nakazato T, Tamura T, Kuwano H, Minegishi T (2006) Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin increases chemosenstivity of CaSki cells to paclitaxel. Eur J Cancer 42:934–947

    Article  PubMed  CAS  Google Scholar 

  8. Figlin RA, Brown E, Armstrong AJ, Akerley W, Benson AB, Burstein HJ, Ettinger DS, Febbo PG, Fury MG, Hudes GR, Kies MS, Kwak EL, Morgan RJ, Mortimer J, Reckamp K, Venook AP, Worden F, Yen Y (2008) NCCN Task Force Report: mTOR inhibition in solid tumors. J Natl Compr Canc Netw 6(Suppl 5):S1–S22

    PubMed  CAS  Google Scholar 

  9. Forastiere A, Shank D, Neuberg D, Taylor SG, DeConti RC, Adams G (1998) Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck: an Eastern Cooperative Oncology Group Trial (PA390). Cancer 82:2270–2274

    Article  PubMed  CAS  Google Scholar 

  10. Fury MG, Pfister DG (2011) Current recommendations for systemic therapy of recurrent and/or metastatic head and neck squamous cell cancer. J Natl Compr Canc Netw 9:681–689

    PubMed  Google Scholar 

  11. Fury MG, Sherman E, Haque S, Korte S, Lisa D, Shen R, Wu N, Pfister DG (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  PubMed  CAS  Google Scholar 

  12. Harding MW (2003) Immunophilins, mTOR, and pharmacodynamic strategies for a targeted cancer therapy. Clin Cancer Res 9:2882–2886

    PubMed  CAS  Google Scholar 

  13. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IGH, Barbarash O, Gokmen E, O’Toole T, Lustarten S, Moore L, Motzer RJ (2007) Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. New Engl J Med 356:2271–2281

    Article  PubMed  CAS  Google Scholar 

  14. Kollmannsberger C, Hirte H, Siu LL, Mazurka J, Chi K, Elit L, Walsh W, Sedarias J, Doyle A, Eisenhauer EA, Oza AM (2012) Temsirolimus in combination with carboplatin and paclitaxel in patients with advanced solid tumors: a NCIC-CTG, phase 1, open-label dose-escalation study (IND 179). Ann Oncol 23:238–244

    Article  PubMed  CAS  Google Scholar 

  15. Molinolo AA, Hewitt SM, Amornphimoltham P, Keelewat S, Rangdaeng S, Garcia AM, Raimondi AR, Jufe R, Itoiz M, Gao Y, Saranath D, Kaleebi GS, Yoo GH, Leak L, Myers EM, Shintani S, Wong D, Massey HD, Yeudall WA, Lonardo F, Ensley J, Gutkind JS (2007) Dissecting the Akt/mammalian target of rapamycin signaling network: emerging results from the head and neck cancer tissue array initiative. Clin Cancer Res 13:4964–4973

    Article  PubMed  CAS  Google Scholar 

  16. Mondesire WH, Jian W, Zhang H, Ensor J, Hung M-C, Mills GB, Meric-Bernstam F (2004) Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 10:7031–7042

    Article  PubMed  CAS  Google Scholar 

  17. Moulder S, Gladish G, Ensor J, Gonzalez-Angulo AM, Cristofanillo M, Murray JM, Booser D, Giordano SH, Brewster A, Moore J, Rivera E, Hortobagyi GN, Tran HT (2011) A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer. Cancer [Epub ahead of print]

  18. Nathan C-AO, Amirghahari N, Rong X, Giordano T, Sibley D, Nordberg M, Glass J, Agarwal A, Caldito G (2007) Mammalian target of rapamycin inhibitors as possible adjuvant therapy for microscopic residual disease in head and neck squamous cell cancer. Cancer Res 67:2160–2168

    Article  PubMed  CAS  Google Scholar 

  19. Oza AM, Kollmannsberger C, Hirte H, Welch S, Siu L, Mazurka J, Sedarias J, Doyle LA, Eisenhauer E (2009) Phase I study of temsirolimus (CCI-779), carboplatin, and paclitaxel in patients with advanced solid tumors: NCI CTG IND 179. J Clin Oncol 27:15s (suppl; abstr 3558)

    Google Scholar 

  20. Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB (2005) Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-three-week schedule) as first-line therapy in women with HER-2 expressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer 6:425–432

    Article  PubMed  CAS  Google Scholar 

  21. Ramalingam SS, Harvey D, Saba N, Owonikoko TK, Kauh J, Shin DM, Sun S-Y, Strychor S, Tighiouart M, Egorin M, Fu H, Khuri FR (2010) Phase I and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel in recurrent/refractory nonsmall cell lung cancer. Cancer 116:3903–3909

    Article  PubMed  CAS  Google Scholar 

  22. Shi Y, Frankel A, Radvanyi LG, Penn LZ, Miller RG, Mills GB (1995) Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res 55:1982–1988

    PubMed  CAS  Google Scholar 

  23. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  24. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer H-R, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Racourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. New Engl J Med 359:1116–1127

    Article  PubMed  CAS  Google Scholar 

  25. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, Amella N, Schueler A, Baselga J (2007) Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based chemotherapy. J Clin Oncol 25:2171–2177

    Article  PubMed  CAS  Google Scholar 

  26. Wangpaichitr M, Wu C, You M, Kuo MT, Feun L, Lampidis T, Savaraj N (2008) Inhibition of mTOR restores cisplatin sensitivity through down-regulation of growth and anti-apoptotic proteins. Eur J Pharm 591:124–127

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Pfizer, Inc.

Author information

Authors and Affiliations

  1. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 532, New York, NY, 10021, USA

    Matthew G. Fury, Eric Sherman, Alan Ho, Katherine W. Kelly, Oby Nwankwo & David G. Pfister

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Nora Katabi

  3. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Camelia Sima

  4. Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Sofia Haque

  5. Department of Medicine, Weill Cornell Medical College, New York, NY, 10021, USA

    Matthew G. Fury, Eric Sherman, Alan Ho & David G. Pfister

Authors
  1. Matthew G. Fury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alan Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nora Katabi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Camelia Sima
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katherine W. Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Oby Nwankwo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sofia Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David G. Pfister
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthew G. Fury.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fury, M.G., Sherman, E., Ho, A. et al. A phase I study of temsirolimus plus carboplatin plus paclitaxel for patients with recurrent or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Cancer Chemother Pharmacol 70, 121–128 (2012). https://doi.org/10.1007/s00280-012-1894-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-012-1894-y

Keywords

Search

Navigation