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A Phase I Study of SPI-077 (Stealth® Liposomal Cisplatin) Concurrent with Radiation Therapy for Locally Advanced Head and Neck Cancer

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Abstract

Background: Liposomal cisplatinpreparations have two potential advantagesover the free drug when combined withradiation therapy (RT): 1) selective tumorlocalization, improving the therapeuticratio, and 2) prolonged half-life, allowingmore radiosensitization. We performed aPhase I study of Stealth® liposomalcisplatin (SPI-077) concurrent with RT forhead and neck squamous cell carcinoma(HNSCC).

Methods: Patients with StageIVa/b HNSCC were treated with SPI-077,given intravenously twice two weeks apart,concurrent with RT (60–72 Gy in 6–7 weeks).The SPI-077 dose was escalated in standardphase I design.

Results: Twenty patientsreceived 38 doses of SPI-077, escalatedfrom 20–200 mg/m2 in six dose levels.Two of these patients received one dosebecause of reversible Grade 3 livertoxicity or rash. Three patients had aGrade 1, and one had a Grade 2 infusionreaction. Four patients had transientlyelevated transaminases: Grade 1 (n = 1),Grade 2 (n = 1), and Grade 3 (n = 2). Grade 3neutropenia occurred in one patient. Therewas no ototoxicity, neurotoxicity, ornephrotoxicity. In-field radiation skin andmucosal toxicities did not appear to beintensified. Ten of 17 patients (59%)finishing treatment achieved initialcomplete response.

Conclusions: Systemic andin-field radiation toxicities of SPI-077were minimal. Infusion reactions wereminimized with a slower and more diluteinitial infusion. Further dose escalationwas stopped in the absence of dose-limitingtoxicity to address the reformulation ofthe liposomally bound cisplatin.Nonetheless, this study shows that highdoses of SPI-077 can be given safely. Thepotentially beneficial therapeutic ratiosuggests that liposomal radiosensitizerpreparations warrant furtherinvestigation.

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References

  1. Patton TF, Repta AJ, Sternson LA: Clinical pharmacology of cisplatin. In: Ames MM, Powis G, Kovach JS (eds) Pharmacokinetics of Anticancer Agents in Humans. Elsevier, Amsterdam, 1983, pp 155–186

    Google Scholar 

  2. Go RS, Adjei AA: Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 17:409–422, 1999

    Google Scholar 

  3. Culy CR, Clemett D, Wiseman LR: Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60:895–924, 2000

    Google Scholar 

  4. Mani S, Manalo J, Bregman D: Novel combinations with oxaliplatin. Oncol 14:52–58, 2000

    Google Scholar 

  5. Gabizon A, Huang SK, Papahadjopoulos D: Sterically stabilized liposomes as drug carriers: pharmacokinetics, tissue distribution and therapeutic effects in tumor-bearing mice. In: Gregoriadis G, Allison AC, Poste G (eds) Targeting of Drugs 3: The Challenges of Peptides and Proteins, Plenum Press, New York, 1992, pp 51–58

    Google Scholar 

  6. De Mario MD, Vogelzang NJ, Janisch L, Tonda M, Amantea MA, Pendyala L, Ratain MJ: A Phase I study of liposome-formulated cisplatin (SPI-077®) given every 3 weeks in patients with advanced cancer (“Abstract”). Proc ASCO 17:883, 1998

    Google Scholar 

  7. Schellens JHM, Groenewegen G, Meerum Terwogt JM, Maliepaard M, Tibben MM, Pluim D, ten Bokkel Huinink WW, Schot M, Welbank H, Blijham GH, Beijnen JH: Phase I and pharmacologic study of Stealth® liposomal encapsulated cisplatin (SPI-077) (“Abstract”). Proc ASCO 18:774, 1999

    Google Scholar 

  8. Huang SK, Hong K, Lee KD, Papahadjopoulos D, Friend DS: Light microscopic localization of silver-enhanced liposome-entrapped colloidal gold in mouse tissues. Biochim Biophys Acta 1069:117–121, 1991

    Google Scholar 

  9. Huang SK, Lee KD, Hong K, Friend DS, Papahadjopoulos D: Microscopic localization of sterically stabilized liposomes in colon carcinoma-bearing mice. Cancer Res 52:5135–5143, 1992

    Google Scholar 

  10. American Joint Committee on Cancer: AJCC Cancer Staging Manual, 5th ed. Lippincott-Raven Publishers, Philadelphia, 1997

    Google Scholar 

  11. National Cancer Institute: Common Toxicity Criteria Manual, Version 2.0. NCI, Bethesda, 1999

    Google Scholar 

  12. Southwest Oncology Group Statistical Center: Chapter 7: Response Assessment. Clinical Research Associate Manual, Vol. I. SWOG Statistical Center, Seattle, 1999

    Google Scholar 

  13. Stewart JS, Lewanski C, Harrington K, Northcote D, Welbank H, Whittaker J: Comparison of Pegylated Liposomal Doxorubicin (PLD) and Pegylated Liposomal Cisplatinum (PLC) in Patients with Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) (“Abstract”). Proc ASCO 19:423a, 2000

    Google Scholar 

  14. Grecula JC, Schuller DE, Smith R, Rhoades CA, Nag S, Bauer CJ, Agrawal A, Au JL, Young D, Gahbauer RA: Long-term follow-up on an intensified treatment regimen for advanced resectable head and neck squamous cell carcinomas. Cancer Invest 19:127–136, 2001

    Google Scholar 

  15. Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16:1310–1317, 1998

    Google Scholar 

  16. Jeremic B, Shibamoto Y, Milicic B, Nikolic N, Dagovic A, Aleksandrovic J, Vaskovic Z, Tadic L: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18:1458–1464, 2000

    Google Scholar 

  17. Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Oudinot P, Bertrand P: Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 91:2081–2086, 1999

    Google Scholar 

  18. Adelstein DJ, Adams GL, Li Y, Wagner H Jr, Kish A, Ensley JF, Schuller DE, Forastiere AA: A Phase III comparison of standard radiation therapy (RT) versus RT plus concurrent cisplatin (DDP) versus split-course RT plus concurrent DDP and 5-fluorouracil in patients with unresectable squamous cell head and neck cancer (SCHNC): an intergroup study (“Abstract”). Proc ASCO 19:1624, 2000

    Google Scholar 

  19. Brizel DM, Albers ME, Fisher SR, Scher RL, Richtsmeier WJ, Hars V, George SL, Huang AT, Prosnitz LR: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798–1804, 1998

    Google Scholar 

  20. Planting AS, Catimel G, de Mulder PH, de Graeff A, Hoppener F, Verweij J, Oster W, Vermorken JB: Randomized study of a short course of weekly cisplatin with or without amifostine in advanced head and neck cancer. EORTC Head and Neck Cooperative Group. Ann Oncol 10:693–700, 1999

    Google Scholar 

  21. Capizzi RL, Oster W: Chemoprotective and radioprotective effects of amifostine: an update of clinical trials. Int J Hematol 72:425–435, 2000

    Google Scholar 

  22. Weiss RB, Christian MC: New cisplatin analogues in development. A review. Drugs 46:360–377, 1993

    Google Scholar 

  23. Al-Sarraf M, Metch B, Kish J, Ensley J, Rinehart JJ, Schuller DE, Coltman CA Jr: Platinum analogs in recurrent and advanced head and neck cancer: a Southwest Oncology Group and Wayne State University Study. Cancer Treat Rep 71:723–726, 1987

    Google Scholar 

  24. Robbins KT, Fontanesi J, Wong FS, Vicario D, Seagren S, Kumar P, Weisman R, Pellitteri P, Thomas JR, Flick P, Palmer R, Weir A 3rd, Kerber C, Murry T, Ferguson R, Los G, Orloff L, Howell SB: A novel organ preservation protocol for advanced carcinoma of the larynx and pharynx. Arch Otolaryngol Head Neck Surg 122:853–857, 1996

    Google Scholar 

  25. Robbins KT, Kumar P, Regine WF, Wong FS, Weir AB 3rd, Flick P, Kun LE, Palmer R, Murry T, Fontanesi J, Ferguson R, Thomas R, Hartsell W, Paig CU, Salazar G, Norfleet L, Hanchett CB, Harrington V, Niell HB: Efficacy of targeted supradose cisplatin and concomitant radiation therapy for advanced head and neck cancer: the Memphis experience. Int J Radiat Oncol Biol Physics 38:263–271, 1997

    Google Scholar 

  26. Alberts DS, Garcia DJ: Safety aspects of pegylated liposomal doxorubicin in patients with cancer. Drugs 54Supp 4:30–35, 1997

    Google Scholar 

  27. Lotem M, Hubert A, Lyass O, Goldenhersh MA, Ingber A, Peretz T, Gabizon A: Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin. Arch Dermatol 136:1475–1480, 2000

    Google Scholar 

  28. Working PK, Newman MS, Sullivan T, Brunner M, Podell M, Sahenk Z, Turner N: Comparative intravenous toxicity of cisplatin solution and cisplatin encapsulated in long-circulating, pegylated liposomes in cynomolgus monkeys. Toxicol Sciences 46:155–165, 1998

    Google Scholar 

  29. Veal GJ, Griffin MJ, Price E, Parry A, Dick GS, Little MA, Yule SM, Morland B, Estlin EJ, Hale JP, Pearson ADJ, Welbank H, Boddy AV: A phase I study in paediatric patients to evaluate the safety and pharmacokinetics of SPI-77, a liposome encapsulated formulation of cisplatin. Brit J Cancer 84:1029–1035, 2001

    Google Scholar 

  30. Koukourakis MI, Koukouraki S, Giatromanolaki A, Archimandritis SC, Skarlatos J, Beroukas K, Bizakis JG, Retalis G, Karkavitsas N, Helidonis ES: Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer. J Clin Oncol 17:3512–3521, 1999

    Google Scholar 

  31. El-Kareh AW, Secomb TW: A mathematical model for comparison of bolus injection, continuous infusion, and liposomal delivery of doxorubicin to tumor cells. Neoplasia 2:325–338, 2000

    Google Scholar 

  32. McGinn CJ, Shewach DS, Lawrence TS. Radiosensitizing nucleosides. J Natl Cancer Inst 88:1193–1203, 1996

    Google Scholar 

  33. Tishler RB, Schiff PB, Geard CR, Hall EJ. Taxol: a novel radiation sensitizer. Int J Radiat Oncol Biol Physics 22:613–617, 1992

    Google Scholar 

  34. Bonner JA, Lawrence TS. Doxorubicin decreases the repair of radiation-induced DNA damage. Int J Radiat Biol 57:55–64, 1990

    Google Scholar 

  35. Harrington KJ, Rowlinson-Busza G, Syrigos KN, Vile RG, Uster PS, Peters AM, Stewart JS. Pegylated liposome-encapsulated doxorubicin and cisplatin enhance the effect of radiotherapy in a tumor xenograft model. Clin Cancer Res 6:4939–4949, 2000

    Google Scholar 

  36. Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A. Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 11:1029–1033, 2000

    Google Scholar 

  37. Muggia FM. Liposomal encapsulated anthracyclines: new therapeutic horizons. Curr Oncol Rep 3:156–162, 2001

    Google Scholar 

Download references

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Authors and Affiliations

  1. Department of Radiation Oncology, Head and Neck Surgery, Hospital of the University of Pennsylvania, USA

    David I. Rosenthal, Li Liu, Mitchell Machtay & Linda K. Miller

  2. University of Pennsylvania School of Medicine, USA

    Sue S. Yom

  3. Department of Medicine, Hematology/Oncology Division, Head and Neck Surgery, Hospital of the University of Pennsylvania, USA

    Kenneth Algazy & Diane Hershock

  4. Department of Otorhinolaryngology, Head and Neck Surgery, Hospital of the University of Pennsylvania, USA

    Randal S. Weber, Gregory S. Weinstein & Ara A. Chalian

  5. Investigational Drug Service, University of Pennsylvania Health System, Philadelphia, PA, USA

    Kenneth Rockwell Jr

  6. ALZA Corporation, Mountain View, CA, USA

    Margaret Tonda & Edward Schnipper

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  1. David I. Rosenthal
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Rosenthal, D.I., Yom, S.S., Liu, L. et al. A Phase I Study of SPI-077 (Stealth® Liposomal Cisplatin) Concurrent with Radiation Therapy for Locally Advanced Head and Neck Cancer. Invest New Drugs 20, 343–349 (2002). https://doi.org/10.1023/A:1016201732368

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